Critical role of intraneuronal Aβ in Alzheimer's disease: Technical challenges in studying intracellular Aβ

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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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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Faculty Opinions recommendation of Critical role of soluble amyloid-β for early hippocampal hyperactivity in a mouse model of Alzheimer's disease.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.716847810.792152806 ◽

2012 ◽

Author(s):

Elizabeth Fisher ◽

Olivia Sheppard

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Critical Role ◽

Amyloid Β ◽

Model Of Alzheimer’S Disease

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May “Mitochondrial Eve” and Mitochondrial Haplogroups Play a Role in Neurodegeneration and Alzheimer's Disease?

International Journal of Alzheimer s Disease ◽

10.4061/2011/709061 ◽

2011 ◽

Vol 2011 ◽

pp. 1-11 ◽

Cited By ~ 4

Author(s):

Elena Caldarazzo Ienco ◽

Costanza Simoncini ◽

Daniele Orsucci ◽

Loredana Petrucci ◽

Massimiliano Filosto ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Critical Role ◽

Protective Role ◽

Oxygen Species ◽

Mitochondrial Haplogroups ◽

Normal Ageing ◽

Apoptotic Pathways ◽

Mitochondrial Eve

Mitochondria, the powerhouse of the cell, play a critical role in several metabolic processes and apoptotic pathways. Multiple evidences suggest that mitochondria may be crucial in ageing-related neurodegenerative diseases. Moreover, mitochondrial haplogroups have been linked to multiple area of medicine, from normal ageing to diseases, including neurodegeneration. Polymorphisms within the mitochondrial genome might lead to impaired energy generation and to increased amount of reactive oxygen species, having either susceptibility or protective role in several diseases. Here, we highlight the role of the mitochondrial haplogroups in the pathogenetic cascade leading to diseases, with special attention to Alzheimer's disease.

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Inhibition of microRNA-155 Alleviates Cognitive Impairment in Alzheimer’s Disease and Involvement of Neuroinflammation

Current Alzheimer Research ◽

10.2174/1567205016666190503145207 ◽

2019 ◽

Vol 16 (6) ◽

pp. 473-482 ◽

Cited By ~ 7

Author(s):

Dandan Liu ◽

Dandan Zhao ◽

Yingkai Zhao ◽

Yan Wang ◽

Yong Zhao ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Functions ◽

Spatial Working Memory ◽

Critical Role ◽

Learning Performance ◽

Intracerebroventricular Infusion ◽

Tnf Α ◽

Current Report

Background: Neuroinflammation has important effects on cognitive functions in the pathophysiological process of Alzheimer’s Disease (AD). In the current report, we determined the effects of microRNA-155 (miR-155) on the levels of IL-1β, IL-6 and TNF-α, and their respective receptors in the hippocampus using a rat model of AD. Methods: Real-time RT-PCR, ELISA and western blot analysis were used to examine the miR-155, PICs and PIC receptors. The Morris water maze and spatial working memory tests were used to assess cognitive functions. Results: miR-155 was increased in the hippocampus of AD rats, accompanied by amplification of IL-1β, IL-6 and TNF-α. Intracerebroventricular infusion of miR-155 inhibitor, but not its scramble attenuated the increases of IL-1β, IL-6 and TNF-α and upregulation of their receptors. MiR-155 inhibitor also attenuated upregulation of apoptotic Caspase-3 in the hippocampus of AD rats. Notably, inhibition of miR- 155 or PIC receptors largely recovered the impaired learning performance in AD rat. Conclusion: We showed the critical role of miR-155 in regulating the memory impairment in AD rats likely via engagement of neuroinflammatory mechanisms, suggesting that miR-155 and its signaling molecules may present prospects in preventing and/or improving the development of the impaired cognitive functions in AD.

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Critical role of methionine-722 in the stimulation of human brain G-proteins and neurotoxicity induced by London familial Alzheimer’s disease (FAD) mutated V717G-APP714–723

Neuroscience ◽

10.1016/j.neuroscience.2006.10.007 ◽

2007 ◽

Vol 144 (2) ◽

pp. 571-578 ◽

Cited By ~ 4

Author(s):

K. Reis ◽

A. Zharkovsky ◽

N. Bogdanovic ◽

E. Karelson ◽

T. Land

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Human Brain ◽

G Proteins ◽

Critical Role ◽

Familial Alzheimer’S Disease ◽

Familial Alzheimer's Disease ◽

Stimulation Of

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The MS4A gene cluster is a key modulator of soluble TREM2 and Alzheimer’s disease risk

Science Translational Medicine ◽

10.1126/scitranslmed.aau2291 ◽

2019 ◽

Vol 11 (505) ◽

pp. eaau2291 ◽

Cited By ~ 30

Author(s):

Yuetiva Deming ◽

Fabia Filipello ◽

Francesca Cignarella ◽

Claudia Cantoni ◽

Simon Hsu ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Genome Wide Association Study ◽

Disease Risk ◽

Critical Role ◽

Age At Onset ◽

Mechanistic Explanation ◽

Genetic Modifiers ◽

A Genome

Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in cerebrospinal fluid (CSF) has been associated with Alzheimer’s disease (AD). TREM2 plays a critical role in microglial activation, survival, and phagocytosis; however, the pathophysiological role of sTREM2 in AD is not well understood. Understanding the role of sTREM2 in AD may reveal new pathological mechanisms and lead to the identification of therapeutic targets. We performed a genome-wide association study (GWAS) to identify genetic modifiers of CSF sTREM2 obtained from the Alzheimer’s Disease Neuroimaging Initiative. Common variants in the membrane-spanning 4-domains subfamily A (MS4A) gene region were associated with CSF sTREM2 concentrations (rs1582763; P = 1.15 × 10−15); this was replicated in independent datasets. The variants associated with increased CSF sTREM2 concentrations were associated with reduced AD risk and delayed age at onset of disease. The single-nucleotide polymorphism rs1582763 modified expression of the MS4A4A and MS4A6A genes in multiple tissues, suggesting that one or both of these genes are important for modulating sTREM2 production. Using human macrophages as a proxy for microglia, we found that MS4A4A and TREM2 colocalized on lipid rafts at the plasma membrane, that sTREM2 increased with MS4A4A overexpression, and that silencing of MS4A4A reduced sTREM2 production. These genetic, molecular, and cellular findings suggest that MS4A4A modulates sTREM2. These findings also provide a mechanistic explanation for the original GWAS signal in the MS4A locus for AD risk and indicate that TREM2 may be involved in AD pathogenesis not only in TREM2 risk-variant carriers but also in those with sporadic disease.

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Neuronal ROS-Induced Glial Lipid Droplet Formation is Altered by Loss of Alzheimer’s Disease-associated Genes

10.1101/2021.03.03.433580 ◽

2021 ◽

Author(s):

Matthew J. Moulton ◽

Scott Barish ◽

Isha Ralhan ◽

Jinlan Chang ◽

Lindsey D. Goodman ◽

...

Keyword(s):

Risk Factors ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Lipid Droplet ◽

Critical Role ◽

Lipid Transfer ◽

Lipid Droplet Formation ◽

Apoe Receptor ◽

Disease Associated Genes

SummaryA growing list of Alzheimer’s disease (AD) genetic risk factors is being identified, but the contribution of these genetic mutations to disease remains largely unknown. Accumulating data support a role of lipid dysregulation and excessive ROS in the etiology of AD. Here, we identified cell-specific roles for eight AD risk-associated genes in ROS-induced glial lipid droplet (LD) formation. We demonstrate that ROS-induced glial LD formation requires two ABCA transporters (ABCA1 and ABCA7) in neurons, the APOE receptor (LRP1), endocytic genes (PICALM, CD2AP, and AP2A2) in glia, and retromer genes (VPS26 and VPS35) in both neurons and glia. Moreover, ROS strongly enhances Aβ42-toxicity in flies and Aβ42-plaque formation in mice. Finally, an ABCA1-activating peptide restores glial LD formation in the APOE4-associated loss of LD. This study places AD risk factors in a neuron-to-glia lipid transfer pathway with a critical role in protecting neurons from ROS-induced toxicity.

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