Role of Mitochondrial Dysfunction in the Pathology of Amyloid-β

Abstract

Mitochondrial dysfunction has been widely reported in several neurodegenerative disorders, including in the brains of patients with Alzheimer’s disease (AD), Parkinson’s disease, and Huntington disease. An increasing number of studies have implicated altered glucose and energy metabolism in patients with AD. There is compelling evidence of abnormalities in some of the key mitochondrial enzymes involved in glucose metabolism, including the pyruvate dehydrogenase and α-ketoglutarate dehydrogenase complexes, which play a great significance role in the pathogenesis of AD. Changes in some of the enzyme activities of the mitochondria found in AD have been linked with the pathology of amyloid-β (Aβ). This review highlights the role of mitochondrial function in the production and clearance of Aβ and how the pathology of Aβ leads to a decrease in energy metabolism by affecting mitochondrial function.

Keywords

Alzheimer’s disease amyloid-β dysfunction mitochondria pathology

INTRODUCTION

Alzheimer’s disease (AD) is a late-onset neurodegenerative disease that impairs cognitive function and causes selective death of neurons in the brain. AD is pathologically characterized with extracellular amyloid plaques that form as a result of the accumu-lation of amyloid-β (Aβ) and intracellular neurofibrillary tangles, which consist mainly of the tau protein [1, 2]. Accumulation of Aβ leads to impaired synaptic plasticity and cognitive function [3, 4]. Changes in many metabolic processes have been involved in the pathogenesis of AD, including mitochondrial dysfunction [5, 6], hypometabolism [7], and abnormalities in the tricarboxylic acid (TCA) cycle [8].

Mitochondria are important organelles, the vital function of which is to generate large amounts of energy in the form of adenosine triphosphate (ATP). Mitochondrial dysfunction affects the production of ATP, which in turn affects the body. It has been hypothesized that mitochondrial dysfunction in AD is the result of the accumulation of Aβ [9], but the mechanism is unclear. The main pathway for glucose metabolism in the brain is the TCA cycle, which takes place in the mitochondria and plays a crucial role in the changes of mitochondrial function [10]. Many studies have indicated a significant decrease in the activity of two key mitochondrial enzymes, the pyruvate dehydrogenase complex (PDHC) and α-ketoglutarate dehydrogenase complex (α-KGDHC), in the AD brain [11 –15]. Moreover, the severity of clinical infirmity in AD is closely related to the degree of hypometabolism in the brain, in which the main pathway for glucose oxidation is the TCA cycle [16]. All the changes observed in the activities of the TCA cycle correlate with the clinical state in patients with AD, suggesting that abnormalities in the TCA cycle decrease metabolism in the AD brain, resulting in deterioration of brain function and clinical presentation [8, 17].

Mitochondria provide and regulate cellular energy and are essential for maintaining appropriate neuronal activity and survival. Abnormalities in mitochondrial function are involved in the pathogenesis of AD in all its stages. This review concentrates on the association between the pathology of Aβ and abnormalities in mitochondrial function in AD.

TRICARBOXYLIC ACID CYCLE

Glucose metabolism refers to a series of complex chemical reactions in the body involving molecules such as glucose and glycogen. Both glucose and gly-cogen can be oxidized in the body to provide energy. The metabolic pathways of sugar in the body include anaerobic hydrolysis of glucose, aerobic oxidation, the pentose phosphate pathway, glycogen synthesis and decomposition, gluconeogenesis, and other hexose metabolism. The most important of these is the TCA cycle in aerobic oxidation (Fig. 1).

Fig. 1

Tricarboxylic acid cycle. Glucose undergoes a series of reactions in the cell to produce pyruvate, which is oxidatively decarboxylated to produce Ac-CoA in the mitochondria for participation in the TCA cycle. Ac-CoA, acetyl-CoA; F6P, fructose-6-phosphate; F1,6BP, fructose-1,6-bisphosphate; G6P, glucose-6-phosphate; 3PG, 3-phosphoglycerate; PEP, phosphoenolpyruvate; TCA, tricarboxylic acid.

The TCA cycle, also known as the citric acid cy-cle or Krebs cycle, is a common metabolic pathway in aerobic organisms. The TCA cycle begins with the oxidation of acetyl-CoA produced by fatty acids, amino acids, or pyruvate and the reaction of citric acid synthase with oxaloacetate to generate citric acid. In the second reaction, citric acid is converted to isocitric acid. Under the regulation of isocitrate dehydroge-nase, isocitrate is decarboxylated to produce α-KGDHC, NADH, and CO₂. Under the action of the α-ketoglutarate dehydrogenase system, α-KGDHC is oxidatively decarboxylated to form succinyl-CoA, NADH, and CO₂. Succinyl-CoA is then converted to succinic acid, and substrate levels are phosphorylated to produce ATP. Succinate dehydrogenase catalyzes the oxidation of succinate to fumaric acid. This enzyme contains iron-sulfur centers and covalently bound FAD. Electrons from succinic acid pass through the FAD and iron-sulfur centers and then enter the electron transfer chain to O₂. Next, fumaric acid is converted into malic acid, which is converted into oxaloacetate by the action of malate dehydrogenase, and the TCA cycle is continued [18]. In a series of enzymatic reactions, the TCA cycle produces re-ducing equivalents of NADH and FADH2, which are necessary to transfer electrons to the mitochondrial respiratory chain, also known as the electron transport chain. The respiratory chain transfers electrons to O₂ to produce water, while coupling oxidative phosphorylation to generate ATP, which provides energy. The TCA cycle is the most efficient way for the body to oxidize sugar or other substances to obtain energy. It is the eventual metabolic pathway of the three major nutrients, sugar, lipids, and amino acids, and is also the hub of their metabolism [19].

AMYLOID-β PEPTIDES

Aβ is a normal product in the brain. A physiological amount of Aβ can inhibit excessive activation of neurons and is necessary to ensure the normal and continuous function of neurons. The Aβ monomer (molecular weight, 4 kDa) is produced in neurons and is mainly formed by the one-time hydrolysis of the amyloid-β protein precursor (AβPP) by β-secretase (BACE1) and γ-secretase. The N-terminus of the AβPP produces AβPP and C99 via β-secretase 1, leading to a large amount of Aβ₄₀ and a small amount of Aβ₄₂ via γ-secretase [20]. There are four subtypes of Aβ, the most common of which are Aβ₄₀ and Aβ₄₂. Under normal circumstances, the production and aggregation of Aβ in the brain is in a dynamic equilibrium as a result of the interaction of AβPP metabolic secretase and Aβ hydrolytic metabolism. When the balance between production and clearance is disrupted, there is abnormal deposition of Aβ in the brain tissue [21]. Excessive production and accumulation of Aβ promotes a series of pathophysiological changes, including overactivation of glial cells, an inflammatory response, and abnormal phosphorylation of the tau protein, causing synaptic damage and neuronal death [22].

MITOCHONDRIAL DYSFUNCTION AND AMYLOID-β

Aβ has toxic effects on mitochondrial respiration, synthesis of ATP, and the activities of various enzymes related to energy production, including the I, II, III, and IV enzyme complexes in the mitochondrial respiratory chain, PDHC, and α-KGDHC [23]. Mitochondria accumulate Aβ derived from the endoplasmic reticulum (ER)/Golgi apparatus or from the mitochondria-associated ER membranes (MAM) [24] (Fig. 2).

Fig. 2

Production of Aβ and its effect on mitochondrial function. ABAD, Aβ-binding alcohol dehydrogenase; ALCAR, acetyl-L-carnitine; CypD, cyclophilin D; Drp1, dynamin-related protein 1; α-KGDHC, α-ketoglutarate dehydrogenase; MAM, mitochondria-associated ER membranes; PDHC, pyruvate dehydrogenase complex; ROS, reactive oxygen species; TOM, translocase of the outer membrane; VDAC1, voltage-dependent anion channel 1.

The MAM form a bridge between the ER and mit-ochondria and are involved in the production of phospholipids, esterification of cholesterol, calcium transport, and communication between two org-anelles [25]. Studies have shown that mitochondrial dysfunction is related to the accumulation of C99 in the MAM. The increase in local C99 promotes various characteristics of AD, including a dynamic imbalance of calcium and lipids, mitochondrial disorders, and ultimately formation of plaques and tangles. Accumulation of C99 in the mitochondria has been detected in animal models of the AD brain [26]. We can speculate that the increased activity of BACE1 causes C99 to accumulate, which can lead to mitochondrial dysfunction and affect the TCA cycle. Aβ affects the ER and mitochondria and interferes with the homeostasis of calcium ions in the cell. In-creasing calcium ion concentrations in the mitochondria lead to a decrease in production of ATP [27]. Aβ enters the mitochondria, induces free radicals, reduces cytochrome oxidase activity, inhibits production of ATP, and can also disrupt the mitochondria and cause structural changes in neurons in AD [28]. Furthermore, Aβ enters the mitochondria and possibly disrupts the electron transport chain, ultimately leading to oxidative damage [27 , 30].

Structural and functional abnormalities of the mit-ochondria are caused by imbalances in the highly conserved GTPase gene. Mitochondrial GTPase genes include dynamin-related protein 1 (Drp1), fission 1 (Fis1), mitofusins 1 and 2 (Mfn1 and Mfn2), and optic atrophy 1 (Opa1) [31 –33]. Mitochondrial division is regulated and maintained by Drp1 and Fis1. Drp1 is involved in several important mitochondrial structures, which are related to some functions of the mitochondria, including fragmentation, phosphorylation, ubiquitination, and cell death [34]. In AD, increased production of Aβ and the interaction between Aβ and Drp1 are pivotal factors in the disruption of the mitochondria, abnormal mitochondrial dynamics, and synaptic damage [35].

Energy hypometabolism is one of the earliest ab-normalities in AD and mild cognitive impairment. Decreased glucose metabolism occurs in areas, where the posterior cingulate gyrus, parietal lobe, and temporal cortex, known to be affected early in AD [36, 37]. Researchers have found that energy deficiency leads to elevated levels of intracellular AβPP fragments in vitro, and the link between energy de-ficiency and the production of Aβ appears to be mediated by BACE1. Specific inhibitors increase the level and activity of BACE1 caused energy deficiency. The energy deficiency caused by specific inhibitors increases the level and activity of BACE1 [38, 39], which leads to an increase in Aβ.

Aβ may lead directly to the impairment of glucose homeostasis, and overexpression of Aβ leads to reduced glucose utilization [40]. Aβ causes mitochondrial dysfunction, including oxidative stress and reduced enzyme activity in the TCA cycle. Aβ is transported into the mitochondria through the translocase of the outer membrane mechanism and can interact with two mitochondrial proteins, Aβ-binding alcohol dehydrogenase (ABAD) and cyclophilin D (CypD), without being degraded by presequence protease, an Aβ-degrading enzyme in the mitochondria [41]. The combination of Aβ and ABAD can change the conformation of Aβ, causing it to combine with NAD+, change the permeability of ABAD, inhibit the activity of its enzyme, prevent the elimination of toxic aldehydes, damage the respiratory enzyme [42], and aggravate mitochondrial dysfunction by decreasing mitochondrial complex IV activity, decreasing O₂ consumption and increasing reactive oxygen species (ROS) [43]. CypD is an integral part of the mitoch-ondrial permeability transition pore and is involved in mitochondrial dysfunction instigated by Aβ. The interaction between Aβ and CypD significantly raises the accumulation and production of mitochondrial ROS. ROS is produced directly by Aβ itself or by Aβ interacting with ABAD; this can lead to the re-cruitment of CypD [44] and in turn formation of the mitochondrial permeability transition pore, causing a decrease in the mitochondrial membrane potential, compromised mitochondrial respiration, increased oxidative stress, release of cytochrome C, and im paired axonal mitochondrial transport [45].

Voltage-dependent anion channel 1 is a multi-fun-ctional protein that is expressed in the mitochondria and other cell compartments, including the plasma membrane, and is a key regulator of the opening and closing of the mitochondrion [46]. It can interact with Aβ and block mitochondrial permeability transition (formed by voltage-dependent anion channel 1, the mitochondrial inner membrane protein, adenine nucleotide transporter, and CypD), which disrupts the transport of mitochondrial proteins and metabolites (ADP and inorganic phosphate), which are essential for completing oxidative phosphorylation and producing mitochondrial ATP. Abnormal transport of proteins and metabolites leads to oxidative phosphorylation and mitochondrial dysfunction [47, 48].

Acetyl-L-carnitine is a precursor of acetyl-CoA, which is an important substance in the TCA cycle. Studies have found that Aβ can participate in the generation of ROS [49], while acetyl-L-carnitine can reduce Aβ-induced ROS and neuronal cell death and to a certain extent provide neuroprotection by maintaining cellular ATP levels [50].

Other studies have shown defects in energy met-abolism in the brains of patients with AD, that is, impaired activity of the α-KGDHC and PDHC, in part due to the interaction of Aβ in the mitochondria in neurons. The α-KGDHC is one of the key enzymes in the TCA cycle. Diminished activity of this complex may contribute to decreased metabolism, which is associated with an increased amount of nitrated proteins in AD [41 , 52]. The PDHC links glycolysis with the TCA cycle through production of acetyl-CoA. Reducing the PDHC results in a decrease in the activity of the TCA cycle [53] Therefore, we conclude that Aβ can influence the TCA cycle by affecting α-KGDHC and PDHC activity, thereby impinging on mitochondrial function.

MITOCHONDRIAL DYSFUNCTION AND AMYLOID-β CLEARANCE

Accumulation of Aβ is thought to be the result of an imbalance between the production and clearance of Aβ. The mechanisms of Aβ clearance include the ubiquitin-proteasome system, the autophagy-ly-sosome system (ALS), transport from the brain to the blood via the blood-brain barrier (BBB), and others [54, 55]. Intracellular Aβ can be cleared by the ubiquitin-proteasome system and the ALS while extracellular Aβ can be degraded by glial phagocytosis. Furthermore, extracellular Aβ in the interstitial fluid and cerebrospinal fluid can be transported to the periphery. Aβ in the interstitial fluid can be tran-sferred to the blood via the BBB or to the cervical lymph nodes via perivascular drainage and lymphatic vessels. Aβ in the cerebrospinal fluid can be transferred to the blood through the blood-cerebrospinal fluid barrier and the arachnoid villi or to the cervical lymph nodes by lymphatic clearance [55] (Fig. 3). Receptors for advanced glycation end-products (RAGE) is an inward transporter of Aβ at the BBB. Peripheral entry of Aβ into the center requires mediation by RAGE. Downregulation of RAGE expression can reduce the amount of peripheral Aβ that enters the nerve center [56]. Microglia are a type of mac-rophage-like phagocyte in the central nervous system that can remove extracellular Aβ by endocytosis and degrade in the cell [57]. Astrocytes can take up and degrade Aβ outside the cell. Low-density lipoprotein receptor-related protein 1 and apolipoprotein E are important cofactors for astrocytes to remove Aβ. In the process of clearing Aβ, apolipoprotein E forms a complex with Aβ, which mediates Aβ through ast-rocytic cells through the low-density lipoprotein rec-eptor-related protein 1 receptor [58]. Endoproteinase degradation is an important pathway for the clearance of Aβ from the brain. These proteases mainly include neprilysin, angiotensin-converting enzyme, insulin degrading enzyme, and matrix metalloproteinases [59].

Fig. 3

Possible mechanisms of Aβ clearance. Intracellular Aβ is mainly degraded via the ubiquitin-proteasome and autophagy-lysosome systems. Extracellular Aβ can be degraded by glial phagocytosis and proteases secreted by neurons and astrocytes. Extracellular proteins in the interstitial fluid can be transported into the blood via the blood-brain barrier or into the lymph nodes by perivascular drainage and glymphatic drainage. Extracellular proteins in the CSF can be removed to the blood via the blood-cerebrospinal fluid barrier or to the lymph nodes by lymphatic drainage via the perineural space and meningeal lymphatic vessels. ACE, angiotensin-converting enzyme; ALS, autophagy-lysosome system; AMPK, AMP-activated protein kinase; BBB, blood-brain barrier; BCSFB, blood-cerebrospinal fluid barrier; CSF, cerebrospinal fluid; IDE, insulin degrading enzyme; ISF, interstitial fluid; MMPS, matrix metalloproteinases; NEP, neprilysin; PPARA, peroxisome proliferator-activated receptor-α; RAGE, receptors for advanced glycation end-products; UPS, ubiquitin-proteasome system.

With the accumulation of Aβ, the activities of the enzymes related to mitochondrial function decrease, and in general, the NADH and FADH2 produced by mitochondria decreases. In addition, the reduction in the production of NADH leads to a decrease in the mitochondrial membrane potential, providing a good entry point for the autophagy mechanism [53]. Autophagy is an important process in eukaryotes that evolves and conserves intracellular materials. In the process, some damaged proteins or organelles are wrapped by autophagic vesicles with a double-layer membrane structure and then sent to lysosomes or vacuoles for degradation and recycling [60 –62]. The autophagy-lysosomal pathway is an important regulator of production and clearance of Aβ, and its abnormal function is considered to be a pathological trigger for abnormal accumulation of Aβ in the AD brain [63]. We can infer that mitochondrial dysfunction will lead to reduced energy metabolism and affect the clearance of Aβ by autophagy.

Parkin is a ubiquitin E3 ligase involved in proteasomal degradation of misfolded proteins [64]. Increasing parkin expression leads to reduced oxidative damage [65]. Parkin ubiquitinates Aβ_1 - 42 in cells and stimulates its removal via the proteasome or ALS. Parkin promotes ubiquitination and proteasome degradation of intracellular Aβ_1 - 42 and plays a protective role in Aβ-deposited neurodegenerative diseases. Parkin also reduces cell death by combating Aβ_1 - 42 toxicity and neurodegeneration [66].

Peroxisome proliferator-activated receptor-α (PPARA) is a key regulator of energy metabolism and mitochondrial and peroxisome functions. It has been reported that PPARA expression is significantly reduced in the brains of AD mice. Studies have found that the activation of PPARA can cause astrocytes and microglia to locate near Aβ plaques in AD mice and enhance the clearance of Aβ. This effect is re-lated to increased PPARA-induced autophagy [67].

AMP-activated protein kinase (AMPK) is a metabolic sensor that participates in intracellular energy metabolism, including autophagy and protein degradation, by controlling multiple homeostasis mechanisms [68]. Activation of AMPK can increase the oxidative metabolism of astrocytes, promote the TCA cycle, and produce ATP, which is conducive to the clearance of Aβ [69]. Activation of AMPK can also significantly inhibit the phosphorylation of mTOR to increase autophagy and promote Aβ clearance [70].

As a clearance system, autophagy is affected by accumulation of Aβ, which directs the secretion of Aβ to the outside of the cell, directly affecting formation of Aβ plaques, a pathological hallmark of AD [53, 71]. The autophagy system plays a crucial role in the pathogenesis of AD, including the modulation of the clearance of Aβ_1 - 42 aggregates [72]. Accordingly, it is understandable that the clearance of Aβ may be related to mitochondrial dysfunction.

TARGETING MITOCHONDRIAL DYSFUNCTION TO TREAT AD

AD is the main cause of dementia in the elderly. Despite decades of research, there is a lack of effe-ctive treatments. Mitochondrial dysfunction is closely related to the pathogenesis of AD, but the relationship between pathological changes in the mit-ochondria and neuronal damage is unclear. So far, the treatment strategy of AD in terms of mitocho-ndrial dysfunction has focused on preventing mitochondrial processes related to oxidative stress and apoptosis [73]. Promoting mitochondrial function and enhancing oxidative respiratory ability was fo-und to promote the growth of axons and formation of dendritic spines in a mouse model of AD and inhibit the decrease of spatial learning and memory ability [74]. Clinical trials of antioxidants with re-lated mechanisms did not produce obvious benefits in patients with AD, although patients on vitamin E initially showed a decrease in cognitive decline com-pared with those on placebo [75]. However, preclinical studies of antioxidants have shown therapeutic potential, especially when directed at the mitochondria and in early treatment of patients with AD, suggesting that antioxidants specifically targeting the mitochondria may be a treatment for AD. SIRT3, the most abundant sirtuin in the brain, is localized to the inner membrane and matrix of the mitochondrion and the nucleus of neurons. Importantly, SIRT3 has a fundamental role in enhancing the mitochondrial antioxidant glutathione, which could devote to slo-wing the aging in mammals. Studies have found that the therapeutic adjustment of SIRT3 activity can imp-rove mitochondrial pathology and neurodegeneration in AD [76]. Moreover, it has previously been re-ported that the mitochondria-targeted antioxidant MitoQ (mitoquinonemesylate:[10-(4,5-dimethoxy-2-methyl-3,6-dioxo-1,4-cyclohexadien-1-yl) decyl , 10-(4,5-dimethoxy-2-methyl-3,6-dioxo-1,4-cyclohexadien-1-yl) decyl](triphenyl)phosphonium methanesulfonate) signific-antly prolongs the lifespan of 3xTg AD mice. These findings support the role of mitochondrial oxidative stress in the etiology of AD and suggest that mit-ochondrial-targeted antioxidants can alleviate sym-ptoms in patients with AD [77]. Mitotempo is a cell-permeable antioxidant specifically targeted to the mitochondria and subsequently eliminates mitochondrial superoxide, which can rescue Aβ-induced mitochondrial dysfunction in primary cultured neurons. This observation suggests that mitotempo holds promise as a therapeutic agent for protecting mitochondrial and neuronal functions in AD-related conditions [6].

CONCLUSIONS AND PERSPECTIVES

In addition to the two classic pathological features of AD (amyloid plaques and neurofibrillary tangles), mitochondrial function also plays a very important role in the overall pathogenesis of AD. The characteristics of patients with AD include mitochondrial dysfunction and metabolic abnormalities. In these patients, region-specific decline in glucose utilization and mitochondrial dysfunction have deleterious consequences for neurons through the increased production of ROS, depletion of ATP, and cell death. This article has focused on the association between Aβ pathology and mitochondrial dysfunction and they are mutually influential and connected. This review provides various strategies that can improve mitochondrial function, have therapeutic prospects for AD, and may be the most promising method of treating the disease. However, further research is needed to clarify the exact mechanism and correlation of mitochondrial changes in AD and ultimately target the mitochondria to treat AD.

Footnotes

ACKNOWLEDGMENTS

This work was supported by the Chongqing Nat-ural Science Foundation, Grant Number: cstc2018jcyjAX0602; the Chongqing Health Commission, Grant Number: 2018ZDXM004; the Science and Technology Planning Project of Yuzhong District of Chongqing, Grant Number: 20180104; the Chon-gqing Health and Family Planning Scientific Res-earch Project, Grant Number: ZY201702042.

Authors’ disclosures available online ().

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