A Perfect sTORm: The Role of the Mammalian Target of Rapamycin (mTOR) in Cerebrovascular Dysfunction of Alzheimer's Disease: A Mini-Review

Cerebrovascular dysfunction is detected prior to the onset of cognitive and histopathological changes in Alzheimer's disease (AD). Increasing evidence indicates a critical role of cerebrovascular dysfunction in the initiation and progression of AD. Recent studies identified the mechanistic/mammalian target of rapamycin (mTOR) as a critical effector of cerebrovascular dysfunction in AD. mTOR has a key role in the regulation of metabolism, but some mTOR-dependent mechanisms are uniquely specific to the regulation of cerebrovascular function. These include the regulation of cerebral blood flow, blood-brain barrier integrity and maintenance, neurovascular coupling, and cerebrovascular reactivity. This article examines the available evidence for a role of mTOR-driven cerebrovascular dysfunction in the pathogenesis of AD and of vascular cognitive impairment and dementia (VCID) and highlights the therapeutic potential of targeting mTOR and/or specific downstream effectors for vasculoprotection in AD, VCID, and other age-associated neurological diseases with cerebrovascular etiology.

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Exercise training ameliorates cerebrovascular dysfunction in a murine model of Alzheimer’s disease: role of the P2Y2 receptor and endoplasmic reticulum stress

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00129.2020 ◽

2020 ◽

Vol 318 (6) ◽

pp. H1559-H1569

Author(s):

Junyoung Hong ◽

Soon-Gook Hong ◽

Jonghae Lee ◽

Joon-Young Park ◽

Jason L. Eriksen ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Exercise Training ◽

Er Stress ◽

The Novel ◽

P2y2 Receptor ◽

Model Of Alzheimer’S Disease ◽

Cerebrovascular Function ◽

Cerebrovascular Dysfunction

A limited study has investigated whether exercise training can improve cerebrovascular function in Alzheimer's disease. The novel findings of the study are that exercise training improves cerebrovascular dysfunction through enhancing P2Y2 receptor-mediated eNOS signaling and reducing ER stress-associated pathways in AD. These data suggest that exercise training, which regulates P2Y2 receptor and ER stress in AD brain, is a potential therapeutic strategy for Alzheimer's disease.

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Decoding the Inter-relationship between Sleep Disorders and Alzheimer’s disease Pathogenesis

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527319666200903161249 ◽

2020 ◽

Vol 19 ◽

Author(s):

Zeba Mueed ◽

Pankaj Kumar Rai ◽

Mohammad A. Kamal ◽

Nitesh Kumar Poddar

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Sleep Disorders ◽

Sleep Disturbances ◽

Mammalian Target Of Rapamycin ◽

Light Therapy ◽

Paired Helical Filaments ◽

Bidirectional Relationship ◽

Causative Agents

Alzheimer’s disease (AD), characterized by abnormally phosphorylated tau, paired helical filaments (PHFs), neurofibrillary tangles (NFTs), deregulated mammalian target of rapamycin (mTOR), Aβ deposits, is a multifactorial disease with sleep disorders being one of the causative agents. Therefore, we have reviewed the literature and have tried to decode the existence of positive feedback, reciprocal and a bidirectional relationship allying between sleep disturbances and AD. Much light has been thrown on the role of tau pathology and amyloid pathology in sleep pathology and its association with AD pathology. We have also discussed the role of melatonin in regulating sleep disorders and AD. The neuroprotective action of melatonin via inhibiting tau hyperphosphorylation and Aβ deposition has also been pondered upon. Moreover, astrocytes involvement in aggravating AD has also been highlighted in this review. Several therapeutic approaches aimed at improving both sleep disorders and AD have been duly discussed such as administration of antidepressants and antihistamines, immunotherapy, metal chelators, melatonin supplementation, light therapy and physical activity. Despite consistent efforts, the complete etiology concerning sleep disorder and AD is still unclear. Therefore, further research is needed to unravel the mechanism involved and also to develop strategies that may help in obstructing AD in its preclinical stage.

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The APOE ε4/ε4 Genotype Potentiates Vascular Fibrin(Ogen) Deposition in Amyloid-Laden Vessels in the Brains of Alzheimer's Disease Patients

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2013.76 ◽

2013 ◽

Vol 33 (8) ◽

pp. 1251-1258 ◽

Cited By ~ 71

Author(s):

Karin Hultman ◽

Sidney Strickland ◽

Erin H Norris

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Critical Role ◽

Apoe Genotype ◽

Postmortem Brain ◽

Amyloid Angiopathy ◽

Apoe Ε4 ◽

Cerebrovascular Dysfunction ◽

Postmortem Brain Tissue ◽

Clotting Protein

Evidence indicates a critical role for cerebrovascular dysfunction in Alzheimer's disease (AD) pathophysiology. We have shown that fibrin(ogen), the principal blood-clotting protein, is deposited in the AD neurovasculature and interacts with beta-amyloid (Ab), resulting in increased formation of blood clots. As apolipoprotein E (ApoE), a lipid-transporting protein with three human isoforms (E2, E3, and E4), also binds to Aβ, we hypothesized that ApoE and fibrin(ogen) may have a combined effect on the vascular pathophysiology in AD. We assessed whether APOE genotype differentially influences vascular fibrin(ogen) deposition in postmortem brain tissue using immunohistochemistry. An increased deposition of fibrin(ogen) was observed in AD cases compared with non-demented controls, and there was a strong correlation between cerebral amyloid angiopathy (CAA) severity and fibrin(ogen) deposition. Moreover, brains from AD cases homozygous for APOE ε4 showed increased deposition of fibrin(ogen), specifically in CAA- and oligomeric Aβ-positive vessels compared with AD APOE ε2 and ε3 allele carriers, an effect that was not directly linked to CAA severity and cerebrovascular atherosclerosis. These data further support a role for fibrin(ogen) in AD pathophysiology and link the APOE ε4/ε4 genotype with increased thrombosis and/or impaired fibrinolysis in the human AD brain.

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Alzheimer's disease and periodontitis - an elusive link

Revista da Associação Médica Brasileira ◽

10.1590/1806-9282.60.02.015 ◽

2014 ◽

Vol 60 (2) ◽

pp. 173-180 ◽

Cited By ~ 16

Author(s):

Abhijit N. Gurav

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Inflammatory Cytokines ◽

Critical Role ◽

Anaerobic Bacteria ◽

Systemic Infection ◽

Low Grade ◽

Inflammatory Status ◽

Pro Inflammatory Cytokines

Alzheimer's disease is the preeminent cause and commonest form of dementia. It is clinically characterized by a progressive descent in the cognitive function, which commences with deterioration in memory. The exact etiology and pathophysiologic mechanism of Alzheimer's disease is still not fully understood. However it is hypothesized that, neuroinflammation plays a critical role in the pathogenesis of Alzheimer's disease. Alzheimer's disease is marked by salient inflammatory features, characterized by microglial activation and escalation in the levels of pro-inflammatory cytokines in the affected regions. Studies have suggested a probable role of systemic infection conducing to inflammatory status of the central nervous system. Periodontitis is common oral infection affiliated with gram negative, anaerobic bacteria, capable of orchestrating localized and systemic infections in the subject. Periodontitis is known to elicit a "low grade systemic inflammation" by release of pro-inflammatory cytokines into systemic circulation. This review elucidates the possible role of periodontitis in exacerbating Alzheimer's disease. Periodontitis may bear the potential to affect the onset and progression of Alzheimer's disease. Periodontitis shares the two important features of Alzheimer's disease namely oxidative damage and inflammation, which are exhibited in the brain pathology of Alzheimer's disease. Periodontitis can be treated and hence it is a modifiable risk factor for Alzheimer's disease.

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Restored glial glutamate transporter EAAT2 function as a potential therapeutic approach for Alzheimer’s disease

Journal of Experimental Medicine ◽

10.1084/jem.20140413 ◽

2015 ◽

Vol 212 (3) ◽

pp. 319-332 ◽

Cited By ~ 58

Author(s):

Kou Takahashi ◽

Qiongman Kong ◽

Yuchen Lin ◽

Nathan Stouffer ◽

Delanie A. Schulte ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Functions ◽

Protein Function ◽

Therapeutic Potential ◽

Critical Role ◽

Glutamate Transporter ◽

Glial Glutamate Transporter ◽

Disease Modifier ◽

And Function

Glutamatergic systems play a critical role in cognitive functions and are known to be defective in Alzheimer’s disease (AD) patients. Previous literature has indicated that glial glutamate transporter EAAT2 plays an essential role in cognitive functions and that loss of EAAT2 protein is a common phenomenon observed in AD patients and animal models. In the current study, we investigated whether restored EAAT2 protein and function could benefit cognitive functions and pathology in APPSw,Ind mice, an animal model of AD. A transgenic mouse approach via crossing EAAT2 transgenic mice with APPSw,Ind. mice and a pharmacological approach using a novel EAAT2 translational activator, LDN/OSU-0212320, were conducted. Findings from both approaches demonstrated that restored EAAT2 protein function significantly improved cognitive functions, restored synaptic integrity, and reduced amyloid plaques. Importantly, the observed benefits were sustained one month after compound treatment cessation, suggesting that EAAT2 is a potential disease modifier with therapeutic potential for AD.

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Anti-autophagic and anti-apoptotic effects of memantine in a SH-SY5Y cell model of Alzheimer's disease via mammalian target of rapamycin-dependent and -independent pathways

Molecular Medicine Reports ◽

10.3892/mmr.2015.4382 ◽

2015 ◽

Vol 12 (5) ◽

pp. 7615-7622 ◽

Cited By ~ 10

Author(s):

GUIJUN SONG ◽

YU LI ◽

LULU LIN ◽

YUNPENG CAO

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cell Model ◽

Mammalian Target Of Rapamycin ◽

Target Of Rapamycin ◽

Model Of Alzheimer’S Disease ◽

Apoptotic Effects

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Discovery of a dual-action small molecule that improves neuropathological features of Alzheimer’s disease mice

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2115082119 ◽

2022 ◽

Vol 119 (3) ◽

pp. e2115082119

Author(s):

Min Hee Park ◽

Kang Ho Park ◽

Byung Jo Choi ◽

Wan Hui Han ◽

Hee Ji Yoon ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Therapeutic Potential ◽

Memory Function ◽

Selective Inhibition ◽

Acid Sphingomyelinase ◽

Hippocampal Neurogenesis ◽

Ghrelin Receptor ◽

Dual Action

Alzheimer’s disease (AD) is characterized by complex, multifactorial neuropathology, suggesting that small molecules targeting multiple neuropathological factors are likely required to successfully impact clinical progression. Acid sphingomyelinase (ASM) activation has been recognized as an important contributor to these neuropathological features in AD, leading to the concept of using ASM inhibitors for the treatment of this disorder. Here we report the identification of KARI 201, a direct ASM inhibitor evaluated for AD treatment. KARI 201 exhibits highly selective inhibition effects on ASM, with excellent pharmacokinetic properties, especially with regard to brain distribution. Unexpectedly, we found another role of KARI 201 as a ghrelin receptor agonist, which also has therapeutic potential for AD treatment. This dual role of KARI 201 in neurons efficiently rescued neuropathological features in AD mice, including amyloid beta deposition, autophagy dysfunction, neuroinflammation, synaptic loss, and decreased hippocampal neurogenesis and synaptic plasticity, leading to an improvement in memory function. Our data highlight the possibility of potential clinical application of KARI 201 as an innovative and multifaceted drug for AD treatment.

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Microglial ApoD Induced NLRC4 Inflammasome Activation Promotes Alzheimer’s Disease Progression

10.21203/rs.3.rs-558819/v1 ◽

2021 ◽

Author(s):

Yaliang Yu ◽

Jianzhou Lv ◽

Dan Ma ◽

Ya Han ◽

Yaheng Zhang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Critical Role ◽

Microglia Activation ◽

Inflammatory Factors ◽

Inflammasome Activation ◽

Cellular Interactions ◽

Brain Functions ◽

Chronic Neuroinflammation

Abstract Alzheimer’s disease (AD) is a progressive neurodegenerative disease with no effective therapies. It’s well-known that chronic neuroinflammation plays a critical role in the onset and progression of AD. Proper neuronal-microglial interactions are essential for brain functions. However, as the main existence of immune cells, determining the role of microglia in Alzheimer’s neuroinflammation and the associated molecular basis has been challenging. Herein, the inflammatory factors in the sera of AD patients were detected and the association with microglia activation was analyzed. The mechanism regarding the microglial inflammation was investigated. The IL6 and TNF-α were found to be significantly increased in the AD stage. Further analysis revealed microglia were extensively activated in AD cerebra releasing mounts of cytokines to impair the neural stem cells (NSCs) function. Moreover, ApoD induced NLRC4 inflammasome was activated in microglia, which gave rise to the proinflammatory phenotype. Targeting the microglial ApoD promoted NSCs self-renewal and inhibited neuron apoptosis. These findings demonstrate the critical role of ApoD in microglial inflammasome activation, and for the first time reveal that microglia-induced inflammation suppresses neuronal proliferation. Our studies establish the cellular basis for microglia activation in AD progression, and shed lights on cellular interactions important for AD treatment.

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New Insights on the Role of Manganese in Alzheimer’s Disease and Parkinson’s Disease

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph16193546 ◽

2019 ◽

Vol 16 (19) ◽

pp. 3546 ◽

Cited By ~ 10

Author(s):

Airton Cunha Martins ◽

Patricia Morcillo ◽

Omamuyovwi Meashack Ijomone ◽

Vivek Venkataramani ◽

Fiona Edith Harrison ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Parkinson’S Disease ◽

Alzheimer's Disease ◽

Parkinson's Disease ◽

Critical Role ◽

Essential Trace Element ◽

Neuronal Function ◽

Therapy Options ◽

Physiological Processes

Manganese (Mn) is an essential trace element that is naturally found in the environment and is necessary as a cofactor for many enzymes and is important in several physiological processes that support development, growth, and neuronal function. However, overexposure to Mn may induce neurotoxicity and may contribute to the development of Alzheimer’s disease (AD) and Parkinson’s disease (PD). The present review aims to provide new insights into the involvement of Mn in the etiology of AD and PD. Here, we discuss the critical role of Mn in the etiology of these disorders and provide a summary of the proposed mechanisms underlying Mn-induced neurodegeneration. In addition, we review some new therapy options for AD and PD related to Mn overload.

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