Morphological and Pathological Characteristics of Brain in Diabetic Encephalopathy

Abstract

Diabetes mellitus is a metabolic disease often accompanied by a series of complications, such as diabetic nephropathy, retinopathy, and diabetic foot. The survival time of diabetics has been significantly prolonged due to advancements in medicine. However, the prolonged survival time for diabetics can increase the prevalence of diabetic central nervous system disease. Diabetic encephalopathy (DE) has become one of the main complications of the disease, and the main clinical manifestation of DE is cognitive dysfunction. However, the typical morphological and pathological characteristics of the brain in DE are rarely systematically reported. Thus, this phenomenon severely restricts the diagnosis and treatment of DE. This article presents a description of the pathology characteristics of DE, including atrophy of the brain (gray matter, white matter, and hippocampus), changes in cerebrovascular morphology and function, impairment of synaptic plasticity, and dysfunction of neuroglia. In addition, abnormalities in the glymphatic clearance system of the brain are closely related to the progression of DE. A review of typical brain morphological and pathological characteristics would aid in the diagnosis and treatment of DE.

Keywords

Alzheimer’s disease cognitive dysfunction diabetic encephalopathy pathological characteristics vascular dementia

INTRODUCTION

Diabetic encephalopathy (DE) refers to cognitive impairment and the neurophysiological and structural changes in the brain caused by diabetes. The pathogenesis of DE is not completely clear, but DE is related to changes in cerebrovascular abnormality, oxidative stress, non-enzymatic protein glycosylation, and insulin abnormality. Dysfunctional cerebral vascular endothelial function and platelet agglutination aggravate the brain and lead to the proliferation of vascular endothelium and increased plasma viscosity, which in turn leads to complications such as lacunar cerebral infarction and cerebral thrombosis [1]. Advanced glycation end products (AGEs) are deposited gradually in the vascular wall and combines with the receptor over a prolonged time in the continuous hyperglycemic state of patients with diabetes. This phenomenon promotes vasodilatation and releases a large number of cytokines, inducing the release of tissue factors such as coagulation factor, thereby inhibiting anticoagulant protein C pathway and ultimately promoting thrombosis. The microvessels that make up the blood– brain barrier in the brain of diabetic rats become diseased, and the vascular permeability increases. Thus, the blood– brain barrier becomes permeable [2]. In general, oxidative stress and AGE formation lead to diabetic cerebrovascular impairment and cognitive impairment [3]. Insulin also contributes to the mechanisms of DE [4] and is a neurotrophic factor for nerve cells. Prolonged severe deficiency of insulin can cause neuronal degeneration and cognitive dysfunction [5]. In addition, abnormal insulin signaling is associated with amyloid deposition in the brain, suggesting that the formation of DE is also associated with amyloid deposition [6, 7]. The main clinical manifestations of DE are learning and memory impairment that seriously develop into dementia [8]. Dementia has several types, such as Alzheimer’s disease (AD), vascular dementia (VaD), dementia with Lewy bodies, frontotemporal dementia, and mixed dementia [9, 10]. AD is the most common form of dementia and accounts for 75% of all dementia cases [11]. Pathological features of AD are mainly age-related plaques and neurofibrillary tangles (NFTs). VaD is the second most common type of dementia that occurs mainly due to insufficient blood supply to the brain, leading to apoptosis or death of neurons and eventually leading to cognitive impairment. DE is intimately related to AD and VaD [12, 13]. In general, amyloid protein and NFTs are the main pathological features of AD. Moreover, phosphorylation of tau proteins is the basis for the formation of NFTs. Increased expression of amyloid peptide and localized phosphorylation of tau proteins were found in the DE brain. Furthermore, pathological manifestations similar to VaD, including endothelial dysfunction, increase in blood– brain barrier permeability, and cerebral blood flow, were found in the DE brain. Therefore, some scholars attribute DE to the pathological changes in VaD. Lewy body dementia is the third most common form of dementia, accounting for around 9.5% of all cases. Its main pathological feature is the presence of Lewy bodies in the brainstem nucleus and neocortex, a neuronal inclusion body containing alpha-synuclein [14]. Clinical features include memory loss, similar to AD. Frontotemporal dementia, characterized by progressive defects in behavior, executive function, or language, is a relatively unusual type of dementia [15]. The most common type of mixed dementia is the combination of AD and VaD, which features the common characteristics of AD and VaD [16]. Neuropathological studies have reported that the increased dementia risk in patients with diabetes mellitus (DM) is primarily related to vascular lesions in the brain, vascular complications, and atherosclerosis. The co-manifestations of DM, AD, and VaD are hypertension and hypercholesterolemia (Fig. 1). Moreover, the crosstalk of DM and the apolipoprotein E (APOE) ɛ4 allele can increase dementia risk [17]. Cerebrovascular damage (microinfarction), which can increase the risk of contracting VaD, is a major occurrence for patients with DM that develops to dementia. Endothelial dysfunction (vascular defects) can induce VaD, which may be related to high oxidative stress levels. The incidence of VaD may be significantly associated with impaired glucose metabolism. DE and AD seem to share a direction relationship. Changes occur in synaptic plasticity at the early stage of AD. The pathological changes in the synapse may be due to axonal transport disturbance and swollen axons. In the AD mouse model, axonal transport disorders and swelling of axons and bulge occurred earlier than other known AD-related pathological changes, including amyloid protein and NFTs. Interestingly, axon and dendrite lesions are typical in DE, and these lesions are associated with cognitive impairment in rats. The hyperglycemia-activated polyol pathway in DE leads to the accumulation of sorbitol, possibly leading to these lesions. The lack of metabolites such as inositol will cause Na⁺– K⁺– ATP enzyme dysfunction, which may lead to the passive influx of water, resulting in the swelling of axons, bulges, and dendrites. In addition, the increased expression of AGEs and its receptor for advanced glycation end products (RAGE) activates the inflammatory pathway, which changes the stability and permeability of the cell membrane and finally leads to the morphological changes in axons and dendrites. Thus, axonal and dendritic lesions and excessive phosphorylation of the tau protein are the possible mechanisms of DE and AD interlinking [18]. AD and VaD have many common characteristics, including risk factors and pathological mechanisms. Although the increased APOE expression and fibrinogen level due to the inflammatory reaction are related to the high incidence of AD and VaD, these events have stronger correlations with VaD than with AD. Similarly, the abnormal intrathecal titer of tumor necrosis factor (TNF-α) is related to both AD and VaD but is more closely related to the occurrence of the latter. Studies have shown that insulin-like growth factor (IGF-1) is negatively correlated with carotid atherosclerosis. The decrease in IGF-1 and the increase in the thickness of the arterial membrane are evident in both AD and VaD. In addition, matrix metalloproteinases (MMPs) MMP-1 2G2G, MMP-1 1G2G, MMP-3 5A5A, and MMP-9 TT genotypes were significantly and independently associated with VaD. MMP-1 2G2G and MMP-3 5A5A genotypes are associated with a high risk of contracting AD for patients with APOE ɛ4. In general, AD is a diffuse degenerative lesion of the brain in the cognitive domain of the temporal and parietal lobe resulting from pathological senile plaques and NFTs. VaD is a cognitive impairment due to vascular factors such as ischemia, bleeding, low perfusion, embolism, and small vascular disease. VaD is mainly a cognitive disorder caused by a series of cerebrovascular diseases. In DE, hyperglycemia and hyperlipidemia can cause cerebral vascular lesions, including vascular endothelial injury, vascular stenosis, vascular wall hyaline degeneration, and abnormal cerebral blood flow. However, whether or not DE causes VaD formation or a correlation exists between VaD and DE needs further study. Pathological manifestations of AD include neuron loss, dystrophic neurites, increased levels of amyloid-β (Aβ), and tau hyperphosphorylation (P-tau) [19]. White matter hyperintensities (WHI) may be related to cerebral amyloid angiopathy. Thus, some WHI may induce amyloid disease and contribute to the development of AD. AGE and the upregulation of its receptor RAGE can be observed in diabetic animals. Expression of the RAGE is enhanced in blood vessels near Aβ deposits in AD [20]. The pathology of AD has obvious overlaps with VaD, including cerebral amyloid angiopathy (CAA), microvascular degeneration, microinfarcts, and white matter lesions. Aβ is closely related to CAA in patients with DM. This finding indicates that cerebral vascular amyloid deposition can result in CAA. The development of CAA is related to Aβ accumulation or clearance. CAA, characterized by vascular damage, contributes greatly to AD. Degenerated microvessel profiles are significantly correlated with neocortical Aβ deposits. APOE is the only recognized gene associated with AD and can increase the risk of VaD [21, 22]. The APOE ɛ4 allele is also a strong factor that induces cerebral amyloid angiopathy in AD [23]. Moreover, immunoreaction and inflammation mediated by microglia are suggested to be important in AD and VaD. Microglial markers (YKL-40 and SCD14) are used as safety markers for monitoring neuro-inflammation and microglia activation. YKL-40 and SCD14 levels usually represent neuronal damage and microglial activation. Additionally, YKL-40 and SCD14 are both increased in AD and VaD [24]. Modulation of microglia in DE may involve CX3CL1, P38 MAPK, and CD200/CD200R signaling pathways [25]. Microglial activation can release pro-inflammatory and neurotoxic factors that contribute to neuronal dysfunction. CX3CL1 is a neuron-secreted chemokine that regulates microglial chemotaxis, activation, and toxicity; releases cytokines from microglia; reduces levels of TNF-α, IL-1β, IL-6, and IL-18; and induces the production of neurotrophic substances. The mice lacked CX3CR1 due to their upregulated tau protein phosphorylation that is linked to increased P38 MAPK activity. Microglial activation can also upregulate P38 MAPK activity and increase tau protein hyperphosphorylation in neurons. Neuronal CD200 is a membrane glycoprotein that can bind to its own receptor (CD200R) on microglia and affect the level of TNF-α. The level of TNF-α is elevated in CD200 knockout mice, which is related to the decline of long-term potentiation (LTP) and subsequent cognitive disorder [26]. In addition, both mortality and pro-inflammatory cytokine levels are higher in CD200 knockout mice. These signaling pathways participate in microglial activation and secretion of pro-inflammatory factors, resulting in neuronal toxicity and eventually leading to DE.

Fig.1

The association between DM, DE, AD, and VaD. Microglia and microvascular lesions play an important role in the relationship between DE, AD, and VaD. DM, diabetes mellitus; DE, diabetic encephalopathy; AD, Alzheimer’s disease; VaD, vascular dementia; WHI, white matter hyperintensities; CAA, cerebral amyloid angiopathy; RAGE, receptor for advanced glycation end products; APOE ɛ4, APOE ɛ4 is a subtype of apolipoprotein E (APOE); Aβ, amyloid β; P-tau, tau hyperphosphorylation.

BRAIN ATROPHY

Brain atrophy due to DE

Changes in brain structure due to DE are mainly whole brain atrophy and brain white matter, gray matter, and hippocampus volume reduction [27]. A brain cross-sectional study by magnetic resonance imaging found that gray matter, white matter, and hippocampus volumes are low in patients with DE. Gray volume loss is mainly in the temporal lobe, anterior cingulate gyrus, and medial prefrontal lobe, though it may also occur in the perihippocampal gyrus, cingulate gyrus, anterior cuneate lobe, insular lobe, and anterior and caudate nucleus of the midbrain. The volume of gray matter in the left hemisphere is lost even more than in the right hemisphere [28]. White matter volume loss is mainly distributed in the frontotemporal area. Mechanisms of DE brain atrophy may be related to endocrine, metabolic, and vascular pathways [29], and are particularly closely linked to the degree of fluctuations in blood glucose in high-frequency rhythms [30].

Brain atrophy due to AD

The atrophy due to AD in the brain is mainly located in the hippocampus and medial temporal lobe [31]. AD atrophy first occurs in the entorhinal cortex and the hippocampus, then spreads to the medial parietal lobe and temporal and frontal lobe-associated regions, ultimately affecting the cortex [32, 33]. In a study of the association between AD and apathy, apathetic patients showed significant reduction in cortical volume in the left anterior cingulate cortex and left lateral orbit of the orbitofrontal cortex, as well as in the left superior frontal and ventral frontal lobes [34]. Findings show that AD brain atrophy is associated with NFTs and amyloid proteins; nerve fiber tangles and macrovascular disease are independently associated with cortical and hippocampal atrophy, whereas amyloid is associated with volume preservation of the hippocampus and cortex [35]. Temporal, parietal, occipital, and frontal cortical atrophy can often be found in early-onset AD patients. Meanwhile, with aging, only atrophy in the medial temporal lobe and medial parietal cortex can be found. Late-onset AD occurs only in patients with early medial temporal lobe atrophy, followed by extensive cortical atrophy [36]. In typical AD, patients exhibit extensive left-sided temporal atrophy [37].

Brain atrophy due to VaD

Studies have shown that a significant decrease in occipital gray matter volume, the anterior corpus callosum area, and the medial temporal lobe can be found in patients with VaD [38]. Patients with VaD and AD account for 27.8% of patients with VaD and whose midbrain atrophy can be observed. The statistical results suggest that midbrain atrophy may be related to AD [39, 40]. In subcortical vascular dementia (SVaD), significant hippocampal atrophy occurs. SVaD and AD both lead to significant hippocampal atrophy, but the proportion of hippocampal atrophy in AD is significantly larger. Specifically, hippocampal volume was reduced by 11.6% in SVaD and 16.6% in AD [41]. In experiments with db/db mice, brain atrophy was associated with age, with no significant change at 4 weeks, significant cortical atrophy 14 weeks later, and finally atrophy in the hippocampus at 26 weeks [42].

DE and other neurodegenerative diseases such as AD and VaD have brain atrophy manifestations such as reduced cortical, hippocampal, and medial temporal lobes. However, the brain atrophy progress of DE is quite different from AD and VaD, and the extent of atrophy of gray and white matter is more prominent in DE. In the cases of AD, VaD, and DE brain atrophy, cerebrovascular lesions, including the stenosis of the wall of the brain, and increase in vascular resistance cause the decrease in cerebral blood perfusion and then brain atrophy, but the specific mechanisms need to be further studied.

CHANGES IN CEREBROVASCULAR FUNCTION AND MORPHOLOGY

Changes in cerebrovascular function and morphology due to DE

Spontaneous bleeding and cerebrovascular injury occur due to DE, and the amount of bleeding increases with age. Cerebral vascular permeability increases while cerebral blood flow and cerebrovascular surface area decrease [43]. The DE brain is known to have increased vascular endothelium and blood viscosity, which may be important factors that contribute to stroke. Furthermore, cerebral hemorrhage rate, vascular injury, and blood– brain barrier function decrease after a stroke. The Ang 1/Ang2/Tie 2 signaling pathway may be one of the causes of vascular injury and blood– brain barrier dysfunction after stroke. Besides, the protein content of MMP9 detected in cerebral blood vessels of diabetic mice was significantly increased, and the neurotrophic function of TRKB could be degraded by MMP9-mediated diabetic rats, disrupting the coupling of cerebrovascular nutrition and making the brain vulnerable; the reason may be that the cerebrovascular MMP9 can be upregulated in DE by an AGE-driven mechanism [44].

The blood– brain barrier is a protective barrier for the physiological functions of brain microcapillaries. The protective effect is enforced by a dynamic interface between blood and brain tissue, which can selectively prevent substances from passing through [45]. The brain microvascular endothelium is the main structure of the blood– brain barrier. The permeability of the blood– brain barrier is increased and its transport function is also impaired due to DE [46]. These effects may be related to the vascular damage caused by superoxide in the cerebrovascular endothelium [47]. Furthermore, reactive oxygen species inactivate endothelial nitric oxide synthase and prostacyclin synthase to impair vascular tone [48]. Another explanation is that increased cerebrospinal fluid/plasma albumin ratio (Qalb) levels are associated with biomarkers of cerebrospinal fluid (CSF) angiogenesis and endothelial dysfunction [49]. Qalb was used as an indicator of blood– brain barrier permeability [50].

Changes in cerebrovascular function and morphology due to AD

The presence of amyloid angiopathy in the pia mater and cortical vessels is the most prominent vascular abnormality due to AD. Changes in microvascular structure are also more frequent at the onset of AD. Studies have found that microvessels surrounded by amyloid show abnormal permeability to endogenous albumin [51]. CAA and microvascular inflammation occur in the mice model with AD and are accompanied by substantial plaque deposits [52]. At the same time, the increased production of Aβ leads to vascular oxidative stress and vasodilation. Vascular oxidative stress, caused by upregulating the vascular angiotensin II type 1 receptor, can lead to vasoconstriction. The vascular angiotensin II type 1 receptor can be activated by activating transcription factors such as nuclear factor kappa B [53]. Disorders in the clearance of Aβ from the brain by neurovascular units may lead to their substantial accumulation in blood vessels and the brain, eventually forming CAA This process can severely damage the integrity of the vessel wall, resulting in microvascular or intravascular bleeding that aggravate neurodegeneration and inflammatory reactions and may result in hemorrhagic stroke [54].

Changes in cerebrovascular function and morphology due to VaD

Cerebrovascular changes due to VaD are manifested as damage to the cerebrovascular and blood– brain barrier [55]. Cerebral microangiopathy is mainly characterized by arteriosclerosis, lacunar infarction, and subtle cortical and subcortical infarcts, as well as diffuse white matter changes and changes in the vessel wall. Arteriosclerosis or CAA is the most common and earliest change in VaD, and then perivascular space, lacunar, and local micro-infarction occurs [56, 57]. Cerebral blood flow was found to have different defects in different regions of AD and VaD. Cerebral blood flow decreased in the bilateral frontal and temporal lobe of patients with AD, whereas that decreased mainly in the left frontal and temporal white matter in patients with VaD. Moreover, DE is associated with more microvascular infarction and cerebral atrophy lacunar infarcts, while neuroinflammation is characteristic of VaD [58].

Changes in cerebrovascular function and morphology, such as the impairment of blood– brain barrier integrity, the vessel wall, and vascular tone, are prominent in patients with DE, AD, or VaD. More importantly, VaD vascular hemorrhage is more obvious in patients with DE compared to those with AD. Bleeding sites and volumes also change with age. In both DE and AD, the endothelial damage caused by oxidative stress, vascular obstruction, and regional insufficiency of blood perfusion are manifested. However, the vascular lesions in DE are mainly elevated by hyperglycemia-induced AGEs, low-density lipoprotein cholesterol, and glycated hemoglobin. AD and VaD seem to share some causes of vascular lesions, such as the release of inflammatory factors, including tumor necrosis factor, abnormal levels of C-reactive protein, and the damage of vascular endothelium caused by oxidative stress [59, 60].

CHANGES IN HIPPOCAMPAL FUNCTION AND MORPHOLOGY

Changes in hippocampal function and morphology due to DE

The hippocampus structure, consisting of the hippocampus, the dentate gyrus, and the pedicel, is a key brain region for many learning and memory forms and is particularly sensitive to glucose homeostasis [61]. DE leads to a decrease in granulosa cell proliferation and neuronal apoptosis or necrosis in CA3 and the dentate gyrus [62]. Moreover, the CA1 and CA2 hippocampus experience a substantial loss of vertebral cells [63]. Changes in hippocampal dendritic cells were associated with a decrease in brain-derived neurotrophic factor (BDNF) levels, while increased BDNF levels through exercise and caloric restriction can increase the density of dendritic spines [64]. The decrease in hippocampal volume is closely related to that in brain volume [65]. Furthermore, control of blood glucose is negatively correlated with the volume of the hippocampus. The hippocampus is more susceptible to disease than other areas in the brain. Based on insulin receptor (IR) expression in a population of discrete neurons (including the hippocampus) of the central nervous system, studies suggest that cognitive enhancement may be mediated by IR expression in the hippocampus [66]. Downregulated IR expression in the hippocampus can impair the plasticity of hippocampal neurons. As shown in a study on LV-IRAS rats, the plasticity may be impaired because the GluN2B subunit level and the basal level of Glu-A1 phosphorylation are decreased in the hippocampus [67, 68]. In conclusion, DE leads to a lower survival rate of hippocampal neurons and an increase in hippocampal neurogenesis, dendritic remodeling, and apoptosis. Its specific mechanisms may include stress hormones, neurotransmitters, neurotrophic factors, inflammation, and aging.

Changes in hippocampal function and morphology due to AD

The hippocampus is a key component of medial temporal lobe memory and shows synapses and intramolecular remodeling in the early stages of AD [69]. Moreover, hippocampal neurogenesis is an early manifestation of AD [70]. Reduced neurogenesis in the hippocampus correlates with increased bone morphogenetic protein BMP6 expression in AD [71]. BMP family growth factor is considered to be an important regulator of neuronal cell fate during neurogenesis and development. The increased expression of Aβ-related BMP6 in AD has a detrimental effect on neurogenesis in the hippocampus. In addition, neuronal loss occurs in multiple regions of the hippocampus, including the entorhinal cortex. Neuronal loss is also the pathological basis of extracellular Aβ deposits and intracellular NFTs.

Changes in hippocampal function and morphology due to VaD

In a study on the integrity of VaD hippocampal tissue, the lateral part of the left hippocampus was atrophied in patients with AD and VaD. The hippocampal atrophy due to AD may be more concentrated than that due to VaD [72]. In addition, the volume of the hippocampus due to subcortical VaD was smaller, the hippocampal CA1 region had a significant inward change [73], and significant hippocampal atrophy occurred. In a study on AD, VaD, and hippocampal morphology measurements [41 74], the hippocampal volume of the AD group was found to be about 5% smaller than that of the VaD group. Changes in the hippocampus due to VaD may be caused by oxidative stress in the hippocampus and mitochondrial dysfunction [75].

Hippocampal function and morphology changes are mainly reflected by hippocampal neuron decrease and atrophy. Since the final clinical manifestations of DE, AD, and VaD are all cognitive impairment, and hippocampus is the main area that controls cognitive function, hippocampal atrophy occurs in patients with DE, AD, and VaD. Cell loss caused by vascular endothelial injury and inadequacy of blood perfusion may also be related to hippocampal atrophy. In DE, AD, and VaD, the specific connection of these three needs further study.

MORPHOLOGICAL AND FUNCTIONAL CHANGES IN SYNAPTIC PROTEINS

Morphological and functional changes in synaptic proteins due to DE

Synaptic loss was found to be parallel to cortical atrophy in DE [42]. Studies have found that impaired synaptic plasticity is associated with inappropriate stimulation of the N-methyl-D-aspartate receptor (NMDAR), which is correlated with the induction of LTP [76, 77]. In addition, IR is enriched in hippocampal synapses and regulates synaptic plasticity through interaction with glutamatergic system. Thus, insulin signaling may affect synaptic plasticity by modulating glutamate receptor expression and trafficking [78]. In a study on cerebral ischemia, IRS-2 was found to have a strong effect on NMDAR-dependent synaptic transmission and plasticity in the hippocampal CA1 region, which may be related to the decrease in GluN1 subunit phosphorylation. Synaptic GluA 1 rapidly forms synapses by stimulating NMDARs. The impairment of synaptic plasticity and neurogenesis are induced by elevated glucocorticoid expression [79].

Morphological and functional changes in synaptic proteins due to AD

Activation of NMDAR leads to synaptic dysfunction in AD [80]. NMDAR is closely related to the depolymerization of microtubules, which reduces the growth of axons and protuberances and eventually leads to cell apoptosis. In addition, Aβ mediates endocytosis of NMDAR subunits and induces degradation of motilin by NMDAR activation. These processes lead to impaired synaptic transmission and decreased LTP. The interaction of Aβ with extracellular NMDAR subunits (GluNl and GluN2B) and the interaction of the peptide with intracellular signaling pathways or with selective scaffold proteins alter synaptic integrity and function [81]. Aβ plays an important role in triggering cognitive deficits by disrupting synaptic signaling pathways. The loss of synaptosomes in AD is as high as 45%, especially in the neocortex and hippocampus [82]. The loss of synapses in their distal dendrites to CA1 pyramidal neurons in the hippocampus of mice is age-related [83]. Aβ oligomers also induce synaptic dysfunction by overregulating NMDARS [84, 85]. Synaptic dysfunction by overstimulating can lead to redox-mediated cytosolic Ca^{2 +} elevation, AMPA receptor (AMPAR) upregulation, and NMDAR endocytosis, subsequently inducing mitochondrial dysfunction, which in turn causes synaptic dysfunction [86].

Morphological and functional changes in synaptic proteins due to VaD

The loss of synapsin is found in VaD as evidenced by the marked decrease in temporal lobe cortical synaptosomal-associated protein SNAP-25 in vascular dementia. The pronounced increase in drebrin is explained by a decrease in synaptic input [87]. Mainly, the regulation of synaptic plasticity is based on NMDAR [88]. Impairment of synaptic plasticity correlates with a decreased expression of NMDAR [89].

The loss of synapsin and abnormity of synaptic plasticity can be observed in DE, AD, and VaD. However, synaptic transmission and plasticity dysfunction mediated by NMDAR binding only can be observed in AD and VaD. Synaptic protein dysfunction is mainly mediated by the IR and the high corticosterone in DE. Furthermore, in the axon transport barrier at the early stage of AD, swollen axons and bulges and axon leakage occur. Similarly, axons thicken and twist and bulges swell in DE, indicating that AD and DE are correlated. However, whether DE can promote the development of AD needs further study.

MORPHOLOGICAL AND FUNCTIONAL CHANGES IN GLIAL CELLS

Morphological and functional changes in glial cells due to DE

Glial cells (including astrocytes and microglia) are a large cell category in the nerve tissue that forms a scaffold network and is involved in neuronal activity. Glial cells support, protect, aid in nutrition, form myelin, and repair a variety of functions. Astrocytes are essential to normal CNS function. Changes in the activity of astrocytes and damage to oxidative stress may lead to diabetes-related cognitive impairment. The neuron damage caused by high blood sugar, ROS, and increases in nitrogen may be mediated by increased oxidative proteins and lipid peroxidation products from cell membranes. Metabolic dysfunction and oxidative stress often lead to rapid changes in glial cells. The key indicator of this response is the glial fibrillary acidic protein (GFAP). GFAP is increased in the cortex and the hippocampus of patients with DE. As a marker of astrocytes, the synthesis of GFAP is increased. The expression of GFAP is commonly used to detect the distribution of glial cells, which is related to neuronal damage in DE [90, 91]. The abnormal expression of GFAP is mostly concentrated in the cortex and the hippocampus [92 –95]. In addition, the activation and modulation of microglia in DE may involve the CX3CL1, p38 MAPK, purinergic, and CD200/CD200R signaling pathways [25 , 97].

Morphological and functional changes in glial cells due to AD

The pathological product of AD, amyloid deposits, can stimulate astrocyte proliferation, and in turn, astrocytes participate in the degradation and division of amyloid deposits [98]. Microglia also plays a similar role. Microglia present different functions in different stages of the disease. In the early stage, microglia activation can degrade Aβ and facilitate the clearance of Aβ deposition. In later stages, microglia activation can aggravate inflammation and lead to pathological damage [99, 100]. Reactive astrocytes abnormally release gamma-aminobutyric acid (GABA) via the bestrophin 1 channel. The released GABA binds to the pre-synaptic GABA receptor and impairs synaptic plasticity and learning and memory ability [101]. Astrocytes exhibit degeneration and atrophy in early AD, including reduced cell volume and surface area [102]. In the later phase of AD, reactive astrocytes are associated with neuritic plaques, such as reactive astrogliosis found in the hippocampus [103, 104]. As important components of astrocyte aquaporin-4, Kir4.1 and dystrophin also decreased in autopsy brain tissue of patients with AD. The decrease in potassium channels (Kir4.1) and anchoring proteins (dystrophin 1) are associated with CAA. The development of CAA is associated with astroglia cells.

Morphological and functional changes in glial cells due to VaD

The Vascular Contributions to Cognitive Impairment and Dementia model showed significant astrocyte peripheral degeneration, including loss of Dp71 anchor protein, a reduced expression of aquaporin AQP4 channels, and a decreased expression of two key potassium channels, Kir 4.1 and MaxiK [105]. Reactive glial proliferation of astrocytes and microglia in the white matter tract of the brain is manifested in a model of vascular cognitive impairment [106].

The abnormal proliferation and activation of astrocytes and microglia are common in AD, VaD, and DE. Some differences may be observed in the proliferation that occurs among these diseases. The proliferation of astrocytes and microglia in the hippocampus is prominent in AD, while that of VaD is concentrated in white matter and that of DE is concentrated in the cortex and the hippocampus. In addition, microglia activation and microglia– neuron interactions play an important role in DE. Microglial markers (YKL-40 and SCD14) are usually representative of neuronal damage and microglial activation. YKL-40 and SCD14 are both increased in AD and VaD. Modulation of microglia in DE may involve the CX3CL1, P38 MAPK, and CD200/CD200R signaling pathways. The increase in the level of YKL-40 and SCD14 in VaD should be further studies to determine whether or not the same signal pathways are used.

ABNORMALITIES IN THE GLYMPHATIC CLEARANCE SYSTEM OF THE BRAIN

In recent years, studies of cognitive decline and risk factors for neurodegenerative diseases have described a biomolecule clearance system that utilizes CSF and interstitial fluid (ISF) convection to remove metabolic waste in the brain, termed the “glymphatic system” [107]. Three parts constitute the glymphatic system: the CSF influx of the artery, the brain parenchymal transport dependent on the astrocyte, and the bypass approach of venous ISF. The loose fibrous matrix around the perivascular space can be considered as the low-resistance highway of CSF influx. Aquaporins can mediate the CSF entering the brain parenchyma. ISF transports waste metabolites to the deep vein, and then the ISF metastasizes from the deep vein to the cervical glymphatic system, thus removing metabolites from the brain [108 –111]. The cerebral glymphatic system is closely related to neurodegenerative diseases, including AD, VaD, and DE.

Abnormalities in the glymphatic clearance system of the brain due to DE

In DE, the clearance of ISF in the hippocampus impairs glymphatic system function. Glymphatic system damage aggravates cognitive impairment. Compared with non-DM mice, DM mice can decrease brain clearance significantly and increase cerebral blood vessels around the gap, resulting in a large number of solute aggregations such as Aβ [112]. The cortical thickness was decreased by 15% by the phosphorylated tau [113]. This phenomenon suggests that tau phosphorylation and amyloid accumulation occurs in DE. The accumulated Aβ deposits after glymphatic injury further negatively affects glymphatic system function in DE. Aquaporins play an irreplaceable role in the transport of CSF from perivascular spaces to brain parenchyma and the removal of metabolites in the glymphatic system. The expression of aquaporin in astrocytes supports the channel of the highly-polarized expression distribution of CSF– ISF, which is mainly located at the end of vascular-oriented astrocytes. Brain clearance in mice that eliminated the astrocyte water channel transporter AQP4 was significantly decreased.

Abnormalities in glymphatic clearance system of the brain due to AD

It was found in AD that amyloid Aβ ₄₀ is distributed from the CSF to the brain parenchyma via the periarterial space, whereas Aβ ₄₂ is mainly limited to the periarterial space [114]. Accumulation of Aβ leads to functional impairment of the glymphatic system, whereas concomitant functional impairment of toxic substance clearance in the glymphatic system aggravates Aβ accumulation and thus aggravates AD [115]. Aβ ₄₂ accumulation represents the functional impairment of the glymphatic system and the diminished expression of AQP4 in the cortex and the hippocampus [116]. AQP4 plays an important role in the clearance of brain-soluble substances in the glymphatic system. Loss of AQP4 in AD increases Aβ accumulation and develops into losses of cerebral amyloid angiopathy, synaptic proteins in the hippocampus and the cortex, and brain-derived neurotrophic factors. AQP4 deficiency increases astrocyte atrophy [117, 118]. A clear direct relationship exists between CSF pressure and Aβ in patients with AD [119]. Studies have shown that the glymphatic system removes extracellular amyloid at twice rates during sleep [120, 121]. In addition, concentrations of T-tau (total protein) and P-tau (phosphorylated protein) are increased in AD CSF [122].

Abnormalities in glymphatic clearance system of the brain due to VaD

In VaD, the performance of the perivascular space is enlarged, and the perivascular space expansion remains a useful biomarker for VaD; furthermore, the expression of aquaporins is decreased, the CSF flow rate is slowed, and the removal rate of harmful substances in the brain is slowed, which indicates the glymphatic dysfunction in VaD [123, 124].

A significant decrease in the glymphatic system function may be found in patients with DE, AD, or VaD, characterized by the increased the perivascular space, which reduces the clearance rate of metabolic waste. Increased T-tau and P-tau concentrations in CSF in AD suggest a reduction in clearance capacity. However, the decrease in P-tau in DE suggests a difference object clearance or pathological processes.

CONCLUSION

Cognitive dysfunction and decreased learning and memory are the common clinical manifestations of DE, AD, and VaD, as shown in Table 1. Brain atrophy; changes in cerebrovascular cell, synapse, and glial cell function and morphology; and the dysfunction of the glymphatic clearance system are all exhibited in these diseases. However, typical brain morphological and pathological characteristics in DE include 1) a more prominent brain atrophy progress and gray and white matter atrophy, 2) the impairment of brain– blood barrier integrity and its increased permeability, 3) insulin signals and corticosterone-mediated decreased synaptic transmission and plasticity, 4) the abnormal activation of astrocytes and microglia, and 5) dysfunction of the glymphatic system. Typical brain morphological and pathological characteristics would benefit the diagnosis and treatment of DE.

Table 1

Brain pathological changes in DE, AD, and VaD

	Encephalatrophy	Cerebrovascular disease	Neuroglia cells	Hippocampus
DE	1) white matter: Frontotemporal region	1) Increased permeability of cerebrovascular vessels	1) Increased expression and activation of astrocytes in hippocampus and cortex	1) The survival of hippocampal cells decreased
	2) grey matter: Temporal lobe, perihippocampal area, cingulate gyrus, precuneiform lobe, island and anterior middle area, and caudate nucleus	2) Reduction of blood flow3) An increase in vascular bleeding	2) Activation of microglia	2) Hippocampal neurogenesis, dendritic structure remodeling and apoptosis increased
AD	1) Entorhinal cortex, hippocampus, medial parietal lobe, temporal side, left frontal lobe region	1) Increased permeability of cerebrovascular vessels	1) Astrocytes degenerate and shrink, including reduced cell volume and surface area	1) Hippocampal neurogenesis, hippocampal neuron decrease
		2) Sediment in blood vessels
		3) Vascular wall breakage
VaD	1) Occipital gray matter and anterior corpus callosum, hippocampus, medial temporal lobe	1) Increased permeability of cerebrovascular vessels 2) Vascular blockage 3) Vascular wall breakage	1) The expression of astrocytes decreased and showed obvious degeneration,	1) The hippocampus atrophy obviously, the CA1 area of hippocampus has obvious introversion change.
			2) Reactive glial hyperplasia

DE, diabetic encephalopathy; AD, Alzheimer’s disease; VaD, vascular dementia.

Footnotes

ACKNOWLEDGMENTS

This work was supported by the National Natural Science Foundation of China (81673707, 81403213) and program for Changjiang Scholars and Innovative Research Team in University (PCSIRT IRT_14R41).

Authors’ disclosures available online ().

References

Dalal

, Parab

(2002) Cerebrovascular disease in type 2 diabetes mellitus. Neurol India 50, 380–385.

Alves

, Oliveira

, Socorro

, Moreira

(2012) Impact of diabetes in blood-testis and blood-brain barriers: Reblances and differences. Curr Diabetes Rev 8, 401–412 sem.

Vlassara

, Palace

(2003) Glycoxidation: The menace of diabetes and aging. Mt Sinai J Med 70, 232–241.

Gispen

, Biessels

(2000) Cognition and synaptic plasticity in diabetes mellitus. Trends Neurosci 23, 542–549.

Cholerton

, Baker

, Craft

(2013) Insulin, cognition, and dementia. Eur J Pharmacol 719, 170–179.

Jimenez

, Torres

, Vizuete

, Sanchez-Varo

, Sanchez-Mejias

, Trujillo-Estrada

, Carmona-Cuenca

, Caballero

, Ruano

, Gutierrez

, Vitorica

(2011) Age-dependent accumulation of soluble amyloid beta (Abeta) oligomers reverses the neuroprotective effect of soluble amyloid precursor protein-alpha (sAPP(alpha)) by modulating phosphatidylinositol 3-kinase (PI3K)/Akt-GSK-3beta pathway in Alzheimer mouse model. J Biol Chem 286, 18414–18425.

Chiang

, Wang

, Xie

, Yau

, Zhong

(2010) PI3 kinase signaling is involved in Abeta-induced memory loss in Drosophila. Proc Natl Acad Sci U S A 107, 7060–7065.

Kopf

, Frölich

(2009) Risk of incident Alzheimer’s disease in diabetic patients: A systematic review of prospective trials. J Alzheimers Dis 16, 677–685.

Sandilyan

, Dening

(2015) Brain function, disease and dementia. Nurs Stand 29, 36–42.

10.

Dening

, Sandilyan

(2015) Dementia: Definitions and types. Nurs Stand 29, 37–42.

11.

Qiu

, Kivipelto

, von

Strauss E

(2009) Epidemiology of Alzheimer’s disease: Occurrence, determinants, and strategies toward intervention. Dialogues Clin Neurosci 11, 111–128.

12.

Baglietto-Vargas

, Shi

, Yaeger

, Ager

, LaFerla

(2016) Diabetes and Alzheimer’s disease crosstalk. Neurosci Biobehav Rev 64, 272–287.

13.

Ninomiya

(2014) Diabetes mellitus and dementia. Curr Diab Rep 14, 487.

14.

Mayo

, Bordelon

(2014) Dementia with Lewy bodies. Semin Neurol 34, 182–188.

15.

Bang

, Spina

, Miller

(2015) Frontotemporal dementia. Lancet 386, 1672–1682.

16.

Bogolepova

(2015) A modern concept of mixed dementia. Zh Nevrol Psikhiatr Im S S Korsakova 115, 120–126.

17.

Takeda

, Martínez

, Kudo

, Tanaka

, Okochi

, Tagami

, Morihara

, Hashimoto

, Cacabelos

(2010) Apolipoprotein E and central nervous system disorders: Reviews of clinical findings. Psychiatry Clin Neurosci 64, 592–607.

18.

Zhou

, Luo

, Dai

(2013) Axonal and dendritic changes are associated with diabetic encephalopathy in rats: An important risk factor for Alzheimer’s disease. J Alzheimers Dis 34, 937–947 Axon.

19.

, Zhang

, Sima

(2007) Alzheimer like changes in rat models of spontaneous diabetes. Diabetes 56, 1817–1824.

20.

Yan

S D

, Chen

, Fu

, Chen

, Zhu

, Roher

, Slattery

, Zhao

, Nagashima

, Morser

, Migheli

, Nawroth

, Stern

, Schmidt

(1996) RAGE and amyloid-beta peptide neurotoxicity in Alzheimer’s disease. Nature 382, 685–691.

21.

Corder

, Saunders

, Strittmatter

, Schmechel

, Gaskell

, Small

, Roses

, Haines

, Pericak-Vance

(1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late-onset families. Science 261, 921–923.

22.

Margaglione

, Seripa

, Gravina

, Grandone

, Vecchione

, Cappucci

, Merla

, Papa

, Postiglione

, Di

Minno G

, Fazio

(1998) Prevalence of apolipoprotein E alleles in healthy subjects and survivors of ischemic stroke: An Italian case-control study. Stroke 29, 399–403.

23.

Premkumar

, Cohen

, Hedera

, Friedland

, Kalaria

(1996) Apolipoprotein E e4 alleles in cerebral amyloid angiopathy and cerebrovascular pathology in Alzheimer’s disease. Am J Pathol 148, 2083–2095.

24.

Olsson

, Hertze

, Lautner

, Zetterberg

, Nägga

, Höglund

, Basun

, Annas

, Lannfelt

, Andreasen

, Minthon

, Blennow

, Hansson

(2013) Microglial markers are elevated in the prodromal phase of Alzheimer’s disease and vascular dementia. J Alzheimers Dis 33, 45–53.

25.

Liu

, Li

, Zhang

, Ye

, Zhou

(2018) Role of microglia-neuron interactions in diabetic encephalopathy. Ageing Res Rev 42, 28–39.

26.

Santello

, Volterra

(2012) TNFα in synaptic function: Switching gears. Trends Neurosci 35, 638–647.

27.

den

Heijer T

, Vermeer

, van Dijk

, Prins

, Koudstaal

, Hofman

, Breteler

(2003) Type 2 diabetes and atrophy of medial temporal lobe structures on brain MRI. Diabetologia 46, 1604–1610.

28.

Moran

, Phan

, Chen

, Blizzard

, Beare

, Venn

, Münch

, Wood

, Forbes

, Greenaway

, Pearson

, Srikanth

(2013) Brain atrophy in type 2 diabetes: Regional distribution and influence on cognition. Diabetes Care 36, 4036–4042.

29.

Exalto

, Whitmer

, Kappele

, Biessels

(2012) An update on type 2 diabetes, vascular dementia and Alzheimer’s disease. Exp Gerontol 47, 858–864.

30.

Cui

, Abduljalil

, Manor

, Peng

, Novak

(2014) Multi-scale glycemic variability: A link to gray matter atrophy and cognitive decline in type 2 diabetes. PLOS One 9, e86284.

31.

Weintraub

, Dietz

, Duda

, Wolk

, Doshi

, Xie

, Davatzikos

, Clark

, Siderowf

(2012) Alzheimer’s disease pattern of brain atrophy predicts cognitive decline in Parkinson’s disease. Brain 135, 170–180.

32.

Fjell

, McEvoy

, Holland

, Dale

, Walhovd

; Alzheimer’s Disease Neuroimaging Initiative (2014) What is normal in normal aging? Effects of aging, amyloid and Alzheimer’s disease on the cerebral cortex and the hippocampus. Prog Neurobiol 117, 20–40.

33.

Moodley

, Chan

(2014) The hippocampus in neurodegenerative disease. Front Neurol Neurosci 34, 95–108.

34.

Tunnard

, Whitehead

, Hurt

, Wahlund

, Mecocci

, Tsolaki

, Vellas

, Spenger

, Kłoszewska

, Soininen

, Lovestone

, Simmons

(2011) Apathy and cortical atrophy in Alzheimer’s disease. Int J Geriatr Psychiatry 26, 741–748.

35.

Crystal

, Schneider

, Bennett

, Leurgans

, Levine

(2014) Associations of cerebrovascular and Alzheimer’s disease pathology with brain atrophy. Curr Alzheimer Res 11, 309–316.

36.

Migliaccio

, Agosta

, Possin

, Canu

, Filippi

, Rabinovici

, Rosen

, Miller

, Gorno-Tempini

(2015) Mapping the progression of atrophy in early-and late-onset Alzheimer’s disease. J Alzheimers Dis 46, 351–364.

37.

Alves

, Soares

, Sampaio

, Gonçalves

ÓF

(2013) Posterior cortical atrophy and Alzheimer’s disease: A meta-analytic review of neuropsychological and brain morphometry studies. Brain Imaging Behav 7, 353–361.

38.

Möller

, Born

, Reiser

, Möller

, Hampel

, Teipel

(2009) Alzheimer-Krankheit und vaskuläre demenz. Bestimmung der atrophie des corpus callosum und des zerebralen kortex. Nervenarzt 80, 54–61.

39.

Sung

, Park

, Lee

, Park

, Shin

, Park

, Oh

, Ma

, Yu

, Kang

, Kim

, Lee

(2009) Midbrain atrophy in subcortical ischemic vascular dementia. J Neurol 256, 1997–2002.

40.

Laakso

M P

, Partanen

, Riekkinen

, Lehtovirta

, Helkala

E L

, Hallikainen

, Hanninen

, Vainio

, Soininen

(1996) Hippocampal volumes in Alzheimer’s disease, Parkinson’s disease with and without dementia, and in vascular dementia An MRI study. Neurology 46, 678–681.

41.

van de Pol

, Gertz

, Scheltens

, Wolf

(2011) Hippocampal atrophy in subcortical vascular dementia. Neurodegener Dis 8, 465–469.

42.

Ramos-Rodriguez

, Ortiz

, Jimenez-Palomares

, Kay

, Berrocoso

, Murillo-Carretero

, Perdomo

, Spires-Jones

, Cozar-Castellano

, Lechuga-Sancho

, Garcia-Alloza

(2013) Differential central pathology and cognitive impairment in pre-diabetic and diabetic mice. Psychoneuroendocrinology 38, 2462–2475.

43.

Fouyas

, Kelly

, Ritchie

, Lammie

, Whittle

(2003) Cerebrovascular responses to pathophysiological insult in diabetic rats. J Clin Neurosci 10, 88–91.

44.

Navaratna

, Fan

, Leung

, Lok

, Guo

, Xing

, Wang

, Lo

E H

(2013) Cerebrovascular degradation of TRKB by MMP9 in the diabetic brain. J Clin Invest 123, 3373–3377.

45.

Daneman

, Prat

(2015) The blood– brain barrier. Cold Spring Harb Perspect Biol 7, a020412.

46.

Prasad

, Sajja

, Naik

, Cucullo

(2014) Diabetes mellitus and blood-brain barrier dysfunction: An overview. J Pharmacovigil 2, 125.

47.

Wan

, Chen

, Li

(2014) The potential mechanisms of Aβ-receptor for advanced glycation end-products interaction disrupting tight junctions of the blood-brain barrier in Alzheimer’s disease. Int J Neurosci 124, 75–81.

48.

Mooradian

(1997) Central nervous system complications of diabetes mellitus— a perspective from the blood– brain barrier. Brain Res Brain Res Rev 23, 210–218.

49.

Meigs

, Hu

, Rifai

, Manson

(2004) Biomarkers of endothelial dysfunction and risk of type 2 diabetes mellitus. JAMA 291, 1978–1986.

50.

Janelidze

, Hertze

, Nägga

, Nilsson

, Wennström

, van Westen

, Blennow

, Zetterberg

, Hansson

(2017) Increased blood-brain barrier permeability is associated with dementia and diabetes but not amyloid pathology or APOE genotype. Neurobiol Aging 51, 104–112.

51.

Hachinski

, Munoz

(1997) Cerebrovascular pathology in Alzheimer’s disease: Cause, effect or epiphenomenon? Ann N Y Acad Sci 826, 1–6.

52.

Giannoni

, Arango-Lievano

, Neves

I D

, Rousset

M C

, Baranger

, Rivera

, Jeanneteau

, Claeysen

, Marchi

(2016) Cerebrovascular pathology during the progression of experimental Alzheimer’s disease. Neurobiol Dis 88, 107–117.

53.

Hame

, Nicolakakis

, Aboulkassim

, Ongali

, Tong

(2008) Oxidative stress and cerebrovascular dysfunction in mouse models of Alzheimer’s disease. Exp Physiol 93, 116–120.

54.

Bell

, Zlokovic

(2009) Neurovascular mechanisms and blood– brain barrier disorder in Alzheimer’s disease. Acta Neuropathol 118, 103–113.

55.

Ueno

, Chiba

, Matsumoto

, Murakami

, Fujihara

, Kawauchi

, Miyanaka

, Nakagawa

(2016) Blood brain barrier damage in vascular dementia. Neuropathology 36, 115–124.

56.

Kalaria

(2018) The pathology and pathophysiology of vascular dementia. Neuropharmacology 134, 226–239.

57.

Meguro

, Tanaka

, Nakatsuka

, Nakamura

, Satoh

(2012) Vascular lesions in mixed dementia, vascular dementia, and Alzheimer disease with cerebrovascular disease: The Kurihara Project. J Neurol Sci 322, 157–160.

58.

van Harten

, de Leeuw

, Weinstein

, Scheltens

, Biessels

(2006) Brain imaging in patients with diabetes: A systematic review. Diabetes Care 29, 2539–2548.

59.

Grammas

, Ovase

(2001) Inflammatory factors are elevated in brain microvessels in Alzheimer’s disease. Neurobiol Aging 22, 837–842.

60.

Engelhart

, Geerlings

, Meijer

, Kiliaan

, Ruitenberg

, van Swieten

, Stijnen

, Hofman

, Witteman

, Breteler

(2004) Inflammatory proteins in plasma and the risk of dementia: The Rotterdam study. Arch Neurol 61, 668–672.

61.

Zhang

, Tan

, Yue

, Vranic

, Wojtowicz

(2008) Impairment of hippocampal neurogenesis in streptozotocin-treated diabetic rats. Acta Neurol Scand 117, 205–210.

62.

, Zhang

, Grunberger

, Sima

(2002) Hippocampal neuronal apoptosis in type 1 diabetes. Brain Res 946, 221–231.

63.

Gold

, Dziobek

, Sweat

, Tirsi

, Rogers

, Bruehl

, Tsui

, Richardson

, Javier

, Convit

(2007) Hippocampal damage and memory impairments as possible early brain complications of type 2 diabetes. Diabetologia 50, 711–719.

64.

Stranahan

, Lee

, Martin

, Maudsley

, Golden

, Cutler

, Mattson

(2009) Voluntary exercise and caloric restriction enhance hippocampal dendritic spine density and BDNF levels in diabetic mice. Hippocampus 19, 951–961.

65.

Burke

, Barnes

(2006) Neural plasticity in the ageing brain. Nat Rev Neurosci 7, 30–40.

66.

Grillo

, Piroli

, Lawrence

, Wrighten

, Green

, Wilson

, Sakai

, Kelly

, Wilson

, Mott

, Reagan

(2015) Hippocampal insulin resistance impairs spatial learning and synaptic plasticity. Diabetes 64, 3927–3936.

67.

Amin

, Younan

, Youssef

, Rashed

, Mohamady

(2013) A histological and functional study on hippocampal formation of normal and diabetic rats. F1000Res 2, 151.

68.

Lebed

, Orlovsky

, Nikonenko

, Ushakova

, Skibo

(2008) Early reaction of astroglial cells in rat hippocampus to streptozotocin-induced diabetes. Neurosci Lett 444, 181–185.

69.

Mufson

, Mahady

, Waters

, Counts

, Perez

, DeKosky

, Ginsberg

, Ikonomovic

, Scheff

, Binder

(2015) Hippocampal plasticity during the progression of Alzheimer’s disease. Neuroscience 309, 51–67.

70.

, Gage

(2011) Adult hippocampal neurogenesis and its role in Alzheimer’s disease. Mol Neurodegener 6, 85.

71.

Crews

, Adame

, Patrick

, Delaney

, Pham

, Rockenstein

, Hansen

, Masliah

(2010) Increased BMP6 levels in the brains of Alzheimer’s disease patients and APP transgenic mice are accompanied by impaired neurogenesis. J Neurosci 30, 12252–12262.

72.

Scher

, Xu

, Korf

, Hartley

, Witter

, Scheltens

, White

, Thompson

, Toga

, Valentino

, Launer

(2011) Hippocampal morphometry in population-based incident Alzheimer’s disease and vascular dementia: The HAAS. J Neurol Neurosurg Psychiatry 82, 373–376.

73.

Kim

, Lee

, Seo

, Kim

, Seong

, Ye

, Cho

, Noh

, Kim

, Yoon

, Oh

, Kim

, Choe

, Lee

, Kim

, Hwang

, Jeong

, Na

(2015) Hippocampal volume and shape in pure subcortical vascular dementia. Neurobiol Aging 36, 485–491.

74.

, Schuff

, Laakso

, Zhu

, Jagust

, Yaffe

, Kramer

, Miller

, Reed

, Norman

, Chui

, Weiner

(2002) Effects of subcortical ischemic vascular dementia and AD on entorhinal cortex and hippocampus. Neurology 58, 1635–1641.

75.

, Liu

, Lin

, Wang

, Du

, Yan

, He

, Yang

, Liu

(2016) Acupuncture reversed hippocampal mitochondrial dysfunction in vascular dementia rats. Neurochem Int 92, 35–42.

76.

Gardoni

, Kamal

, Bellone

, Biessels

, Ramakers

, Cattabeni

, Gispent

, Di

Luca M

(2002) Effects of streptozotocin-diabetes on the hippocampal NMDA receptor complex in rats. J Neurochem 80, 438–447.

77.

Liu

, Brown

JC 3rd

, Webster

, Morrisett

, Monaghan

(1995) Insulin potentiates N-methyl-D-aspartate receptor activity in Xenopus oocytes and rat hippocampus. Neurosci Lett 192, 5–8.

78.

Costello

, Claret

, Al-Qassab

, Plattner

, Irvine

, Choudhury

, Giese

, Withers

, Pedarzani

(2012) Brain deletion of insulin receptor substrate 2 disrupts hippocampal synaptic plasticity and metaplasticity. PLoS One 7, e31124.

79.

Stranahan

, Arumugam

, Cutler

, Lee

, Egan

, Mattson

(2008) Diabetes impairs hippocampal function through glucocorticoid-mediated effects on new and mature neurons. Nat Neurosci 11, 309–317.

80.

Mota

, Ferreira

, Rego

(2014) Dysfunctional synapse in Alzheimer’s disease - A focus on NMDA receptors. Neuropharmacology 76, 16–26.

81.

Pozueta

, Lefort

, Shelanski

(2013) Synaptic changes in Alzheimer’s disease and its models. Neuroscience 251, 51–65.

82.

Matsuzaki

, Honkura

, Ellis-Davies

, Kasai

(2004) Structural basis of long-term potentiation in single dendritic spines. Nature 429, 761–766.

83.

Neuman

, Molina-Campos

, Musial

, Price

, Oh

, Wolke

, Buss

, Scheff

, Mufson

, Nicholson

(2015) Evidence for Alzheimer’s disease-linked synapse loss and compensation in mouse and human hippocampal CA1 pyramidal neurons. Brain Struct Funct 220, 3143–3165.

84.

Gouras

, Willén

, Faideau

(2014) The inside-out amyloid hypothesis and synapse pathology in Alzheimer’s disease. Neurodegener Dis 13, 142–146.

85.

, Okamoto

, Lipton

, Xu

(2014) Oligomeric Aβ-induced synaptic dysfunction in Alzheimer’s disease. Mol Neurodegener 9, 48.

86.

Sheng

, Sabatini

, Südhof

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

87.

Sinclair

, Tayler

, Love

(2015) Synaptic protein levels altered in vascular dementia. Neuropathol Appl Neurobiol 41, 533–543.

88.

Zhang

, Li

, Xu

, Yang

(2014) The role of N-methyl-D-aspartate receptor in Alzheimer’s disease. J Neurol Sci 339, 123–129.

89.

Yang

, Liu

, Xie

, Liu

, Tian

(2015) Effects of repetitive transcranial magnetic stimulation on synaptic plasticity and apoptosis in vascular dementia rats. Behav Brain Res 281, 149–155.

90.

Calon

, Lim

, Morihara

, Yang

, Ubeda

, Salem

Jr , Frautschy

, Cole

(2005) Dietary n-3 polyunsaturated fatty acid depletion activates caspases and decreases NMDA receptors in the brain of a transgenic mouse model of Alzheimer’s disease. Eur J Neurosci 22, 617–626.

91.

Tsang

, Vinters

, Cummings

, Wong

, Chen

, Lai

(2008) Alterations in NMDA receptor subunit densities and ligand binding to glycine recognition sites are associated with chronic anxiety in Alzheimer’s disease. Neurobiol Aging 29, 1524–1532.

92.

Baydas

, Reiter

, Yasar

, Tuzcu

, Akdemir

, Nedzvetskii

(2003) Melatonin reduces glial reactivity in the hippocampus, cortex, and cerebellum of streptozotocin-induced diabetic rats. Free Radic Biol Med 35, 797–804.

93.

Baydas

, Nedzvetskii

, Tuzcu

, Yasar

, Kirichenko

S V

(2003) Increase of glial fibrillary acidic protein and S-100B in hippocampus and cortex of diabetic rats: Effects of vitamin E. Eur J Pharmacol 462, 67–71.

94.

Guven

, Yavuz

, Cam

, Comunoglu

, Sevi’nc

(2009) Central nervous system complications of diabetes in streptozotocin-induced diabetic rats: A histopathological and immunohistochemical examination. Int J Neurosci 119, 1155–1169.

95.

Saravia

, Revsin

, Gonzalez

Deniselle MC

, Gonzalez

, Roig

, Lima

, Homo-Delarche

, De Nicola

(2002) Increased astrocyte reactivity in the hippocampus of murine models of type 1 diabetes: The nonobese diabetic (NOD) and streptozotocin-treated mice. Brain Res 957, 345–353.

96.

Hussain

, Mansouri

, Sjöholm

, Patrone

, Darsalia

(2014) Evidence for cortical neuronal loss in male type 2 diabetic Goto-Kakizaki rats. J Alzheimers Dis 41, 551–560.

97.

, Xu

, Wang

, Yu

(2011) Microglial activation during acute cerebral infarction in the presence of diabetes mellitus. Neurol Sci 32, 1075–1079.

98.

Wisniewski

, Wegiel

(1991) Spatial relationships between astrocytes and classical plaque components. Neurobiol Aging 12, 593–600.

99.

Miller

, Streit

(2007) The effects of aging, injury and disease on microglial function a case for cellular senescence. Neuron Glia Biol 3, 245–253.

100.

Streit

, Sammons

, Kuhns

, Sparks

(2004) Dystrophic microglia in the aging human brain. Glia 45, 208–212.

101.

, Yarishkin

, Hwang

, Chun

, Park

, Woo

D H

, Bae

, Kim

, Lee

, Chun

, Park

, Lee

, Hong

, Kim

, Oh

, Park

, Lee

, Yoon

, Kim

, Jeong

, Shim

, Bae

, Cho

, Kowall

, Ryu

, Hwang

, Kim

, Lee

(2014) GABA from reactive astrocytes impairs memory in mouse models of Alzheimer’s disease. Nat Med 20, 886–896.

102.

Kulijewicz-Nawrot

, Verkhratsky

, Chvátal

, Syková

, Rodríguez

(2012) Astrocytic cytoskeletal atrophy in the medial prefrontal cortex of a triple transgenic mouse model of Alzheimer’s disease. J Anat 221, 252–262.

103.

Olabarria

, Noristani

, Verkhratsky

, Rodríguez

(2011) Age-dependent decrease in glutamine synthetase expression in the hippocampal astroglia of the triple transgenic Alzheimer’s disease mouse model: Mechanism for deficient glutamatergic transmission? Mol Neurodegener 6, 55.

104.

Wilcock

, Vitek

, Colton

(2009) Vascular amyloid alters astrocytic water and potassium channels in mouse models and humans with Alzheimer’s disease. Neuroscience 159, 1055–1069.

105.

Sudduth

, Weekman

, Price

, Gooch

, Woolums

, Norris

, Wilcock

(2017) Time-course of glial changes in the hyperhomocysteinemia model of vascular cognitive impairment and dementia (VCID). Neuroscience 341, 42–51.

106.

Saggu

, Schumacher

, Gerich

, Rakers

, Tai

, Delekate

, Petzold

(2016) Astroglial NF-kB contributes to white matter damage and cognitive impairment in a mouse model of vascular dementia. Acta Neuropathol Commun 4, 76.

107.

Liao

, Padera

(2013) Lymphatic function and immune regulation in health and disease. Lymphat Res Biol 11, 136–143.

108.

Iliff

, Wang

, Liao

, Plogg

, Peng

, Gundersen

, Benveniste

, Vates

, Deane

, Goldman

, Nagelhus

, Nedergaard

(2012) A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β . Sci Transl Med 4, 147ra111.

109.

Iliff

, Nedergaard

(2013) Is there a cerebral lymphatic system?, Stroke 44, S93–S95.

110.

Johnston

, Zakharov

, Papaiconomou

, Salmasi

, Armstrong

(2004) Evidence of connections between cerebrospinal fluid and nasal lymphatic vessels in humans, non-human primates and other mammalian species. Cerebrospinal Fluid Res 1, 2.

111.

Murtha

, Yang

, Parsons

, Levi

, Beard

, Spratt

, McLeod

(2014) Cerebrospinal fluid is drained primarily via the spinal canal and olfactory route in young and aged spontaneously hypertensive rats. Fluids Barriers CNS 11, 12.

112.

Jiang

, Zhang

, Ding

, Davoodi-Bojd

, Li

, Sadry

, Nedergaard

, Chopp

, Zhang

(2017) Impairment of the glymphatic system after diabetes. J Cereb Blood Flow Metab 37, 1326–1337.

113.

Moran

, Beare

, Phan

, Bruce

, Callisaya

, Srikanth

(2015) Type 2 diabetes mellitus and biomarkers of neurodegeneration. Neurology 85, 1123–1130.

114.

Peng

, Achariyar

, Li

, Liao

, Mestre

, Hitomi

, Regan

, Kasper

, Peng

, Ding

, Benveniste

, Nedergaard

, Deane

(2016) Suppression of glymphatic fluid transport in a mouse model of Alzheimer’s disease. Neurobiol Dis 93, 215–225.

115.

Wostyn

, Van Dam

, Audenaert

, Killer

, De Deyn

, De Groot

(2015) A new glaucoma hypothesis: A role of glymphatic system dysfunction. Fluids Barriers CNS 12, 16.

116.

Xia

, Yang

, Sun

, Qi

, Li

(2017) Mechanism of depression as a risk factor in the development of Alzheimer’s disease: The function of AQP4 and the glymphatic system. Psychopharmacology (Berl) 234, 365–379.

117.

, Xiao

, Chen

, Huang

, Marshall

, Gao

, Cai

, Wu

, Hu

, Xiao

(2015) Deletion of aquaporin-4 in APP/PS1 mice exacerbates brain Aβ accumulation and memory deficits. Mol Neurodegener 10, 58.

118.

Burfeind

, Murchison

, Westaway

, Simon

, Erten-Lyons

, Kaye

, Quinn

, Iliff

(2017) The effects of noncoding aquaporin-4 single-nucleotide polymorphisms on cognition and functional progression of Alzheimer’s disease. Alzheimers Dement (N Y) 3, 348–359.

119.

Schirinzi

, Di Lazzaro

, Sancesario

, Colona

, Scaricamazza

, Mercuri

, Martorana

, Sancesario

(2017) Levels of amyloid-beta-42 and CSF pressure are directly related in patients with Alzheimer’s disease. J Neural Transm (Vienna) 124, 1621–1625.

120.

Nesse

, Finch

, Nunn

(2017) Does selection for short sleep duration explain human vulnerability to Alzheimer’s disease?, Evol Med Public Health. doi: 10.1093/emph/eow035 .

121.

Yulug

, Hanoglu

, Kilic

(2017) Does sleep disturbance affect the amyloid clearance mechanisms in Alzheimer’s disease? Psychiatry Clin Neurosci 71, 673–677.

122.

Zetterberg

(2017) Review: Tau in biofluids - relation to pathology, imaging and clinical features. Neuropathol Appl Neurobiol 43, 194–199.

123.

Venkat

, Chopp

, Zacharek

, Cui

, Zhang

, Li

, Lu

, Zhang

, Liu

, Chen

(2017) White matter damage and glymphatic dysfunction in a model of vascular dementia in rats with no prior vascular pathologies. Neurobiol Aging 50, 96–106.

124.

Wang

, Ding

, Deng

, Guo

, Wang

, Iliff

, Nedergaard

(2017) Focal solute trapping and global glymphatic pathway impairment in a murine model of multiple microinfarcts. J Neurosci 37, 2870–2877.