Mitochondrial Dysfunction and Synaptic Transmission Failure in Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is a chronic neurodegenerative disorder, in which multiple risk factors converge. Despite the complexity of the etiology of the disease, synaptic failure is the pathological basis of cognitive impairment, the cardinal sign of AD. Decreased synaptic density, compromised synaptic transmission, and defected synaptic plasticity are hallmark synaptic pathologies accompanying AD. However, the mechanisms by which synapses are injured in AD-related conditions have not been fully elucidated. Mitochondria are a critical organelle in neurons. The pivotal role of mitochondria in supporting synaptic function and the concomitant occurrence of mitochondrial dysfunction with synaptic stress in postmortem AD brains as well as AD animal models seem to lend the credibility to the hypothesis that mitochondrial defects underlie synaptic failure in AD. This concept is further strengthened by the protective effect of mitochondrial medicine on synaptic function against the toxicity of amyloid-β, a key player in the pathogenesis of AD. In this review, we focus on the association between mitochondrial dysfunction and synaptic transmission deficits in AD. Impaired mitochondrial energy production, deregulated mitochondrial calcium handling, excess mitochondrial reactive oxygen species generation and release play a crucial role in mediating synaptic transmission deregulation in AD. The understanding of the role of mitochondrial dysfunction in synaptic stress may lead to novel therapeutic strategies for the treatment of AD through the protection of synaptic transmission by targeting to mitochondrial deficits.

Keywords

Alzheimer’s disease mitochondrial dysfunction synaptic injury synaptic mitochondria synaptic transmission

INTRODUCTION

Characterized by progressive cognitive decline, Alzheimer’s disease (AD) is the most common type of dementia attacking the aged population [1]. Among the known risk factors, age is the leading one in particular for the sporadic form of AD, with the incidence of this neurological disorder dramatically rising in an exponential pattern after 65 years of age [2 –4]. The pathological hallmarks of AD include extracellular and intracellular deposition of amyloid beta (Aβ) [5 –9], neurofibrillary tangles (NFTs) [10 –12], synaptic failure [13 –16], and neuronal loss [14, 17] in AD sensitive brain regions such as the hippocampus, neocortex, and nucleus basalis of Meynert [10, 18]. Clinical and pathological studies have shown a strong correlation between synaptic deficits and the degree of memory loss in AD [13 –16]. Of note,discernible changes of synapses have been detectedin the neocortex of patients, even in the very early stage of AD or with mild cognitive impairment (MCI), who have little or mild Aβ plaques and neurofibrillary tangles as well as neuronal death [19]. Such findings indicate that AD is a disease of synaptic dysfunction [20 –25].

In the central nervous system (CNS), synapses are the contact sites of neurons to pass signals via synaptic transmission, also known as neurotransmission. Electric neurotransmission plays a critical role in the development of the nervous system, while the communications between CNS neurons in fully developed adults are predominantly dependent on the function of chemical synapses, at which neurotransmitters are released from the presynapses and target postsynaptic receptors to induce the downstream cascades related to synaptic activity [21, 26]. In recent years, increasing lines of evidence have implicated the essential and unique role of mitochondria in synaptic transmission. It is proposed that mitochondria are involved in each and every stage of neurotransmission including the synthesis and storage of neurotransmitters, the trafficking of synaptic vesicles (SVs), and the release of neurotransmitters from the presynapses, as well as the recycling of SVs [27 –30]. It is generally accepted that mitochondria support synaptic transmission primarily via their functions in maintaining calcium homeostasis, providing energy, and regulating the production of reactive oxygen species (ROS), as well as synthesizing essential intermediates or final products of several neurotransmitters [27 –30]. Conceivably, mitochondrial deficits impair synaptic activity at pathological states [30 –33]. Indeed, the concomitant occurrence of synaptic stress and mitochondrial dysfunction has been repeatedly identified in many neurodegenerative diseases including AD [33, 34]. Furthermore, the protection of mitochondrial function preserves synaptic activity in AD-related pathophysiological settings in both basic and clinical platforms [35, 36], reinforcing the direct link between the two pathological processes accompanying AD. Thus, elucidating the relationship between mitochondrial abnormalities and synaptic injury in AD will foster us a better understanding of the pathogenesis of this neurodegenerative disease and hopefully lead to the development of therapeutic strategies for the protection of synaptic activity and the subsequentcognitive function.

Here, we focus on mitochondrial pathology in AD and discuss the link between mitochondrial dysfunction and chemical synaptic transmission impairment in this chronic neurological disorder.

SYNAPTIC TRANSMISSION CHANGES IN AD

It is a well-documented notion that synaptic activity is the basis of cognition and weakened synapses are closely associated with cognitive deficits [37]. In the past decades, histological studies have determined that synaptic alterations including synaptic loss, altered synaptic architecture, and compromised synaptic transmission as well as defected synaptic plasticity are characteristics of AD and the aging brains [21 , 38–41]. Importantly, the degree of these synaptic changes correlates with the severity of cognitive decline in AD [21]. Although the molecular mechanisms causing synaptic failure in AD have not been elucidated in detail, Aβ toxicity, tau hyperphosphorylation, and mitochondrial dysfunction have been implicated as critical involvingfactors conjointly disrupting synapses [22 , 42–44].

Alterations of neurotransmitters in AD

Neurotransmitters are a group of small molecules that serve as the chemical messengers to transmit signals from one neuron to another or to other cell types. Ever since the identification of acetylcholine (ACh) and norepinephrine (NE) as neurotransmitters, currently there are more than 100 types of neurotransmitters on the list, which is still expanding [45]. The classic and very simplified definition of a neurotransmitter is a chemical that has been synthesized, then packaged and stored in SVs in presynapses, and ready to be released to synaptic clefts to regulate the excitatory state of other cells by acting on the receptors at postsynapses. By their influence on the excitatory state of the cells, neurotransmitters can be categorized into two clear-cut groups, excitatory and inhibitory [45]. It should be noted that some neurotransmitters such as ACh may have both excitatory and inhibitory effects depending on the types of receptors at the postsynapses [46, 47].

Owing to the progress in neurochemistry, neurotransmitter deregulation in AD brains has been intensively studied since the mid-twentieth century and still remains a target of great interest to date. The study on cholinergic system in AD dates back to the discovery of ACh [48 –53]. Pathological studies of AD brains have found that severe lesions in nucleus basalis of Meynert, hippocampus, and neocortex are prominent in postmortem AD brains [54]. The hypothesis of cholinergic system deregulation in AD is built on the abundance and critical function of cholinergic neurons in these brain regions. This concept has been subsequently supported by the findings of severe degeneration of cholinergic neurons, reduced ACh synthesis and levels, decreased choline levels as well as down-regulated activity of choline acetyltransferase (ChAT), and the deregulations of ACh receptors in AD brains [47 , 55–61]. Moreover, the concentration of ACh in the cerebrospinal fluid (CSF) extracted from AD patients is significantly reduced, and the levels of CSF ACh are proportionate to the severity of cognitive deficits in AD [62 –64]. These observations have confirmed the perturbations of cholinergic system in the development of AD and further implicated the possibility of using CSF ACh as a diagnostic biomarker of AD. Indeed, efforts to rescue ACh deficits in AD by the application of acetylcholinesterase inhibitors such as donepezil, rivastigmine, and galantamine have demonstrated benefits for the treatment of AD [65, 66]. Despite their modest benefits and side-effects, acetylcholinesterase inhibitors are among the very few agents currently used as the first-line treatment for AD.

Another critical neurotransmitter associated with AD is glutamate, which is a member of amino-acid neurotransmitter family. Glutamate is the most plentiful excitatory signal messenger for a majority of synapses in neocortex and hippocampus [67, 68]. The ionotropic glutamate receptors, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) and n-methyl-D-aspartate receptor (NMDAR), play a key role in mediating synaptic transmission and synaptic plasticity [69, 70]. Although glutamate carries important physiological function, excess glutamatergic activation causes prolonged calcium overloading at postsynapses that perturbs mitochondrial function and some key intracellular signaling transduction pathways, eventually leading to severe synaptic injury. The devastating effects of glutamate excitotoxicity on synaptic activity and neuronal survival have been discerned in a variety of pathological scenarios including AD [71, 72]. A study using magnetic resonance spectroscopy measured glutamate plus glutamine (Gx) levels in bilateral posterior cingulate gyrus of AD and MCI patients as well as the age-matched non-AD controls, and found significant decreased Gx levels in AD brains; while the levels of glutamate in MCI brains were comparable to those in the control subjects [73]. However, another study showed no change in the levels of Gx in the frontal lobes from probable AD [74]. The results seem to suggest that the cerebral Gx levels are significantly changed at the late stage of AD. But it cannot be excluded that the changes of Gx in AD brains is region-specific. This needs further investigation. Interestingly, the studies on glutamate and glutamine in CSF from AD patients have found decreased glutamine [75] while significantly increased glutamate levels [76 –79], which does not match the results collected from the AD brains. Although the mechanisms of this disparity are not clear, the aforementioned evidence at least suggests the dysmetabolism of glutamate/glutamine in AD-related pathological settings. Other than the changes of glutamate, alterations of glutamate receptor, NMDAR in particular, have also been observed in AD brains. Evidence has shown the hypersensitivity of NMDAR to glutamate in AD brains and the resultant glutamatergic toxicity leads to synaptic injury. Such NMDAR hypersensitivity might be the result of Aβ-induced intracellular calcium elevation and magnesium removal from the receptor [71, 80]. Apart from the direct role of Aβ in enhancing NMDAR sensitivity, Aβ may also impose indirect disruptive regulation on NMDAR activity, thus reducing the NMDAR-associated long-term potentiation. In addition, mitochondrial dysfunction-associated neuronal oxidative stress, calcium dysmetabolism, and ATP deficiency are as well proposed to contribute to the glutamate excitotoxicity of AD neurons [81 –84].

Interestingly, a significant reduction of the density of NMDAR has been detected in AD neocortex and hippocampus, where Aβ deposition is heavy [85 –87], which may underlie NMDAR hyposensitivity in the late stage of AD. In consistent with the influence of glutamatergic toxicity on synaptic function, memantine, a glutamate receptor antagonist has demonstrated some modest protection of memory loss in AD patients [88 –90]. In addition to glutamate, gamma-aminobutyric acid (GABA) is another amino-acid neurotransmitter whose deregulation has been linked to synaptic stress in AD brains. Decreased levels of GABA, an inhibitory neurotransmitter, has been reported in patients with severe AD [91]. The deficits of GABAergic system are thought to contribute to synaptic perturbations through the interrupted crosstalk between GABAergic, cholinergic, and glutamatergic synapses due to the loss of inhibitory function of GABAergicneurons [92].

Alterations in monoamine neurotransmitters have also been reported in AD patients. The lesions in locus coeruleus, the major brain area for the synthesis of NE, and reduced brain NE levels have been implicated in memory loss and psychiatric symptoms in AD [93, 94]. The supplementation of NE has exhibited protection against Aβ-induced mitochondrial dysfunction and neuronal stress in cultured mouse neurons. Furthermore, the administration of adrenergic receptor agonists attenuates Aβ toxicity-associated cognitive impairment in mice; such protective effects are thought to be the result of enhanced NE release [95, 96]. Another example of deregulated monoamine neurotransmitter in AD is dopamine. Dopaminergic system defects, which are generally implicated in the pathogenesis of Parkinson’s disease (PD), have as well been linked to AD [97, 98]. A previous study has compared the difference of dopaminergic system deficits in PD, AD, and AD with parkinsonism and found that although all of them have loss of presynaptic dopamine receptor D2 (DRD2) and decreased levels of tyrosine hydroxylase, these three groups demonstrated distinct patterns of lesions sites, which may explain the difference in extrapyramidal symptoms between each of them [99]. In addition, the dopaminergic changes were almost restricted to the nucleus accumbens in AD patients absent of PD-like symptoms, while the AD with parkinsonism group showed more severe damages in rostral caudate and putamen. In sharp contrast, the PD group had more vulnerability in the substantia nigra and ventral tegmental region [99]. Intriguingly, when they compared the levels of postsynaptic DRD2, DRD2 was preserved in the examined extrapyramidal system in AD groups but not the AD with parkinsonism group [100]. A more recent study has suggested that dopamine may mitigate cognitive impairment in AD at least in part through the interaction of dopaminergic and cholinergic systems [101]. However, although emerging evidence has highlighted the function of the dopaminergic system in the consolidation of memory [102, 103], the correlation between dopaminergic system deficits and AD cognitive impairment has not yet been comprehensively investigated.

Neurotransmitter alterations and their contribution to the development of AD are still a fast growing topic. Importantly, current pharmaceutical therapies for AD treatment are predominantly stemmed from the studies on neurotransmitters. With the identification of new neurotransmitters and the progress in AD research, in-depth studies on neurotransmitters in AD still hold promise for the future development of novel therapeutic strategies to protect synaptic function and memory in AD.

Deficits of synaptic vesicle cycling in AD

Neurotransmitter release and reuse are through SV cycling. Stepwise, SV cycling includes the loading of neurotransmitters into SVs, the SV trafficking to and docking at the active zone of presynapses, the releasing of neurotransmitters, and at last the endocytosis and recycling of SVs [104]. In addition to synaptic loss, dramatically decreased expression levels of SV proteins and their coding mRNAs have been discerned in vast areas of postmortem AD brains including most part of the neocortex, limbic system, basal ganglia, and cerebellum; and the changes have a strong correlation to cognitive impairment [19 , 105–111]. It should be mentioned that the severity of these changes varies; and the relatively AD sensitive brain regions such as hippocampus, frontal, temporal, and parietal lobes, where there are more severe Aβ deposition, tau pathology, and mitochondrial damages, are early affected areas and demonstrate a greater loss of SV proteins and their coding mRNAs [108 –111]. Another prominent change potentially leading to defected SV cycling in AD is the perturbations of signaling transduction pathways including cyclic-AMP-dependent protein kinase A (PKA), Ca2+/ calmodulin-dependent kinase II (CaMKII), and protein kinase C (PKC). Those signaling transduction pathways play critical roles in modulating the functional status of several SV and synaptic plasma membrane proteins via phosphorylation, thus potentiating presynaptic activity. In fact, deregulated activities of CaMKII [112 –115], PKA [116, 117], and PKC [118, 119] have been repeatedly linked to compromised synaptic activity and neuronal death in AD. The dysfunction of these transduction pathways is at least in part associated with calcium dysmetabolism, ATP deficiency, and oxidative stress in AD neurons [112, 120].

Direct evidence of altered SV cycling in AD-relevant conditions was obtained predominantly in cultured neurons given the difficulty in recording SV exocytosis and endocytosis in an in vivo setting in AD patients or AD animal models. In a previous study, Aβ at nanomolar level induces severely impaired synaptic transmission in cultured mouse hippocampal neurons. With Aβ-induced reduction in the expression levels of SV proteins and postsynaptic receptors, the exposure of Aβ significantly disrupts SV depletion and recycling [121]. Furthermore, the effects of tau abnormalities on SV exo- and endocytosis through the damages on the integrity and functionality of microtubules have also been proposed to undermine SV mobilization in AD [122].

Therefore, a large number of direct and indirect evidence have pointed to the deregulation of neurotransmitters and SV exo- and endocytosis in AD-relevant pathological settings. To elucidate the mechanisms underlying the synaptic transmission deficits is of paramount importance for our understanding of synaptic injury and cognitive declinein AD.

MITOCHONDRIA AND SYNAPTIC TRANSMISSION

Mitochondria are a key organelle in eukaryotic cells. In addition to their role in energy metabolism, mitochondria have multiple traits of critical functions including regulating intracellular calcium homeostasis, maintaining intracellular redox balance and mediating cell apoptosis and necrosis. Thus, mitochondria have a fundamental role in the life and death of cells. Of note, strong evidence has suggested the multiplicity of mitochondrial functions. Some mitochondrial functions are even cell-type specific. For example, mitochondria in steroidogenic cells carry the function of steroid hormone biosynthesis [123]; and mitochondria are essential sites for fatty acid synthesis in adipose and liver tissues [124 –126]. Moreover, mitochondria have been found to be involved in RNA metabolism [127]. Chen and colleagues have reported the role of mitochondria in cell innate immune system mediating cellular anti-viral pathways [128]. It is therefore not surprising that more and more investigators have embraced the concept of mitochondrial heterogeneity. It is said that mitochondria are morphologically and functionally heterogeneous in different cell types as well as in different compartments of a single cell. Neurons represent a typical pattern of mitochondrial heterogeneity. Based on their physical position and functionality, neuronal mitochondria are categorized into several different subgroups, among which mitochondria at synapses or namely synaptic mitochondria are generally accepted to play an important role in supporting synaptic activity.

Synaptic mitochondria are a subpopulation of neuronal mitochondria specifically residing at synapses. Due to their extremely physical proximity to synapses, synaptic mitochondria are critical in assisting synaptic transmission.

Mitochondria and neurotransmitter synthesis and storage

The synthesis and packaging of some key neurotransmitters significantly rely on mitochondria. For example, ACh is synthesized from choline and acetyl co-enzyme A (Acetyl CoA); and the reaction is catalyzed by the enzyme called ChAT. Humans directly obtain choline from the diet; while Acetyl CoA is synthesized at mitochondria by using pyruvate from the glycolysis [129 –136]. The synthesized ACh is subsequently transported into SVs through ACh transporter (VAChT) [137] via an ATP consuming process and then stored in SVs [138]. Another example is glutamate, which is critical for glutamatergic synapses. Due to the deficiency of pyruvate carboxylase in neurons [139 –141], glutamate is synthesized in astrocytes [142 –144] and then delivered into neurons by glutamate transporters [144, 145]. The synthesis of glutamate is at astrocyte mitochondria through multi-steps to convert oxaloacetate to α-ketoglutarate and eventually the final product, glutamate [142 –144]. Other than their function in the synthesis of glutamate, the transport of glutamate from astrocytes into neurons and the packaging of glutamate into SVs are energy consuming processes significantly relying on the ATP producing function of mitochondria [144, 145]. In fact, neuronal mitochondria are also known to play a critical role in the de novo synthesis of several other key neurotransmitters such as NE [146 –148], dopamine [148, 149], GABA [150, 151], and serotonin [151, 152]. Again, mitochondria are indispensable for the packaging of these neurotransmitters into SVs by providing ATP. In addition, mitochondria also have indirect influence on the production of non-classical neurotransmitters including adenosine, ATP, and nitric oxide via the function of mitochondria in the metabolism of these molecules. Therefore, mitochondria are extremely essential for the synthesis, packaging and storage of a number of neurotransmitters, the dysfunction of which are thought to be associated with AD.

Mitochondria and synaptic vesicle cycling

The process of synaptic transmission (that is, SV exocytosis) is initiated by calcium entry into presynapses via the voltage-gated calcium channels, which triggers the depolarization of the plasma membrane [153, 154]. By measuring the large synapses of the Calyx of Held, it is estimated that the depolarization-driven calcium transients last for around 400–500 μs [155]. The time course of calcium pulse may vary in different types of neurons depending on the size of the synapses. But in general the rise of calcium levels in the cytoplasm is transitory followed by a quick dissipation of the calcium sparks, which brings to an end of the neurotransmitter release [155, 156]. The aforementioned synaptic calcium handling mechanisms require the coordination of calcium influx and fast removal. The involving role of mitochondria in the two processes has received considerable attention. First, the activation of the voltage-gated calcium channel-forming Ca²⁺-ATPases predominantly relies on mitochondrial ATP provision [157, 158]. On the other hand, mitochondria are the major calcium sequestering unit at synapses and play a key role in maintaining the intra-synaptic calcium homeostasis [158 –160]. Previous studies have shown that mitochondria at synapses buffer calcium following the depolarization-evoked calcium influx and dissipate intra-synaptic Ca²⁺ to resting levels in mouse retinal bipolar cells [158] and at the rat Calyx of Held [161] as well as the mouse motor nerve terminals [162]. Another important piece of evidence showing mitochondrial role in regulating calcium during synaptic transmission was collected from a study on mitochondrial conductance during the activation of the giant synapses in squid. Jonas and the colleagues found that the elevation of mitochondrial conductance is closely associated with the synaptic stimulation-driven calcium transients in the presynapses and lasts throughout the whole process of post-tetanic potentiation [163]. It could be argued that mitochondria are not the only calcium storing organelle at synapses and the calcium-retention capacity of endoplasmic reticulum (ER) should not be overlooked. Indeed, it has been suggested that mitochondria and ER vesicles near the active zone have similar extent of effect in regulating intra-synaptic calcium levels during synaptic activation [164]; while notably other studies indicated that the calcium uptake by mitochondria is more rapid than that by ER [165 –167]. More than their role as the calcium bank, mitochondria and ER also release calcium, which has been identified to contribute to the production of miniature excitatory post synaptic currents in mouse hippocampal and neocortical neurons [168, 169] and the sustainment of prolonged SV exocytosis [165].

Of note, synapses have a high demand of ATP to energize the trafficking, exocytosis, and endocytosis of SVs. To meet the synaptic energy demand, mitochondria are delivered to dock at synapses, and these synaptic mitochondria serve as the in situ energy warehouse to fuel synapses [27 , 170–173].

Furthermore, mitochondria are the major source of ROS in neurons. It has been suggested that superoxide at physiological levels may serve as a key regulator for synaptic transmission- and plasticity-related signaling molecules, receptors and channels, which are critical for long-term potentiation induction and memory formation. For example, scavenging superoxide through the overexpression of extracellular superoxide dismutase (SOD) in mice surprisingly inhibits long-term potentiation and long-term memory [174, 175]. Moreover, genetic mutation on or pharmaceutical inhibition of NADPH oxidase suppresses NMDAR activation-dependent ERK signaling transduction pathway in mouse CA1 region, which further implicates the critical role of ROS in synaptic activity [176]. However, the information of the physiological role of ROS in synaptic transmission and plasticity is still extremely limited, which is in sharp contrast to our knowledge on the disruptive effect of excess ROS on synaptic activity at pathological states.

In addition, it should not be neglected the indirect impacts of mitochondrial dysfunction on the functions of synaptic activity-modulating signaling pathways through ATP deficiency, calcium perturbations, and oxidative stress [112, 120].

Put together, mitochondrial function in ATP production, calcium homeostasis regulation, and redox balance maintenance is pivotal for the potentiation of synaptic transmission. Deficits in mitochondrial particularly synaptic mitochondrial function are detrimental to synaptic activity and strength.

MITOCHONDRIAL DYSFUNCTION IN AD: THE LINK TO SYNAPTIC TRANSMISSION FAILURE

The role of mitochondrial dysfunction in synaptic injury in AD has received considerable attention [177 –180]. Mitochondrial dysfunction has been found in AD patients [181 –185] and AD animal models [8 , 186–190] as well as in Aβ-insulted cells [191 –193]. Importantly, despite the coincidence of mitochondrial dysfunction and synaptic stress in AD-related conditions, increasing evidence has shown that synaptic mitochondrial dysfunction occurs prior to severe synaptic injury in early stage AD [34 , 195] as well as in young AD animal models [187 , 196–199]. This further implicates the promoting role of mitochondrial deregulation in potentiating synaptic stress in AD.

Synaptic transmission has a very intensive energy demand and the majority of brain ATP is consumed to support synaptic activity [200]. Neuronal ATP is almost exclusively provided by mitochondria through oxidative phosphorylation (OXPHOS). It is noteworthy that mitochondrial OXPHOS deficits and ATP deficiency are hallmark pathologies in AD brains [201, 202]. Much work has been done on the defects of electron transfer chain (ETC) in AD mitochondria. Decreased activities of mitochondrial complexes I through IV have been detected in the neocortex and hippocampus from postmortem AD brains; while the deactivation of mitochondrial complex IV is more prominent with altered steady-state composition of this enzyme [203 –207]. The deregulation of mitochondrial complex IV in neocortex has also been determined in AD animal models overexpressing human form Aβ [9 , 209]. Furthermore, mitochondrial ETC deficits are not just confined in AD sensitive brain regions. Decreased mitochondrial complex IV activity has been detected in platelets from AD patients [210, 211] and MCI subjects [211], suggesting mitochondrial ETC deficits are a systemic change in AD. In addition to the studies on mitochondrial complexes I to IV in AD, the functional status of mitochondrial complex V also known as F1Fo ATP synthase in AD has long been overlooked. This enzyme locates in the inner mitochondrial membrane and constitutes the primary site for OXPHOS [212]. In our recent study, we have found alterations of mitochondrial complex V in postmortem MCI and AD temporal lobes as well as in synaptic mitochondria from an AD mouse model [187]. The deregulation of mitochondrial complex V in AD-related conditions has a strong association with loss of its oligomycin sensitivity conferring protein (OSCP) subunit and the interplay of OSCP with Aβ. The deregulation of mitochondrial complex V leads to severe mitochondrial dysfunction and compromised synaptic transmission. Noteworthy, the restoration of OSCP rescues synaptic transmission from Aβ toxicity in cultured mouse neurons [187]. Put together, impaired mitochondrial ETC and defected mitochondrial OXPHOS are a primary pathology in AD, which results in insufficient ATP provision to fuel synaptic transmission.

Calcium influx is the initiative step of SV exocytosis. As discussed above (“Mitochondria and synaptic vesicle cycling”), normal synaptic mitochondrialcalcium handling capacity is essential for synaptic transmission. Mitochondrial permeability transition pore (mPTP) is a non-selective trans-inner mitochondrial membrane pore. Over-activation of mPTP has been proposed to be a critical mechanism underlying compromised mitochondrial calcium buffering capacity in AD [208 , 213–217]. Excess mPTP leads to decreased mitochondrial calcium retention, collapsed mitochondrial membrane potential, reduced OXPHOS efficiency, and elevated ROS production and release, as well as ruptured mitochondrial membrane, eventually cell death [218, 219]. Although the exact molecular identity of mPTP still remains to be elucidated, a mitochondrial matrix protein called cyclophilin D (CypD) is a determined key regulator of mPTP formation [218, 219]. In our previous studies, we have found that the blockade of mPTP by genetic depletion of CypD confers protection against Aβ-mediated mitochondrial dysfunction as well as synaptic loss and synaptic transmission deficits in an AD mouse model [191 , 208], suggesting the deleterious impact of mPTP overactivation on synaptic transmission. This concept has further been supported by our recent study. Based on recent studies showing the role of mitochondrial F1Fo ATP synthase in the formation of mPTP [220, 221], we studied F1Fo ATP synthase (mitochondrial complex V) dysfunction in AD. We have determined the correlation of F1Fo ATP synthase deregulation and the activation of mPTP in AD-related conditions [187]. Of note, the restoration of F1Fo ATP synthase mitigates synaptic transmission injury in Aβ-insulted neurons [187]. Given the dual roles of F1Fo ATP synthase deregulation in ATP production and mPTP formation as well as the function of CypD, these studies suggest that defected synaptic transmission in AD-relevant conditions is associated, at least in part, with mPTP activation-induced mitochondrial calcium perturbations.

Impaired mitochondrial function results in excess ROS production and the resultant oxidative damages to neurons; and oxidative stress is characteristic of AD brains [222]. Several studies have found that lipid oxidation in presynaptic cytoplasm membrane obstructs the fusion pore opening, thus blocking the SV exocytosis leading to the abnormal detention of SVs in the active zone of presynapses [223, 224]. Moreover, oxidative stress induces hyperphosphorylation of tau through the inactivation of protein phosphatase 1 and 2A, causing abnormal tau aggregation [120], which blocks SV trafficking. Since mitochondria are known as the major source of ROS inneurons, previous attempts to scavenge mitochondrial ROS have shown significant protection against Aβ-induced synaptic injury. Dumont and the colleagues found that the overexpression of mitochondrial SOD significantly ameliorates mouse synaptic dysfunction and cognitive impairment in an AD mouse model expressing human form Aβ [225]. This is in agreement with Massaad and the colleagues’ study [23]. These observations suggest the protective effect of reducing mitochondria-generated ROS on synaptic function in an AD mouse model and also serve as indirect evidence of the devastating role of excess ROS in mediating synaptic stress in AD-related pathological settings. Furthermore, similar protection has been reported by eliminating ROS using pharmaceutical approaches. The application of antioxidants, in particular mitochondria-targeted antioxidants such as mitoQ, SS peptides, mitochondrial SOD mimetic, and many others prevent synaptic degeneration from Aβ toxicity [226 –228], which further confirms the contributing role of mitochondria-mediated oxidative stress in AD synaptic failure. Therefore, considering the physiological function of ROS in synaptic transmission and synaptic plasticity and the disruptive effect of excess ROS in particular mitochondrial ROS, it has been proposed that ROS act as a “double-edged sword” with respect to synaptic plasticity and memory consolidation [229]. To this end, how to eliminate excess mitochondrial ROS production while maintaining a physiological level of ROS would be an intriguing and critical scientific issue for the treatment of synaptic failure in AD.

To exert mitochondrial function in supporting synaptic transmission, it is a prerequisite that mitochondria accumulate at presynapses. Mitochondrial motility and dynamics are critical aspects of mitochondrial biology in neurons. Neurons are highly polarized cells and soma are the primary sites for mitochondrial generation. Newborn mitochondria are delivered to the terminal ends of neurites and anchor at synapses. During the transportation, mitochondria constantly change their morphology via the fission and fusion processes to accommodate their host cell’s requirement. Indeed, deregulated mitochondrial motility and dynamics have deleterious impacts on synaptic transmission in diseases including AD [230] evidenced by the observations that suppressed neuronal mitochondrial movement and imbalanced mitochondrial fusion/fission are prominent in AD-related conditions. Zhu and the colleagues performed pioneer and comprehensive studies on alterations of neuronal mitochondrial dynamics in AD brains and Aβ-overexpressing cell lines [231]. They have found significantly deceased expression levels of optical atrophy 1, mitofusin 1 and 2, and dynamin-like protein 1 (Dlp1) with the concomitant elevation of mitochondrial fission 1 protein in the postmortem hippocampal tissues from AD patients. These results serve as solid evidence of neuronal mitochondrial fusion/fission imbalance toward increased mitochondrial fragmentation in AD brains. Importantly, they also observed increased mitochondrial accumulation in soma and lessened mitochondrial distribution in the neurites in AD hippocampal neurons, implicating the altered patterns of neuronal mitochondrial motility with increased mitochondrial anterograde transport in AD conditions [231]. These findings were soon verified in AD brains and AD animal models as well as Aβ-insulted cell lines by many other groups [42 , 232]. Notably, in an Aβ-rich environment, anterograde movement of axonal mitochondria is more vulnerable than retrograde movement [42, 191], which helps to interpret the evacuation of mitochondria from synapses and increased retrieval of axonal mitochondria to soma in AD neurons. In addition to the changes of expression levels of mitochondrial fusion and fission proteins, two other groups have found increased Dlp1 S-nitrosylation in AD [233], and Dlp1 interaction with Aβ [193], which may also play critical roles in promoting axonal mitochondrial fragmentation in AD-related environment. In our previous study, we have found the inhibition of mPTP by CypD depletion ameliorates intra-axonal calcium perturbations and oxidative stress in Aβ-treated neurons. The blockade of mPTP protects axonal mitochondrial motility and dynamics, and importantly preserves synaptic transmission from Aβ toxicity. In view of the critical role of normal axonal mitochondrial distribution and morphology in maintaining synaptic activity, the protection of synaptic transmission by mPTP inhibition has the implication to be associated with the ameliorated axonal mitochondrial motility and dynamics [191].

CONCLUSIONS AND PERSPECTIVES

Synaptic deficits form the pathological basis of cognitive impairment, the cardinal sign of AD. Synaptic loss, synaptic transmission reduction, and synaptic plasticity impairment are early pathology in AD brains and exacerbate with the progress of cognitive decline in AD. Therefore, to understand the molecular basis of synaptic injury is of paramount importance for our understanding of the pathogenesis of AD as well as for the development of preventive and therapeutic strategies for the treatment. However, our knowledge is still limited for a full description of the mechanisms underlying synaptic failure in AD, given the complicated nature of the potentiation and regulation of synaptic activity and, more importantly, the many unknowns about the pathogenesis of AD.

Indeed, despite the determined genetic risk factors for familial AD, the etiology of sporadic AD still remains enigmatic. Mitochondrial cascade hypothesis as an important supplementation to the prevailing Aβ cascade and tauopathy hypotheses has provided us an alternative avenue to understand the pathogenesis of AD, in particular its sporadic form [234]. Of note, the role of mitochondrial deficits in synaptic injury in AD has been firmly built on a large amount of, and still emerging, evidence. Mitochondria are actively involved in each and every step of synaptic transmission via their critical functions in providing energy, keeping intracellular redox balance, and maintaining intrasynaptic calcium homeostasis, as well as regulating key signaling transduction pathways, and synthesizing the intermediates and/or final products of several key neurotransmitters. The pivotal role of mitochondria in synaptic transmission, the early mitochondrial dysfunction, and the concomitant mitochondrial and synaptic injury in postmortem AD brains and the AD animal models, as well as the protective effect of mitochondrial medicine [35, 227], have lent credibility to the hypothesis that mitochondrial deficits confer susceptibility to synaptic impairment in AD (Fig. 1). However, to fully address this concept, there are still many critical questions to be answered, e.g., which one happens first in AD, synaptic injury or mitochondrial dysfunction? What are the detailed mechanisms causing mitochondrial defects in AD-related conditions? Does synaptic injury in turn reinforces mitochondrial dysfunction in AD, thus forming a vicious cycle? The answers to these questions will foster a better understanding of synaptic failure and memory loss in AD. It is true that treatments targeting mitochondria are not likely to be the miraculous cure to stop synaptic injury and restore cognitive function in AD, but protecting mitochondria still holds very high promise as of now, not only because of the critical role mitochondrial dysfunction plays in synaptic injury in AD, but also because of the lack of the definite cause of synaptic failure in this chronic neurodegenerative disorder.

Fig.1

Working hypothesis. In Alzheimer’s disease (AD)-related conditions, the convergent effects of amyloid-β (Aβ), tauopathology, and other unknown factors induce mitochondrial dysfunction, thus leading to reduced ATP production, deregulated calcium homeostasis, and excess reactive oxygen species (ROS) generation, decreased production of some key neurotransmitters and their intermediates, as well as perturbed cell signaling cascades. These changes affect synaptic transmission, eventually causing synaptic failure in AD. PKA, protein kinase A; PKC, protein kinase C; CAMKII, Ca2+/ calmodulin-dependent kinase II; SV, synaptic vesicle.

Authors’ disclosures available online (http://j-alz.com/manuscript-disclosures/16-0702r1).

Footnotes

ACKNOWLEDGMENTS

This study is supported by research funding from NIH (R00AG037716, 1R01AG053588), NSFC (31271145, 81200847) and SDNSF (JQ201318). LGwas supported by the Alzheimer’s Association (NIRG-12-242803 and AARG-16-442863).

References

Querfurth

, LaFerla

(2010) Alzheimer’s disease. N Engl J Med 362, 329–344.

Kidd

(2008) Alzheimer’s disease, amnestic mild cognitive impairment, and age-associated memory impairment: Current understanding and progress toward integrative prevention. Altern Med Rev 13, 85–115.

Swerdlow

(2011) Brain aging, Alzheimer’s disease, and mitochondria. Biochim Biophys Acta 1812, 1630–1639.

Blennow

, de Leon

, Zetterberg

(2006) Alzheimer’s disease. Lancet 368, 387–403.

Landon

, Kidd

(1989) Amyloid in Alzheimer’s disease. Biochem Soc Trans 17, 69–72.

Selkoe

(2008) Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and behavior. Behav Brain Res 192, 106–113.

, Hong

, Shepardson

, Walsh

, Shankar

, Selkoe

(2009) Soluble oligomers of amyloid Beta protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake. Neuron 62, 788–801.

Lustbader

, Cirilli

, Lin

, Xu

, Takuma

, Wang

, Caspersen

, Chen

, Pollak

, Chaney

, Trinchese

, Liu

, Gunn-Moore

, Lue

, Walker

, Kuppusamy

, Zewier

, Arancio

, Stern

, Yan

, Wu

(2004) ABAD directly links Abeta to mitochondrial toxicity in Alzheimer’s disease. Science 304, 448–452.

Caspersen

, Wang

, Yao

, Sosunov

, Chen

, Lustbader

, Xu

, Stern

, McKhann

, Yan

(2005) Mitochondrial Abeta: A potential focal point for neuronal metabolic dysfunction in Alzheimer’s disease. FASEB J 19, 2040–2041.

10.

Braak

, Del Trecidi

(2015) Neuroanatomy and pathology of sporadic Alzheimer’s disease. Adv Anat Embryol Cell Biol 215, 1–162.

11.

Alafuzoff

, Arzberger

, Al-Sarraj

, Bodi

, Bogdanovic

, Braak

, Bugiani

, Del-Tredici

, Ferrer

, Gelpi

, Giaccone

, Graeber

, Ince

, Kamphorst

, King

, Korkolopoulou

, Kovacs

, Larionov

, Meyronet

, Monoranu

, Parchi

, Patsouris

, Roggendorf

, Seilhean

, Tagliavini

, Stadelmann

, Streichenberger

, Thal

, Wharton

, Kretzschmar

(2008) Staging of neurofibrillary pathology in Alzheimer’s disease: A study of the BrainNet Europe Consortium. Brain Pathol 18, 484–496.

12.

Yen

, Liu

, Hall

, Yan

, Stern

, Dickson

(1995) Alzheimer neurofibrillary lesions: Molecular nature and potential roles of different components. Neurobiol Aging 16, 381–387.

13.

Davies

, Mann

, Sumpter

, Yates

(1987) A quantitative morphometric analysis of the neuronal and synaptic content of the frontal and temporal cortex in patients with Alzheimer’s disease. J Neurol Sci 78, 151–164.

14.

Terry

, Masliah

, Salmon

, Butters

, DeTeresa

, Hill

, Hansen

, Katzman

(1991) Physical basis of cognitive alterations in Alzheimer’s disease: Synapse loss is the major correlate of cognitive impairment. Ann Neurol 30, 572–580.

15.

Dickson

, Crystal

, Bevona

, Honer

, Vincent

, Davies

(1995) Correlations of synaptic and pathological markers with cognition of the elderly. Neurobiol Aging 16, 285–298; discussion 298-304.

16.

Sze

, Troncoso

, Kawas

, Mouton

, Price

, Martin

(1997) Loss of the presynaptic vesicle protein synaptophysin in hippocampus correlates with cognitive decline in Alzheimer disease. J Neuropathol Exp Neurol 56, 933–944.

17.

Braak

, Del Tredici

, Schultz

, Braak

(2000) Vulnerability of select neuronal types to Alzheimer’s disease. Ann N Y Acad Sci 924, 53–61.

18.

Arendt

, Bigl

, Arendt

, Tennstedt

(1983) Loss of neurons in the nucleus basalis of Meynert in Alzheimer’s disease, paralysis agitans and Korsakoff’s Disease. Acta Neuropathol 61, 101–108.

19.

Masliah

, Mallory

, Alford

, DeTeresa

, Hansen

, McKeel

Jr , Morris

(2001) Altered expression of synaptic proteins occurs early during progression of Alzheimer’s disease. Neurology 56, 127–129.

20.

Selkoe

(2002) Alzheimer’s disease is a synaptic failure. Science 298, 789–791.

21.

Sheng

, Sabatini

, Sudhof

(2012) Synapses and Alzheimer’s disease. Cold Spring Harb Perspect Biol 4, pii: a005777.

22.

, Klann

(2012) Amyloid beta: Linking synaptic plasticity failure to memory disruption in Alzheimer’s disease. J Neurochem 120(Suppl 1), 140–148.

23.

Massaad

, Washington

, Pautler

, Klann

(2009) Overexpression of SOD-2 reduces hippocampal superoxide and prevents memory deficits in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci U S A 106, 13576–13581.

24.

Oddo

, Caccamo

, Shepherd

, Murphy

, Golde

, Kayed

, Metherate

, Mattson

, Akbari

, LaFerla

(2003) Triple-transgenic model of Alzheimer’s disease with plaques and tangles: Intracellular Abeta and synaptic dysfunction. Neuron 39, 409–421.

25.

Rowan

, Klyubin

, Wang

, Anwyl

(2005) Synaptic plasticity disruption by amyloid beta protein: Modulation byotential Alzheimer’s disease modifying therapies. Biochem Soc Trans 33, 563–567.

26.

Bennett

(2000) Electrical synapses, a personal perspective (or history). Brain Res Brain Res Rev 32, 16–28.

27.

Vos

, Lauwers

, Verstreken

(2010) Synaptic mitochondria in synaptic transmission and organization of vesicle pools in health and disease. Front Synaptic Neurosci 2, 139.

28.

Storozhuk

, Ivanova

, Balaban

, Kostyuk

(2005) Possible role of mitochondria in posttetanic potentiation of GABAergic synaptic transmission in rat neocortical cell cultures. Synapse 58, 45–52.

29.

Csordas

, Thomas

, Hajnoczky

(1999) Quasi-synaptic calcium signal transmission between endoplasmic reticulum and mitochondria. EMBO J 18, 96–108.

30.

Jeanneteau

, Arango-Lievano

(2016) Linking mitochondria to synapses: New insights for stress-related neuropsychiatric disorders. Neural Plast 2016, 3985063.

31.

Okazawa

, Ikawa

, Tsujikawa

, Kiyono

, Yoneda

(2014) Brain imaging for oxidative stress and mitochondrial dysfunction in neurodegenerative diseases. Q J Nucl Med Mol Imaging 58, 387–397.

32.

Reddy

(2014) Misfolded proteins, mitochondrial dysfunction, and neurodegenerative diseases. Biochim Biophys Acta 1842, 1167.

33.

Reddy

, Manczak

, Mao

, Calkins

, Reddy

, Shirendeb

(2010) Amyloid-beta and mitochondria in aging and Alzheimer’s disease: Implications for synaptic damage and cognitive decline. J Alzheimers Dis 20(Suppl 2), S499–512.

34.

, Guo

, Yan

(2012) Synaptic mitochondrial pathology in Alzheimer’s disease. Antioxid Redox Signal 16, 1467–1475.

35.

, Yan

(2010) Mitochondrial medicine for neurodegenerative diseases. Int J Biochem Cell Biol 42, 560–572.

36.

Reddy

(2008) Mitochondrial medicine for aging and neurodegenerative diseases. Neuromolecular Med 10, 291–315.

37.

Morrison

, Baxter

(2012) The ageing cortical synapse: Hallmarks and implications for cognitive decline. Nat Rev Neurosci 13, 240–250.

38.

, Lu

(2012) Synapses and dendritic spines as pathogenic targets in Alzheimer’s disease. Neural Plast 2012, 247150.

39.

Koffie

, Hyman

, Spires-Jones

(2011) Alzheimer’s disease: Synapses gone cold. Mol Neurodegener 6, 63.

40.

Lippa

, Hamos

, Pulaski-Salo

, DeGennaro

, Drachman

(1992) Alzheimer’s disease and aging: Effects on perforant pathway perikarya and synapses. Neurobiol Aging 13, 405–411.

41.

Adams

(1991) Structural plasticity of synapses in Alzheimer’s disease. Mol Neurobiol 5, 411–419.

42.

Calkins

, Reddy

(2011) Amyloid beta impairs mitochondrial anterograde transport and degenerates synapses in Alzheimer’s disease neurons. Biochim Biophys Acta 1812, 507–513.

43.

Reddy

(2011) Abnormal tau, mitochondrial dysfunction, impaired axonal transport of mitochondria, and synaptic deprivation in Alzheimer’s disease. Brain Res 1415, 136–148.

44.

Reddy

, Beal

(2008) Amyloid beta, mitochondrial dysfunction and synaptic damage: Implications for cognitive decline in aging and Alzheimer’s disease. Trends Mol Med 14, 45–53.

45.

Rangel-Gomez

, Meeter

(2016) Neurotransmitters and novelty: A systematic review. J Psychopharmacol 30, 3–12.

46.

de Blas

, Mahler

(1976) Studies on nicotinic acetylcholine receptors in mammalian brain VI. Isolation of a membrane fraction enriched in receptor function for different neurotransmitters. Biochem Biophys Res Commun 72, 24–32.

47.

Melancon

, Tarr

, Panarese

, Wood

, Lindsley

(2013) Allosteric modulation of the M1 muscarinic acetylcholine receptor: Improving cognition and a potential treatment for schizophrenia and Alzheimer’s disease. Drug Discov Today 18, 1185–1199.

48.

Bozzi

, Zubiani

(1952) Use of acetylcholine administered intravenously refracta dosi in the treatment of presenile and senile psychoses. Riv Sper Freniatr Med Leg Alien Ment 76, 263–268.

49.

Spillane

, Goodhart

, White

, Bowen

, Davison

(1977) Choline in Alzheimer’s disease. Lancet 2, 826–827.

50.

Renvoize

, Jerram

(1979) Choline in Alzheimer’s disease. N Engl J Med 301, 330.

51.

Smith

, Swash

, Exton-Smith

, Phillips

, Overstall

, Piper

, Bailey

(1978) Choline therapy in Alzheimer’s disease. Lancet 2, 318.

52.

Ehrenstein

, Galdzicki

, Lange

(1997) The choline-leakage hypothesis for the loss of acetylcholine in Alzheimer’s disease. Biophys J 73, 1276–1280.

53.

Kumar

, Giacobini

, Markwell

(1989) CSF choline and acetylcholinesterase in early-onset vs. late-onset Alzheimer’s disease patients. Acta Neurol Scand 80, 461–466.

54.

Palmer

, Gershon

(1990) Is the neuronal basis of Alzheimer’s disease cholinergic or glutamatergic? FASEB J 4, 2745–2752.

55.

Babic

(1999) The cholinergic hypothesis of Alzheimer’s disease: A review of progress. J Neurol Neurosurg Psychiatry 67, 558.

56.

Francis

, Palmer

, Snape

, Wilcock

(1999) The cholinergic hypothesis of Alzheimer’s disease: A review of progress. J Neurol Neurosurg Psychiatry 66, 137–147.

57.

Schliebs

, Arendt

(2011) The cholinergic system in aging and neuronal degeneration. Behav Brain Res 221, 555–563.

58.

Strac

, Muck-Seler

, Pivac

(2015) Neurotransmitter measures in the cerebrospinal fluid of patients with Alzheimer’s disease: A review. Psychiatr Danub 27, 14–24.

59.

Lombardo

, Maskos

(2015) Role of the nicotinic acetylcholine receptor in Alzheimer’s disease pathology and treatment. Neuropharmacology 96, 255–262.

60.

Jiang

, Li

, Zhang

, Zhao

, Bu

, Xu

, Zhang

(2014) M1 muscarinic acetylcholine receptor in Alzheimer’s disease. Neurosci Bull 30, 295–307.

61.

Kantarci

, Weigand

, Petersen

, Boeve

, Knopman

, Gunter

, Reyes

, Shiung

, O’Brien

, Smith

, Ivnik

, Tangalos

, Jack

Jr (2007) Longitudinal 1H MRS changes in mild cognitive impairment and Alzheimer’s disease. Neurobiol Aging 28, 1330–1339.

62.

Mohs

, Davis

, Greenwald

, Mathe

, Johns

, Horvath

, Davis

(1985) Clinical studies of the cholinergic deficit in Alzheimer’s disease. II. Psychopharmacologic studies. J Am Geriatr Soc 33, 749–757.

63.

Davis

, Mohs

, Greenwald

, Mathe

, Johns

, Horvath

, Davis

(1985) Clinical studies of the cholinergic deficit in Alzheimer’s disease. I. Neurochemical and neuroendocrine studies. J Am Geriatr Soc 33, 741–748.

64.

Tohgi

, Abe

, Hashiguchi

, Saheki

, Takahashi

(1994) Remarkable reduction in acetylcholine concentration in the cerebrospinal fluid from patients with Alzheimer type dementia. Neurosci Lett 177, 139–142.

65.

Hashimoto

, Kazui

, Matsumoto

, Nakano

, Yasuda

, Mori

(2005) Does donepezil treatment slow the progression of hippocampal atrophy in patients with Alzheimer’s disease? Am J Psychiatry 162, 676–682.

66.

Giacobini

(2001) Do cholinesterase inhibitors have disease-modifying effects in Alzheimer’s disease? CNS Drugs 15, 85–91.

67.

Gruol

, Netzeband

, Parsons

(1996) Ca2+ signaling pathways linked to glutamate receptor activation in the somatic and dendritic regions of cultured cerebellar purkinje neurons. J Neurophysiol 76, 3325–3340.

68.

Parsons

, Danysz

, Quack

(1998) Glutamate in CNS disorders as a target for drug development: An update. Drug News Perspect 11, 523–569.

69.

Liu

, Lewis

, Shi

, Brown

, Xu

(2014) Differential requirement for NMDAR activity in SAP97beta-mediated regulation of the number and strength of glutamatergic AMPAR-containing synapses. J Neurophysiol 111, 648–658.

70.

Faleiro

, Jones

, Kauer

(2003) Rapid AMPAR/NMDAR response to amphetamine: A detectable increase in AMPAR/NMDAR ratios in the ventral tegmental area is detectable after amphetamine injection. Ann N Y Acad Sci 1003, 391–394.

71.

Butterfield

, Pocernich

(2003) The glutamatergic system and Alzheimer’s disease: Therapeutic implications. CNS Drugs 17, 641–652.

72.

Cacabelos

, Takeda

, Winblad

(1999) The glutamatergic system and neurodegeneration in dementia: Preventive strategies in Alzheimer’s disease. Int J Geriatr Psychiatry 14, 3–47.

73.

Fayed

, Modrego

, Rojas-Salinas

, Aguilar

(2011) Brain glutamate levels are decreased in Alzheimer’s disease: A magnetic resonance spectroscopy study. Am J Alzheimers Dis Other Demen 26, 450–456.

74.

Ernst

, Chang

, Melchor

, Mehringer

(1997) Frontotemporal dementia and early Alzheimer disease: Differentiation with frontal lobe H-1 MR spectroscopy. Radiology 203, 829–836.

75.

Smith

, Bowen

, Francis

, Snowden

, Neary

(1985) Putative amino acid transmitters in lumbar cerebrospinal fluid of patients with histologically verified Alzheimer’s dementia. J Neurol Neurosurg Psychiatry 48, 469–471.

76.

Jimenez-Jimenez

, Molina

, Gomez

, Vargas

, de Bustos

, Benito-Leon

, Tallon-Barranco

, Orti-Pareja

, Gasalla

, Arenas

(1998) Neurotransmitter amino acids in cerebrospinal fluid of patients with Alzheimer’s disease. J Neural Transm (Vienna) 105, 269–277.

77.

Jimenez-Jimenez

, Molina

, Vargas

, Gomez

, Navarro

, Benito-Leon

, Orti-Pareja

, Gasalla

, Cisneros

, Arenas

(1996) Neurotransmitter amino acids in cerebrospinal fluid of patients with Parkinson’s disease. J Neurol Sci 141, 39–44.

78.

Kaiser

, Schoenknecht

, Kassner

, Hildebrandt

, Kinscherf

, Schroeder

(2010) Cerebrospinal fluid concentrations of functionally important amino acids and metabolic compounds in patients with mild cognitive impairment and Alzheimer’s disease. Neurodegener Dis 7, 251–259.

79.

Ferrarese

, Aliprandi

, Tremolizzo

, Stanzani

, De Micheli

, Dolara

, Frattola

(2001) Increased glutamate in CSF and plasma of patients with HIV dementia. Neurology 57, 671–675.

80.

Olivares

, Deshpande

, Shi

, Lahiri

, Greig

, Rogers

, Huang

(2012) N-methyl D-aspartate (NMDA) receptor antagonists and memantine treatment for Alzheimer’s disease, vascular dementia and Parkinson’s disease. Curr Alzheimer Res 9, 746–758.

81.

Gray

, Patel

(1995) Neurodegeneration mediated by glutamate and beta-amyloid peptide: A comparison and possible interaction. Brain Res 691, 169–179.

82.

Mattson

, Cheng

, Davis

, Bryant

, Lieberburg

, Rydel

(1992) beta-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity. J Neurosci 12, 376–389.

83.

Mattson

, Pedersen

, Duan

, Culmsee

, Camandola

(1999) Cellular and molecular mechanisms underlying perturbed energy metabolism and neuronal degeneration in Alzheimer’s and Parkinson’s diseases. Ann N Y Acad Sci 893, 154–175.

84.

Parameshwaran

, Dhanasekaran

, Suppiramaniam

(2008) Amyloid beta peptides and glutamatergic synaptic dysregulation. Exp Neurol 210, 7–13.

85.

Kravitz

, Gaisler-Salomon

, Biegon

(2013) Hippocampal glutamate NMDA receptor loss tracks progression in Alzheimer’s disease: Quantitative autoradiography in postmortem human brain. PLoS One 8, e81244.

86.

Kurup

, Zhang

, Xu

, Venkitaramani

, Haroutunian

, Greengard

, Nairn

, Lombroso

(2010) Abeta-mediated NMDA receptor endocytosis in Alzheimer’s disease involves ubiquitination of the tyrosine phosphatase STEP61. J Neurosci 30, 5948–5957.

87.

Jacob

, Koutsilieri

, Bartl

, Neuen-Jacob

, Arzberger

, Zander

, Ravid

, Roggendorf

, Riederer

, Grunblatt

(2007) Alterations in expression of glutamatergic transporters and receptors in sporadic Alzheimer’s disease. J Alzheimers Dis 11, 97–116.

88.

, Yu

, Chen

, Clay

, Toumi

, Milea

(2015) Memantine for treatment of moderate or severe Alzheimer’s disease patients in urban China: Clinical and economic outcomes from a health economic model. Expert Rev Pharmacoecon Outcomes Res 15, 565–578.

89.

Wilkinson

, Wirth

, Goebel

(2014) Memantine in patients with moderate to severe Alzheimer’s disease: Meta-analyses using realistic definitions of response. Dement Geriatr Cogn Disord 37, 71–85.

90.

Nakamura

, Kitamura

, Homma

, Shiosakai

, Matsui

(2014) Efficacy and safety of memantine in patients with moderate-to-severe Alzheimer’s disease: Results of a pooled analysis of two randomized, double-blind, placebo-controlled trials in Japan. Expert Opin Pharmacother 15, 913–925.

91.

Mohr

, Bruno

, Foster

, Gillespie

, Cox

, Hare

, Tamminga

, Fedio

, Chase

(1986) GABA-agonist therapy for Alzheimer’s disease. Clin Neuropharmacol 9, 257–263.

92.

Solas

, Puerta

, Ramirez

(2015) Treatment options in Alzheimer’s disease: The GABA Story. Curr Pharm Des 21, 4960–4971.

93.

German

, Manaye

, White

3rd , Woodward

, McIntire

, Smith

, Kalaria

, Mann

(1992) Disease-specific patterns of locus coeruleus cell loss. Ann Neurol 32, 667–676.

94.

Yates

, Simpson

, Gordon

, Maloney

, Allison

, Ritchie

, Urquhart

(1983) Catecholamines and cholinergic enzymes in pre-senile and senile Alzheimer-type dementia and Down’s syndrome. Brain Res 280, 119–126.

95.

Scullion

, Kendall

, Marsden

, Sunter

, Pardon

(2011) Chronic treatment with the alpha2-adrenoceptor antagonist fluparoxan prevents age-related deficits in spatial working memory in APPxPS1 transgenic mice without altering beta-amyloid plaque load or astrocytosis. Neuropharmacology 60, 223–234.

96.

Gibbs

, Maksel

, Gibbs

, Hou

, Summers

, Small

(2010) Memory loss caused by beta-amyloid protein is rescued by a beta(3)-adrenoceptor agonist. Neurobiol Aging 31, 614–624.

97.

Yates

, Allison

, Simpson

, Maloney

, Gordon

(1979) Dopamine in Alzheimer’s disease and senile dementia. Lancet 2, 851–852.

98.

Martorana

, Koch

(2014) Is dopamine involved in Alzheimer’s disease? Front Aging Neurosci 6, 252.

99.

Murray

, Weihmueller

, Marshall

, Hurtig

, Gottleib

, Joyce

(1995) Damage to dopamine systems differs between Parkinson’s disease and Alzheimer’s disease with parkinsonism. Ann Neurol 37, 300–312.

100.

Joyce

, Murray

, Hurtig

, Gottlieb

, Trojanowski

(1998) Loss of dopamine D2 receptors in Alzheimer’s disease with parkinsonism but not Parkinson’s or Alzheimer’s disease. Neuropsychopharmacology 19, 472–480.

101.

Martorana

, Mori

, Esposito

, Kusayanagi

, Monteleone

, Codeca

, Sancesario

, Bernardi

, Koch

(2009) Dopamine modulates cholinergic cortical excitability in Alzheimer’s disease patients. Neuropsychopharmacology 34, 2323–2328.

102.

Gelao

, Fazio

, Selvaggi

, Di Giorgio

, Taurisano

, Quarto

, Romano

, Porcelli

, Mancini

, Masellis

, Ursini

, De Simeis

, Caforio

, Ferranti

, Lo Bianco

, Rampino

, Todarello

, Popolizio

, Blasi

, Bertolino

(2014) DRD2 genotype predicts prefrontal activity during working memory after stimulation of D2 receptors with bromocriptine. Psychopharmacology (Berl) 231, 2361–2370.

103.

Lewis

(2012) Learning and memory: Dopamine boosts ageing memories. Nat Rev Neurosci 13, 812.

104.

Sudhof

(2004) The synaptic vesicle cycle. Annu Rev Neurosci 27, 509–547.

105.

Baloyannis

, Manolidis

(2000) Synaptic alterations in the vestibulocerebellar system in Alzheimer’s disease–a Golgi and electron microscope study. Acta Otolaryngol 120, 247–250.

106.

Sze

, Bi

, Kleinschmidt-DeMasters

, Filley

, Martin

(2000) Selective regional loss of exocytotic presynaptic vesicle proteins in Alzheimer’s disease brains. J Neurol Sci 175, 81–90.

107.

Lassmann

, Weiler

, Fischer

, Bancher

, Jellinger

, Floor

, Danielczyk

, Seitelberger

, Winkler

(1992) Synaptic pathology in Alzheimer’s disease: Immunological data for markers of synaptic and large dense-core vesicles. Neuroscience 46, 1–8.

108.

Masliah

, Honer

, Mallory

, Voigt

, Kushner

, Hansen

, Terry

(1994) Topographical distribution of synaptic-associated proteins in the neuritic plaques of Alzheimer’s disease hippocampus. Acta Neuropathol 87, 135–142.

109.

Masliah

, Terry

, Alford

, DeTeresa

, Hansen

(1991) Cortical and subcortical patterns of synaptophysinlike immunoreactivity in Alzheimer’s disease. Am J Pathol 138, 235–246.

110.

Masliah

, Terry

, DeTeresa

, Hansen

(1989) Immunohistochemical quantification of the synapse-related protein synaptophysin in Alzheimer disease. Neurosci Lett 103, 234–239.

111.

Honer

(2003) Pathology of presynaptic proteins in Alzheimer’s disease: More than simple loss of terminals. Neurobiol Aging 24, 1047–1062.

112.

Ghosh

, Giese

(2015) Calcium/calmodulin-dependent kinase II and Alzheimer’s disease. Mol Brain 8, 78.

113.

Zhang

, Cheng

, Zhou

, Zhang

(2009) Age-related expression of calcium/calmodulin-dependent protein kinase II A in the hippocampus and cerebral cortex of senescence accelerated mouse prone/8 mice is modulated by anti-Alzheimer’s disease drugs. Neuroscience 159, 308–315.

114.

Wang

, Chen

, Hu

, Lu

, Zhou

, Liu

(2005) The expression of calcium/calmodulin-dependent protein kinase II-alpha in the hippocampus of patients with Alzheimer’s disease and its links with AD-related pathology. Brain Res 1031, 101–108.

115.

Simonian

, Elvhage

, Czernik

, Greengard

, Hyman

(1994) Calcium/calmodulin-dependent protein kinase II immunostaining is preserved in Alzheimer’s disease hippocampal neurons. Brain Res 657, 294–299.

116.

Kim

, Nairn

, Cairns

, Lubec

(2001) Decreased levels of ARPP-19 and PKA in brains of Down syndrome and Alzheimer’s disease. J Neural Transm Suppl 263–272.

117.

Blanchard

, devi Raghunandan

, Roder

, Ingram

(1994) Hyperphosphorylation of human TAU by brain kinase PK40erk beyond phosphorylation by cAMP-dependent PKA: Relation to Alzheimer’s disease. Biochem Biophys Res Commun 200, 187–194.

118.

Talman

, Pascale

, Jantti

, Amadio

, Tuominen

(2016) PKC activation as a potential therapeutic strategy in Alzheimer’s disease: Is there a role for ELAV-like proteins? Basic Clin Pharmacol Toxicol 119, 149–160.

119.

Hongpaisan

, Sun

, Alkon

(2011) PKC epsilon activation prevents synaptic loss, Abeta elevation, and cognitive deficits in Alzheimer’s disease transgenic mice. J Neurosci 31, 630–643.

120.

Kamat

, Kalani

, Rai

, Swarnkar

, Tota

, Nath

, Tyagi

(2016) Mechanism of oxidative stress and synapse dysfunction in the pathogenesis of Alzheimer’s disease: Understanding the therapeutics strategies. Mol Neurobiol 53, 648–661.

121.

Parodi

, Sepulveda

, Roa

, Opazo

, Inestrosa

, Aguayo

(2010) Beta-amyloid causes depletion of synaptic vesicles leading to neurotransmission failure. J Biol Chem 285, 2506–2514.

122.

Erez

, Shemesh

, Spira

(2014) Rescue of tau-induced synaptic transmission pathology by paclitaxel. Front Cell Neurosci 8, 34.

123.

Miller

(2013) Steroid hormone synthesis in mitochondria. Mol Cell Endocrinol 379, 62–73.

124.

Fujiwara

, Hosaka

, Matsuda

, Okamura-Ikeda

, Motokawa

, Suzuki

, Nakagawa

, Taniguchi

(2007) Crystal structure of bovine lipoyltransferase in complex with lipoyl-AMP. J Mol Biol 371, 222–234.

125.

Howard

Jr (1968) Control of fatty acid synthesis in mitochondrial membranes. Biochim Biophys Acta 164, 448–450.

126.

Donaldson

, Wit-Peeters

, Scholte

(1970) Fatty acid synthesis in rat liver: Relative contributions of the mitochondrial, microsomal and non-particulate systems. Biochim Biophys Acta 202, 35–42.

127.

Hiltunen

, Schonauer

, Autio

, Mittelmeier

, Kastaniotis

, Dieckmann

(2009) Mitochondrial fatty acid synthesis type II: More than just fatty acids. J Biol Chem 284, 9011–9015.

128.

Seth

, Sun

, Ea

, Chen

(2005) Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3. Cell 122, 669–682.

129.

Tatsumi

, Tsuji

, Anglade

, Motelica-Heino

, Soeda

, Katayama

(1995) Synthesis, storage and release of acetylcholine at and from growth cones of rat central cholinergic neurons in culture. Neurosci Lett 202, 25–28.

130.

Collier

(1986) Choline analogues: Their use in studies of acetylcholine synthesis, storage, and release. Can J Physiol Pharmacol 64, 341–346.

131.

Hancox

, Scrimshire

(1982) Refinement and validation of a model describing synthesis storage and release of acetylcholine at the neuromuscular junction. J Biomed Eng 4, 206–212.

132.

Hancox

, Scrimshire

(1981) A proposed model for the synthesis, storage and release of acetylcholine at the neuromuscular junction. J Biomed Eng 3, 183–195.

133.

Gundersen

(1980) The effects of botulinum toxin on the synthesis, storage and release of acetylcholine. Prog Neurobiol 14, 99–119.

134.

Greene

, Rein

(1977) Synthesis, storage and release of acetylcholine by a noradrenergic pheochromocytoma cell line. Nature 268, 349–351.

135.

Walker

, Ramage

, Woodruff

(1974) An electrophysiological study of the storage, synthesis and release of acetylcholine from an identifiable inhibitory synapse in the brain of Helix aspersa. Neuropharmacology 13, 29–38.

136.

Potter

(1970) Synthesis, storage and release of [14C]acetylcholine in isolated rat diaphragm muscles. J Physiol 206, 145–166.

137.

Parsons

, Bahr

, Gracz

, Kaufman

, Kornreich

, Nilsson

, Rogers

(1987) Acetylcholine transport: Fundamental properties and effects of pharmacologic agents. Ann N Y Acad Sci 493, 220–233.

138.

Varoqui

, Erickson

(1996) Active transport of acetylcholine by the human vesicular acetylcholine transporter. J Biol Chem 271, 27229–27232.

139.

, Drejer

, Hertz

, Schousboe

(1983) Pyruvate carboxylase activity in primary cultures of astrocytes and neurons. J Neurochem 41, 1484–1487.

140.

Shank

, Bennett

, Freytag

, Campbell

(1985) Pyruvate carboxylase: An astrocyte-specific enzyme implicated in the replenishment of amino acid neurotransmitter pools. Brain Res 329, 364–367.

141.

Cesar

, Hamprecht

(1995) Immunocytochemical examination of neural rat and mouse primary cultures using monoclonal antibodies raised against pyruvate carboxylase. J Neurochem 64, 2312–2318.

142.

Waagepetersen

, Qu

, Schousboe

, Sonnewald

(2001) Elucidation of the quantitative significance of pyruvate carboxylation in cultured cerebellar neurons and astrocytes. J Neurosci Res 66, 763–770.

143.

Patel

(1974) The effect of ketone bodies on pyruvate carboxylation by rat brain mitochondria. J Neurochem 23, 865–867.

144.

Pardo

, Contreras

, Satrustegui

(2013) De novo synthesis of glial glutamate and glutamine in young mice requires aspartate provided by the neuronal mitochondrial aspartate-glutamate carrier Aralar/AGC1. Front Endocrinol (Lausanne) 4, 149.

145.

Grewer

, Gameiro

, Zhang

, Tao

, Braams

, Rauen

(2008) Glutamate forward and reverse transport: From molecular mechanism to transporter-mediated release after ischemia. IUBMB Life 60, 609–619.

146.

Nagatsu

, Levitt

, Udenfriend

(1964) Tyrosine hydroxylase. The initial step in norepinephrine biosynthesis. J Biol Chem 239, 2910–2917.

147.

Laduron

(1974) Biosynthesis of catecholamines: New concepts. Actual Pharmacol (Paris) 27, 45–67.

148.

Gasnier

(2000) The loading of neurotransmitters into synaptic vesicles. Biochimie 82, 327–337.

149.

Daubner

, Le

, Wang

(2011) Tyrosine hydroxylase and regulation of dopamine synthesis. Arch Biochem Biophys 508, 1–12.

150.

Buddhala

, Hsu

, Wu

(2009) A novel mechanism for GABA synthesis and packaging into synaptic vesicles. Neurochem Int 55, 9–12.

151.

Van der Kloot

(2003) Loading and recycling of synaptic vesicles in the Torpedo electric organ and the vertebrate neuromuscular junction. Prog Neurobiol 71, 269–303.

152.

Rooke

, Li

, Keung

(2000) The mitochondrial monoamine oxidase-aldehyde dehydrogenase pathway: A potential site of action of daidzin. J Med Chem 43, 4169–4179.

153.

, Chin

(2003) The molecular machinery of synaptic vesicle exocytosis. Cell Mol Life Sci 60, 942–960.

154.

Ghosh

, Greenberg

(1995) Calcium signaling in neurons: Molecular mechanisms and cellular consequences. Science 268, 239–247.

155.

Meinrenken

, Borst

, Sakmann

(2002) Calcium secretion coupling at calyx of Held governed by nonuniform channel-vesicle topography. J Neurosci 22, 1648–1667.

156.

Zucker

(1999) Calcium- and activity-dependent synaptic plasticity. Curr Opin Neurobiol 9, 305–313.

157.

Zenisek

, Matthews

(2000) The role of mitochondria in presynaptic calcium handling at a ribbon synapse. Neuron 25, 229–237.

158.

Wan

, Nixon

, Heidelberger

(2012) Regulation of presynaptic calcium in a mammalian synaptic terminal. J Neurophysiol 108, 3059–3067.

159.

Malli

, Graier

(2010) Mitochondrial Ca2+ channels: Great unknowns with important functions. FEBS Lett 584, 1942–1947.

160.

Gunter

, Sheu

(2009) Characteristics and possible functions of mitochondrial Ca(2+) transport mechanisms. Biochim Biophys Acta 1787, 1291–1308.

161.

Billups

, Forsythe

(2002) Presynaptic mitochondrial calcium sequestration influences transmission at mammalian central synapses. J Neurosci 22, 5840–5847.

162.

David

, Barrett

(2003) Mitochondrial Ca2+ uptake prevents desynchronization of quantal release and minimizes depletion during repetitive stimulation of mouse motor nerve terminals. J Physiol 548, 425–438.

163.

Jonas

, Buchanan

, Kaczmarek

(1999) Prolonged activation of mitochondrial conductances during synaptic transmission. Science 286, 1347–1350.

164.

Mironov

, Symonchuk

(2006) ER vesicles and mitochondria move and communicate at synapses. J Cell Sci 119, 4926–4934.

165.

Pivovarova

, Pozzo-Miller

, Hongpaisan

, Andrews

(2002) Correlated calcium uptake and release by mitochondria and endoplasmic reticulum of CA3 hippocampal dendrites after afferent synaptic stimulation. J Neurosci 22, 10653–10661.

166.

Rizzuto

(2003) Calcium mobilization from mitochondria in synaptic transmitter release. J Cell Biol 163, 441–443.

167.

Rizzuto

, Bernardi

, Pozzan

(2000) Mitochondria as all-round players of the calcium game. J Physiol 529(Pt 1), 37–47.

168.

Simkus

, Stricker

(2002) The contribution ofintracellular calcium stores to mEPSCs recordedin layer II neurones of rat barrel cortex. J Physiol 545, 521–535.

169.

Emptage

, Reid

, Fine

(2001) Calcium stores in hippocampal synaptic boutons mediate short-term plasticity, store-operated Ca2+ entry, and spontaneous transmitter release. Neuron 29, 197–208.

170.

Dale

, Frenguelli

(2009) Release of adenosine and ATP during ischemia and epilepsy. Curr Neuropharmacol 7, 160–179.

171.

Attwell

, Laughlin

(2001) An energy budget for signaling in the grey matter of the brain. J Cereb Blood Flow Metab 21, 1133–1145.

172.

Hollenbeck

(2005) Mitochondria and neurotransmission: Evacuating the synapse. Neuron 47, 331–333.

173.

Nguyen

, Marin

, Atwood

(1997) Synaptic physiology and mitochondrial function in crayfish tonic and phasic motor neurons. J Neurophysiol 78, 281–294.

174.

Thiels

, Klann

(2002) Hippocampal memory and plasticity in superoxide dismutase mutant mice. Physiol Behav 77, 601–605.

175.

Thiels

, Urban

, Gonzalez-Burgos

, Kanterewicz

, Barrionuevo

, Chu

, Oury

, Klann

(2000) Impairment of long-term potentiation and associative memory in mice that overexpress extracellular superoxide dismutase. J Neurosci 20, 7631–7639.

176.

Kishida

, Pao

, Holland

, Klann

(2005) NADPH oxidase is required for NMDA receptor-dependent activation of ERK in hippocampal area CA1. J Neurochem 94, 299–306.

177.

Reddy

(2009) Role of mitochondria in neurodegenerative diseases: Mitochondria as a therapeutic target in Alzheimer’s disease. CNS Spectr 8, 13–18; discussion 14-16.

178.

Reddy

, Beal

(2005) Are mitochondria critical in the pathogenesis of Alzheimer’s disease? Brain Res Brain Res Rev 49, 618–632.

179.

Lezi

, Swerdlow

(2012) Mitochondria in neurodegeneration. Adv Exp Med Biol 942, 269–286.

180.

Swerdlow

, Kish

(2002) Mitochondria in Alzheimer’s disease. Int Rev Neurobiol 53, 341–385.

181.

Moreira

, Siedlak

, Wang

, Santos

, Oliveira

, Tabaton

, Nunomura

, Szweda

, Aliev

, Smith

, Zhu

, Perry

(2007) Increased autophagic degradation of mitochondria in Alzheimer disease. Autophagy 3, 614–615.

182.

Moreira

, Zhu

, Wang

, Lee

, Nunomura

, Petersen

, Perry

, Smith

(2010) Mitochondria: A therapeutic target in neurodegeneration. Biochim Biophys Acta 1802, 212–220.

183.

Moreira

, Smith

, Zhu

, Honda

, Lee

, Aliev

, Perry

(2005) Oxidative damage and Alzheimer’s disease: Are antioxidant therapies useful? Drug News Perspect 18, 13–19.

184.

Bubber

, Haroutunian

, Fisch

, Blass

, Gibson

(2005) Mitochondrial abnormalities in Alzheimer brain: Mechanistic imlications. Ann Neurol 57, 695–703.

185.

Gibson

, Sheu

, Blass

(1998) Abnormalities of mitochondrial enzymes in Alzheimer disease. J Neural Transm (Vienna) 105, 855–870.

186.

Calkins

, Manczak

, Mao

, Shirendeb

, Reddy

(2011) Impaired mitochondrial biogenesis, defective axonal transport of mitochondria, abnormal mitochondrial dynamics and synaptic degeneration in a mouse model of Alzheimer’s disease. Hum Mol Genet 20, 4515–4529.

187.

Beck

, Guo

, Phensy

, Tian

, Wang

, Tandon

, Gauba

, Lu

, Pascual

, Kroener

, Du

(2016) Deregulation of mitochondrial F1FO-ATP synthase via OSCP in Alzheimer’s disease. Nat Commun 7, 11483.

188.

Wang

, Guo

, Lu

, Sun

, Shao

, Beck

, Li

, Ramachandran

, Du

(2016) Synaptosomal mitochondrial dysfunction in 5xFAD mouse model of Alzheimer’s disease. PLoS One 11, e0150441.

189.

, Guo

, Gauba

, Tian

, Wang

, Tandon

, Shankar

, Beck

, Du

(2015) Transient cerebral ischemia promotes brain mitochondrial dysfunction and exacerbates cognitive impairments in young 5xFAD mice. PLoS One 10, e0144068.

190.

Manczak

, Anekonda

, Henson

, Park

, Quinn

, Reddy

(2006) Mitochondria are a direct site of A beta accumulation in Alzheimer’s disease neurons: Implications for free radical generation and oxidative damage in disease progression. Hum Mol Genet 15, 1437–1449.

191.

Guo

, Du

, Yan

, Wu

, McKhann

, Chen

, Yan

(2013) Cyclophilin D deficiency rescues axonal mitochondrial transport in Alzheimer’s neurons. PLoS One 8, e54914.

192.

Manczak

, Reddy

(2012) Abnormal interaction between the mitochondrial fission protein Drp1 and hyperphosphorylated tau in Alzheimer’s disease neurons: Implications for mitochondrial dysfunction and neuronal damage. Hum Mol Genet 21, 2538–2547.

193.

Manczak

, Calkins

, Reddy

(2011) Impaired mitochondrial dynamics and abnormal interaction of amyloid beta with mitochondrial protein Drp1 in neurons from patients with Alzheimer’s disease: Implications for neuronal damage. Hum Mol Genet 20, 2495–2509.

194.

Hirai

, Aliev

, Nunomura

, Fujioka

, Russell

, Atwood

, Johnson

, Kress

, Vinters

, Tabaton

, Shimohama

, Cash

, Siedlak

, Harris

, Jones

, Petersen

, Perry

, Smith

(2001) Mitochondrial abnormalities in Alzheimer’s disease. J Neurosci 21, 3017–3023.

195.

Zhang

, Trushin

, Christensen

, Bachmeier

, Gateno

, Schroeder

, Yao

, Itoh

, Sesaki

, Poon

, Gylys

, Patterson

, Parisi

, Diaz Brinton

, Salisbury

, Trushina

(2016) Altered brain energetics induces mitochondrial fission arrest in Alzheimer’s disease. Sci Rep 6, 18725.

196.

, Guo

, Yan

, Sosunov

, McKhann

, Yan

(2010) Early deficits in synaptic mitochondria in an Alzheimer’s disease mouse model. Proc Natl Acad Sci U S A 107, 18670–18675.

197.

, Guo

, Wu

, Sosunov

, McKhann

, Chen

, Yan

(2014) Cyclophilin D deficiency rescues Abeta-impaired PKA/CREB signaling and alleviates synaptic degeneration. Biochim Biophys Acta 1842, 2517–2527.

198.

Balietti

, Giorgetti

, Casoli

, Solazzi

, Tamagnini

, Burattini

, Aicardi

, Fattoretti

(2013) Early selective vulnerability of synapses and synaptic mitochondria in the hippocampal CA1 region of the Tg2576 mouse model of Alzheimer’s disease. J Alzheimers Dis 34, 887–896.

199.

Reddy

, Tripathi

, Troung

, Tirumala

, Reddy

, Anekonda

, Shirendeb

, Calkins

, Reddy

, Mao

, Manczak

(2012) Abnormal mitochondrial dynamics and synaptic degeneration as early events in Alzheimer’s disease: Implications to mitochondria-targeted antioxidant therapeutics. Biochim Biophys Acta 1822, 639–649.

200.

Shulman

, Rothman

, Behar

, Hyder

(2004) Energetic basis of brain activity: Implications for neuroimaging. Trends Neurosci 27, 489–495.

201.

Hoyer

(1996) Oxidative metabolism deficiencies in brains of patients with Alzheimer’s disease. Acta Neurol Scand Suppl 165, 18–24.

202.

Cunnane

, Nugent

, Roy

, Courchesne-Loyer

, Croteau

, Tremblay

, Castellano

, Pifferi

, Bocti

, Paquet

, Begdouri

, Bentourkia

, Turcotte

, Allard

, Barberger-Gateau

, Fulop

, Rapoport

(2011) Brain fuel metabolism, aging, and Alzheimer’s disease. Nutrition 27, 3–20.

203.

Parker

Jr. , Parks

, Filley

, Kleinschmidt-DeMasters

(1994) Electron transport chain defects in Alzheimer’s disease brain. Neurology 44, 1090–1096.

204.

Parker

Jr , Parks

(1995) Cytochrome c oxidase in Alzheimer’s disease brain: urification and characterization. Neurology 45, 482–486.

205.

Kish

, Mastrogiacomo

, Guttman

, Furukawa

, Taanman

, Dozic

, Pandolfo

, Lamarche

, DiStefano

, Chang

(1999) Decreased brain protein levels of cytochrome oxidase subunits in Alzheimer’s disease and in hereditary spinocerebellar ataxia disorders: A nonspecific change? J Neurochem 72, 700–707.

206.

Mutisya

, Bowling

, Beal

(1994) Cortical cytochrome oxidase activity is reduced in Alzheimer’s disease. J Neurochem 63, 2179–2184.

207.

Maurer

, Zierz

, Moller

(2000) A selective defect of cytochrome c oxidase is present in brain of Alzheimer disease patients. Neurobiol Aging 21, 455–462.

208.

, Guo

, Fang

, Chen

, Sosunov

, McKhann

, Yan

, Wang

, Zhang

, Molkentin

, Gunn-Moore

, Vonsattel

, Arancio

, Chen

, Yan

(2008) Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer’s disease. Nat Med 14, 1097–1105.

209.

, Guo

, Zhang

, Rydzewska

, Yan

(2011) Cyclophilin D deficiency improves mitochondrial function and learning/memory in aging Alzheimer disease mouse model. Neurobiol Aging 32, 398–406.

210.

Fisar

, Hroudova

, Hansikova

, Spacilova

, Lelkova

, Wenchich

, Jirak

, Zverova

, Zeman

, Martasek

, Raboch

(2016) Mitochondrial respiration in the platelets of patients with Alzheimer’s disease. Curr Alzheimer Res 13, 930–941.

211.

Valla

, Schneider

, Niedzielko

, Coon

, Caselli

, Sabbagh

, Ahern

, Baxter

, Alexander

, Walker

, Reiman

(2006) Impaired platelet mitochondrial activity in Alzheimer’s disease and mild cognitive impairment. Mitochondrion 6, 323–330.

212.

Carbajo

, Kellas

, Yang

, Runswick

, Montgomery

, Walker

, Neuhaus

(2007) How the N-terminal domain of the OSCP subunit of bovine F1Fo-ATP synthase interacts with the N-terminal region of an alpha subunit. J Mol Biol 368, 310–318.

213.

Sanz-Blasco

, Valero

, Rodriguez-Crespo

, Villalobos

, Nunez

(2008) Mitochondrial Ca2+ overload underlies Abeta oligomers neurotoxicity providing an unexpected mechanism of neuroprotection by NSAIDs. PLoS One 3, e2718.

214.

Moreira

, Santos

, Moreno

, Rego

, Oliveira

(2002) Effect of amyloid beta-peptide on permeability transition pore: A comparative study. J Neurosci Res 69, 257–267.

215.

Moreira

, Santos

, Moreno

, Oliveira

(2001) Amyloid beta-peptide promotes permeability transition pore in brain mitochondria. Biosci Rep 21, 789–800.

216.

Shevtzova

, Kireeva

, Bachurin

(2001) Effect of beta-amyloid peptide fragment 25-35 on nonselective permeability of mitochondria. Bull Exp Biol Med 132, 1173–1176.

217.

Manczak

, Reddy

(2012) Abnormal interaction of VDAC1 with amyloid beta and phosphorylated tau causes mitochondrial dysfunction in Alzheimer’s disease. Hum Mol Genet 21, 5131–5146.

218.

Baines

, Kaiser

, Purcell

, Blair

, Osinska

, Hambleton

, Brunskill

, Sayen

, Gottlieb

, Dorn

, Robbins

, Molkentin

(2005) Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature 434, 658–662.

219.

Gutierrez-Aguilar

, Baines

(2015) Structuralmechanisms of cyclophilin D-dependent control of the mitochondrial permeability transition pore. Biochim Biophys Acta 1850, 2041–2047.

220.

Alavian

, Beutner

, Lazrove

, Sacchetti

, Park

, Licznerski

, Li

, Nabili

, Hockensmith

, Graham

, Porter

Jr , Jonas

(2014) An uncoupling channel within the c-subunit ring of the F1FO ATP synthase is the mitochondrial permeability transition pore. Proc Natl Acad Sci U S A 111, 10580–10585.

221.

Giorgio

, von Stockum

, Antoniel

, Fabbro

, Fogolari

, Forte

, Glick

, Petronilli

, Zoratti

, Szabo

, Lippe

, Bernardi

(2013) Dimers of mitochondrial ATP synthase form the permeability transition pore. Proc Natl Acad Sci U S A 110, 5887–5892.

222.

Reddy

, Zhu

, Perry

, Smith

(2009) Oxidative stress in diabetes and Alzheimer’s disease. J Alzheimers Dis 16, 763–774.

223.

Arai

, Saito

, Takatsu

, Fukui

, Urano

(2011) Dysfunction of the fusion of pre-synaptic plasma membranes and synaptic vesicles caused by oxidative stress, and its prevention by vitamin E. J Alzheimers Dis 24, 759–766.

224.

Omoi

, Arai

, Saito

, Takatsu

, Shibata

, Fukuzawa

, Sato

, Abe

, Fukui

, Urano

(2006) Influence of oxidative stress on fusion of pre-synaptic plasma membranes of the rat brain with phosphatidyl choline liposomes, and protective effect of vitamin E. J Nutr Sci Vitaminol (Tokyo) 52, 248–255.

225.

Dumont

, Wille

, Stack

, Calingasan

, Beal

, Lin

(2009) Reduction of oxidative stress, amyloid deposition, and memory deficit by manganese superoxide dismutase overexpression in a transgenic mouse model of Alzheimer’s disease. FASEB J 23, 2459–2466.

226.

Manczak

, Mao

, Calkins

, Cornea

, Reddy

, Murphy

, Szeto

, Park

, Reddy

(2010) Mitochondria-targeted antioxidants protect against amyloid-beta toxicity in Alzheimer’s disease neurons. J Alzheimers Dis 20(Suppl 2), S609–S631.

227.

Calkins

, Manczak

, Reddy

(2012) Mitochondria-targeted antioxidant SS31 prevents amyloid beta-induced mitochondrial abnormalities and synaptic degeneration in Alzheimer’s disease. Pharmaceuticals (Basel) 5, 1103–1119.

228.

, Hoeffer

, Wong

, Massaad

, Zhou

, Iadecola

, Murphy

, Pautler

, Klann

(2011) Amyloid beta-induced impairments in hippocampal synaptic plasticity are rescued by decreasing mitochondrial superoxide. J Neurosci 31, 5589–5595.

229.

Lin

, Beal

(2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443, 787–795.

230.

Cai

, Davis

, Sheng

(2011) Regulation of axonal mitochondrial transport and its impact on synaptic transmission. Neurosci Res 70, 9–15.

231.

Wang

, Su

, Lee

, Li

, Perry

, Smith

, Zhu

(2009) Impaired balance of mitochondrial fission and fusion in Alzheimer’s disease. J Neurosci 29, 9090–9103.

232.

Decker

, Lo

, Unger

, Ferreira

, Silverman

(2010) Amyloid-beta peptide oligomers disrupt axonal transport through an NMDA receptor-dependent mechanism that is mediated by glycogen synthase kinase 3beta in primary cultured hippocampal neurons. J Neurosci 30, 9166–9171.

233.

Cho

, Nakamura

, Fang

, Cieplak

, Godzik

, Gu

, Lipton

(2009) S-nitrosylation of Drp1 mediates beta-amyloid-related mitochondrial fission and neuronal injury. Science 324, 102–105.

234.

Swerdlow

, Burns

, Khan

(2014) The Alzheimer’s disease mitochondrial cascade hypothesis: Progress and perspectives. Biochim Biophys Acta 1842, 1219–1231.