The Dual Role of Glutamatergic Neurotransmission in Alzheimer’s Disease: From Pathophysiology to Pharmacotherapy

Alzheimer’s disease (AD) is an age-related dementia and neurodegenerative disorder, characterized by Aβ and tau protein deposition impairing learning, memory and suppressing synaptic plasticity of neurons. Increasing evidence suggests that there is a link between the glucose and glutamate alterations with age that down-regulates glucose utilization reducing glutamate levels in AD patients. Deviations in brain energy metabolism reinforce the development of AD by hampering glutamate levels in the brain. Glutamate is a nonessential amino acid and the major excitatory neurotransmitter synthesized from glucose. Alterations in cerebral glucose and glutamate levels precede the deposition of Aβ plaques. In the brain, over 40% of neuronal synapses are glutamatergic and disturbances in glutamatergic function have been implicated in pathophysiology of AD. Nevertheless, targeting the glutamatergic system seems to be a promising strategy to develop novel, improved therapeutics for AD. Here, we review data supporting the involvement of the glutamatergic system in AD pathophysiology as well as the efficacy of glutamatergic agents in this neurodegenerative disorder. We also discuss exciting new prospects for the development of improved therapeutics for this devastating disorder.

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Prostacyclin Promotes Degenerative Pathology in a Model of Alzheimer’s disease

10.1101/2020.04.15.039842 ◽

2020 ◽

Author(s):

Tasha R. Womack ◽

Craig Vollert ◽

Odochi Nwoko ◽

Monika Schmitt ◽

Sagi Montazari ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Disorder ◽

Amyloid Β ◽

Chronic Neuroinflammation ◽

Model Of Alzheimer’S Disease ◽

Amyloid Accumulation ◽

Prostaglandin H ◽

The Brain

AbstractAlzheimer’s disease (AD) is a progressive neurodegenerative disorder that is the most common cause of dementia in aged populations. A substantial amount of data demonstrates that chronic neuroinflammation can accelerate neurodegenerative pathologies, while epidemiological and experimental evidence suggests that the use of anti-inflammatory agents may be neuroprotective. In AD, chronic neuroinflammation results in the upregulation of cyclooxygenase and increased production of prostaglandin H2, a precursor for many vasoactive prostanoids. While it is well-established that many prostaglandins can modulate the progression of neurodegenerative disorders, the role of prostacyclin (PGI2) in the brain is poorly understood. We have conducted studies to assess the effect of elevated prostacyclin biosynthesis in a mouse model of AD. Upregulated prostacyclin expression significantly worsened multiple measures associated with amyloid disease pathologies. Mice overexpressing both amyloid and PGI2 exhibited impaired learning and memory and increased anxiety-like behavior compared with non-transgenic and PGI2 control mice. PGI2 overexpression accelerated the development of amyloid accumulation in the brain and selectively increased the production of soluble amyloid-β 42. PGI2 damaged the microvasculature through alterations in vascular length and branching; amyloid expression exacerbated these effects. Our findings demonstrate that chronic prostacyclin expression plays a novel and unexpected role that hastens the development of the AD phenotype.

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Role of TREM2 in Alzheimer's Disease and its Consequences on β- Amyloid, Tau and Neurofibrillary Tangles

Current Alzheimer Research ◽

10.2174/1567205016666190903102822 ◽

2020 ◽

Vol 16 (13) ◽

pp. 1216-1229 ◽

Cited By ~ 6

Author(s):

Anurag K. Singh ◽

Gaurav Mishra ◽

Anand Maurya ◽

Rajendra Awasthi ◽

Komal Kumari ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Disorder ◽

Tau Pathology ◽

Functional Roles ◽

Age Related ◽

Β Amyloid ◽

The Impact ◽

Neuronal Stress

: Alzheimer's Disease (AD) is age-related neurodegenerative disorder recognized by a steadily gradual cognitive decline that has devastating personal and socioeconomic implications. Recently, some genetic factors for AD have been identified which attracted wide attention of researchers in different areas of AD biology and possible new therapeutic targets. Alternative forms of triggering receptor expressed on myeloid cells 2 (TREM2) genes are examples of such risk factors, which contribute higher risk for developing AD. Comprehending TREM2 function pledge to provide salient insight into how neuroinflammation contributes to AD pathology. The dearth of microglial TREM2 shepherd to augmented tau pathology is couple with frequent enhancement of activated neuronal stress kinases. The involvement of TREM2 in the regulation of tau-associated innate immune response of the CNS has clearly demonstrated through these findings. However, whether decrease level of TREM2 assists pathology of tau through changed clearance and pathological escalation of tau or through direct contact between microglia and neuron and any alternative possible mechanisms need to examine. This review briefly summarizes distinct functional roles of TREM2 in AD pathology and highlights the TREM2 gene regulation. We have also addressed the impact of TREM2 on β-amyloid plaques and tau pathology in Alzheimer’s disease.

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Conditional genetic deletion of CSF1 receptor in microglia ameliorates the physiopathology of Alzheimer’s disease

10.21203/rs.3.rs-100845/v1 ◽

2020 ◽

Author(s):

Vincent Pons ◽

Pascal Lévesque ◽

Marie-Michèle Plande ◽

Serge Rivest

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Disorder ◽

Innate Immune ◽

Compensatory Mechanism ◽

Knock Out ◽

Genetic Deletion ◽

The Impact ◽

The Brain

Abstract BackgroundAlzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia in the world. Microglia are the innate immune cells of CNS, their proliferation, activation and survival in pathologic and healthy brain have previously been shown to be highly dependent on CSF1R.MethodsHere we investigate the impact of such receptor on AD etiology and microglia. We deleted CSF1R using Cre/Lox system, the knock-out (KO) is restricted to microglia in the APP/PS1 mouse model. We induced the knock-out at 3-month-old, before plaque formation and evaluated both 6 and 8-month-old groups of mice.ResultsOur findings demonstrated that CSF1R KO did not impair microglial survival and proliferation at 6 and 8 months of age in APP cKO compared to their littermate controls groups APPSwe/PS1. We have also shown that cognitive decline is delayed in CSF1R-deleted mice. Ameliorations of AD etiology is associated with a decrease in plaque volume in cortex and hippocampus area. A compensating system seems to take place following the knock-out, since TREM2/β-Catenin and IL-34 expression are significantly increased. Such a compensatory mechanism may promote microglial survival and phagocytosis of Aβ in the brain.ConclusionsOur results provide new insights on the role of CSF1R in microglia and how it interacts with the TREM2/β-Catenin and IL-34 system to clear Aβ and ameliorates the physiopathology of AD.

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The Role of HDL and HDL Mimetic Peptides as Potential Therapeutics for Alzheimer’s Disease

Biomolecules ◽

10.3390/biom10091276 ◽

2020 ◽

Vol 10 (9) ◽

pp. 1276

Author(s):

Dustin Chernick ◽

Rui Zhong ◽

Ling Li

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Large Scale ◽

Neurodegenerative Disorder ◽

Current Evidence ◽

High Density Lipoproteins ◽

Increased Risk ◽

Mimetic Peptides ◽

The Brain

The role of high-density lipoproteins (HDL) in the cardiovascular system has been extensively studied and the cardioprotective effects of HDL are well established. As HDL particles are formed both in the systemic circulation and in the central nervous system, the role of HDL and its associated apolipoproteins in the brain has attracted much research interest in recent years. Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder and the leading cause of dementia worldwide, for which there currently exists no approved disease modifying treatment. Multiple lines of evidence, including a number of large-scale human clinical studies, have shown a robust connection between HDL levels and AD. Low levels of HDL are associated with increased risk and severity of AD, whereas high levels of HDL are correlated with superior cognitive function. Although the mechanisms underlying the protective effects of HDL in the brain are not fully understood, many of the functions of HDL, including reverse lipid/cholesterol transport, anti-inflammation/immune modulation, anti-oxidation, microvessel endothelial protection, and proteopathy modification, are thought to be critical for its beneficial effects. This review describes the current evidence for the role of HDL in AD and the potential of using small peptides mimicking HDL or its associated apolipoproteins (HDL-mimetic peptides) as therapeutics to treat AD.

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Glutamate Metabolism in Mitochondria is Closely Related to Alzheimer’s Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-210595 ◽

2021 ◽

pp. 1-22

Author(s):

Jiayi Song ◽

Xuehan Yang ◽

Ming Zhang ◽

Chunyan Wang ◽

Li Chen

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Central Nervous System ◽

Important Determinant ◽

Glutamate Uptake ◽

Glutamate Metabolism ◽

Metabolic Balance ◽

Excitatory Neurotransmitter ◽

The Brain

Glutamate is the main excitatory neurotransmitter in the brain, and its excitatory neurotoxicity is closely related to the occurrence and development of Alzheimer’s disease. However, increasing evidence shows that in the process of Alzheimer’s disease, glutamate is not only limited to its excitotoxicity as a neurotransmitter but also related to the disorder of its metabolic balance. The balance of glutamate metabolism in the brain is an important determinant of central nervous system health, and the maintenance of this balance is closely related to glutamate uptake, glutamate circulation, intracellular mitochondrial transport, and mitochondrial metabolism. In this paper, we intend to elaborate the key role of mitochondrial glutamate metabolism in the pathogenesis of Alzheimer’s disease and review glutamate metabolism in mitochondria as a potential target in the treatment of Alzheimer’s disease.

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Efficacy and Safety of Ketone Supplementation or Ketogenic Diets for Alzheimer's Disease: A Mini Review

Frontiers in Nutrition ◽

10.3389/fnut.2021.807970 ◽

2022 ◽

Vol 8 ◽

Author(s):

Matthieu Lilamand ◽

François Mouton-Liger ◽

Emmanuelle Di Valentin ◽

Marta Sànchez Ortiz ◽

Claire Paquet

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Disorder ◽

Ketone Bodies ◽

Amyloid Peptide ◽

Nutritional Interventions ◽

Ketogenic Diets ◽

Age Related ◽

Β Amyloid ◽

The Brain

Alzheimer's disease (AD) is the most frequent age-related neurodegenerative disorder, with no curative treatment available so far. Alongside the brain deposition of β-amyloid peptide and hyperphosphorylated tau, neuroinflammation triggered by the innate immune response in the central nervous system, plays a central role in the pathogenesis of AD. Glucose usually represents the main fuel for the brain. Glucose metabolism has been related to neuroinflammation, but also with AD lesions. Hyperglycemia promotes oxidative stress and neurodegeneration. Insulinoresistance (e.g., in type 2 diabetes) or low IGF-1 levels are associated with increased β-amyloid production. However, in the absence of glucose, the brain may use another fuel: ketone bodies (KB) produced by oxidation of fatty acids. Over the last decade, ketogenic interventions i.e., ketogenic diets (KD) with very low carbohydrate intake or ketogenic supplementation (KS) based on medium-chain triglycerides (MCT) consumption, have been studied in AD animal models, as well as in AD patients. These interventional studies reported interesting clinical improvements in animals and decrease in neuroinflammation, β-amyloid and tau accumulation. In clinical studies, KS and KD were associated with better cognition, but also improved brain metabolism and AD biomarkers. This review summarizes the available evidence regarding KS/KD as therapeutic options for individuals with AD. We also discuss the current issues and potential adverse effects associated with these nutritional interventions. Finally, we propose an overview of ongoing and future registered trials in this promising field.

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Administration of anti-ERMAP antibody ameliorates Alzheimer’s disease in mice

Journal of Neuroinflammation ◽

10.1186/s12974-021-02320-x ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Haiyan Liu ◽

Jin Zhao ◽

Yujun Lin ◽

Min Su ◽

Laijun Lai

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

T Cells ◽

T Cell ◽

Cognitive Performance ◽

Neurodegenerative Disorder ◽

Age Related ◽

Macrophage Phagocytosis ◽

B7 Family ◽

The Brain

Abstract Background Alzheimer’s disease (AD) is a devastating age-related neurodegenerative disorder and characterized by progressive loss of memory and cognitive functions, which are associated with amyloid-beta (Aβ) plaques. Immune cells play an important role in the clearance of Aβ deposits. Immune responses are regulated by immune regulators in which the B7 family members play a crucial role. We have recently identified erythroid membrane-associated protein (ERMAP) as a novel B7 family-related immune regulator and shown that ERMAP protein affects T cell and macrophage functions. Methods We produced a monoclonal antibody (mAb) against ERMAP protein and then determined the ability of the mAb to affect cognitive performance and AD pathology in mice. Results We have shown that the anti-ERMAP mAb neutralizes the T cell inhibitory activity of ERMAP and enhances macrophages to phagocytose Aβ in vitro. Administration of the mAb into AD mice improves cognitive performance and reduces Aβ plaque load in the brain. This is related to increased proportion of T cells, especially IFNγ-producing T cells, in the spleen and the choroid plexus (CP), enhanced expression of immune cell trafficking molecules in the CP, and increased migration of monocyte-derived macrophages into the brain. Furthermore, the production of anti-Aβ antibodies in the serum and the macrophage phagocytosis of Aβ are enhanced in the anti-ERMAP mAb-treated AD mice. Conclusions Our results suggest that manipulating the ERMAP pathway has the potential to provide a novel approach to treat AD patients.

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Hypoxia-Induced Neuroinflammation in Alzheimer’s Disease: Potential Neuroprotective Effects of Centella asiatica

Frontiers in Physiology ◽

10.3389/fphys.2021.712317 ◽

2021 ◽

Vol 12 ◽

Author(s):

Aqilah Hambali ◽

Jaya Kumar ◽

Nur Fariesha Md Hashim ◽

Sandra Maniam ◽

Muhammad Zulfadli Mehat ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Therapeutic Agent ◽

Neurodegenerative Disorder ◽

Centella Asiatica ◽

Neuroprotective Effects ◽

Drug Candidates ◽

The Brain ◽

Pro Inflammatory Cytokines

Alzheimer’s disease (AD) is a neurodegenerative disorder that is characterised by the presence of extracellular beta-amyloid fibrillary plaques and intraneuronal neurofibrillary tau tangles in the brain. Recurring failures of drug candidates targeting these pathways have prompted research in AD multifactorial pathogenesis, including the role of neuroinflammation. Triggered by various factors, such as hypoxia, neuroinflammation is strongly linked to AD susceptibility and/or progression to dementia. Chronic hypoxia induces neuroinflammation by activating microglia, the resident immune cells in the brain, along with an increased in reactive oxygen species and pro-inflammatory cytokines, features that are common to many degenerative central nervous system (CNS) disorders. Hence, interests are emerging on therapeutic agents and plant derivatives for AD that target the hypoxia-neuroinflammation pathway. Centella asiatica is one of the natural products reported to show neuroprotective effects in various models of CNS diseases. Here, we review the complex hypoxia-induced neuroinflammation in the pathogenesis of AD and the potential application of Centella asiatica as a therapeutic agent in AD or dementia.

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Conditional Genetic Deletion of CSF1 Receptor in Microglia Ameliorates the Physiopathology of Alzheimer’s Disease

10.21203/rs.3.rs-80698/v1 ◽

2020 ◽

Author(s):

Vincent Pons ◽

Pascal Lévesque ◽

Marie-Michèle Plande ◽

Serge Rivest

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Disorder ◽

Innate Immune ◽

Compensatory Mechanism ◽

Knock Out ◽

Genetic Deletion ◽

The Impact ◽

The Brain

Abstract Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia in the world. Microglia are the innate immune cells of CNS, their proliferation, activation and survival in pathologic and healthy brain have previously been shown to be highly dependent on CSF1R. Methods: Here we investigate the impact of such receptor on AD etiology and microglia. We deleted CSF1R using Cre/Lox system, the knock-out (KO) is restricted to microglia in the APP/PS1 mouse model. We induced the knock-out at 3-month-old, before plaque formation and evaluated both 6 and 8-month-old groups of mice. Results: Our findings demonstrated that CSF1R KO did not impair microglial survival and proliferation at 6 and 8 months of age in APP cKO compared to their littermate controls groups APPSwe/PS1. We have also shown that cognitive decline is delayed in CSF1R-deleted mice. Ameliorations of AD etiology is associated with a decrease in plaque volume in cortex and hippocampus area. A compensating system seems to take place following the knock-out, since TREM2/β-Catenin and IL-34 expression are significantly increased. Such a compensatory mechanism may promote microglial survival and phagocytosis of Aβ in the brain. Conclusions: Our results provide new insights on the role of CSF1R in microglia and how it interacts with the TREM2/β-Catenin and IL-34 system to clear Aβ and ameliorates the physiopathology of AD.

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Western Diet Induces Impairment of Liver-Brain Axis Accelerating Neuroinflammation and Amyloid Pathology in Alzheimer's Disease

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.654509 ◽

2021 ◽

Vol 13 ◽

Author(s):

Angelika Wiȩckowska-Gacek ◽

Anna Mietelska-Porowska ◽

Dominik Chutorański ◽

Małgorzata Wydrych ◽

Jan Długosz ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Disorder ◽

Neurological Diseases ◽

Amyloid Β ◽

Western Diet ◽

Amyloid Pathology ◽

Old Mice ◽

The Brain

Alzheimer's disease (AD) is an aging-dependent, irreversible neurodegenerative disorder and the most common cause of dementia. The prevailing AD hypothesis points to the central role of altered cleavage of amyloid precursor protein (APP) and formation of toxic amyloid-β (Aβ) deposits in the brain. The lack of efficient AD treatments stems from incomplete knowledge on AD causes and environmental risk factors. The role of lifestyle factors, including diet, in neurological diseases is now beginning to attract considerable attention. One of them is western diet (WD), which can lead to many serious diseases that develop with age. The aim of the study was to investigate whether WD-derived systemic disturbances may accelerate the brain neuroinflammation and amyloidogenesis at the early stages of AD development. To verify this hypothesis, transgenic mice expressing human APP with AD-causing mutations (APPswe) were fed with WD from the 3rd month of age. These mice were compared to APPswe mice, in which short-term high-grade inflammation was induced by injection of lipopolysaccharide (LPS) and to untreated APPswe mice. All experimental subgroups of animals were subsequently analyzed at 4-, 8-, and 12-months of age. APPswe mice at 4- and 8-months-old represent earlier pre-plaque stages of AD, while 12-month-old animals represent later stages of AD, with visible amyloid pathology. Already short time of WD feeding induced in 4-month-old animals such brain neuroinflammation events as enhanced astrogliosis, to a level comparable to that induced by the administration of pro-inflammatory LPS, and microglia activation in 8-month-old mice. Also, WD feeding accelerated increased Aβ production, observed already in 8-month-old animals. These brain changes corresponded to diet-induced metabolic disorders, including increased cholesterol level in 4-months of age, and advanced hypercholesterolemia and fatty liver disease in 8-month-old mice. These results indicate that the westernized pattern of nourishment is an important modifiable risk factor of AD development, and that a healthy, balanced, diet may be one of the most efficient AD prevention methods.

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