Long genes are more frequently affected by somatic mutations and show reduced expression in Alzheimer's disease: Implications for disease etiology

Alzheimer’s disease, a highly prevalent form of dementia, targets neuron function beginning from the hippocampal region and expanding outwards. Alzheimer’s disease is caused by elevated levels of heavy metals, such as lead, zinc, and copper. Copper is found in many areas of daily life, raising a concern as to how this metal and Alzheimer’s disease are related. Previous studies have not identified the common pathways between excess copper and Alzheimer’s disease etiology. Our review corroborates that both copper and Alzheimer’s disease target the hippocampus, cerebral cortex, cerebellum, and brainstem, affecting motor skills and critical thinking. Additionally, Aβ plaque formation was analyzed beginning from synthesis at the APP parent protein site until Aβ plaque formation was completed. Structural changes were also noted. Further analysis revealed a relationship between amyloid-beta plaques and copper ion concentration. As copper ion levels increased, it bound to the Aβ monomer, expediting the plaque formation process, and furthering neurodegeneration. These conclusions can be utilized in the medical community to further research on the etiology of Alzheimer’s disease and its relationships to copper and other metal-induced neurotoxicity.

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The Alzheimer’s disease-associated protective Plcγ2-P522R variant promotes immune functions

Molecular Neurodegeneration ◽

10.1186/s13024-020-00402-7 ◽

2020 ◽

Vol 15 (1) ◽

Author(s):

Mari Takalo ◽

Rebekka Wittrahm ◽

Benedikt Wefers ◽

Samira Parhizkar ◽

Kimmo Jokivarsi ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Immune Cell ◽

Therapeutic Option ◽

Immune Functions ◽

Disease Etiology ◽

Cell Functions ◽

Bv2 Microglia ◽

Brain Mrna ◽

Protective Variant

Abstract Background Microglia-specific genetic variants are enriched in several neurodegenerative diseases, including Alzheimer’s disease (AD), implicating a central role for alterations of the innate immune system in the disease etiology. A rare coding variant in the PLCG2 gene (rs72824905, p.P522R) expressed in myeloid lineage cells was recently identified and shown to reduce the risk for AD. Methods To assess the role of the protective variant in the context of immune cell functions, we generated a Plcγ2-P522R knock-in (KI) mouse model using CRISPR/Cas9 gene editing. Results Functional analyses of macrophages derived from homozygous KI mice and wild type (WT) littermates revealed that the P522R variant potentiates the primary function of Plcγ2 as a Pip2-metabolizing enzyme. This was associated with improved survival and increased acute inflammatory response of the KI macrophages. Enhanced phagocytosis was observed in mouse BV2 microglia-like cells overexpressing human PLCγ2-P522R, but not in PLCγ2-WT expressing cells. Immunohistochemical analyses did not reveal changes in the number or morphology of microglia in the cortex of Plcγ2-P522R KI mice. However, the brain mRNA signature together with microglia-related PET imaging suggested enhanced microglial functions in Plcγ2-P522R KI mice. Conclusion The AD-associated protective Plcγ2-P522R variant promotes protective functions associated with TREM2 signaling. Our findings provide further support for the idea that pharmacological modulation of microglia via TREM2-PLCγ2 pathway-dependent stimulation may be a novel therapeutic option for the treatment of AD.

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Detection of prospective memory deficits in mild cognitive impairment of suspected Alzheimer’s disease etiology using a novel event-based prospective memory task

Journal of the International Neuropsychological Society ◽

10.1017/s1355617708090127 ◽

2009 ◽

Vol 15 (1) ◽

pp. 154-159 ◽

Cited By ~ 50

Author(s):

ALBERTO BLANCO-CAMPAL ◽

ROBERT F. COEN ◽

BRIAN A. LAWLOR ◽

JOSEPH B. WALSH ◽

TERESA E. BURKE

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Prospective Memory ◽

Small Sample ◽

Cutoff Score ◽

Convenience Sample ◽

Disease Etiology ◽

Event Based

AbstractWe investigated the relative discriminatory efficacy of an event-based prospective memory (PM) task, in which specificity of the instructions and perceptual salience of the PM cue were manipulated, compared with two widely used retrospective memory (RM) tests (Rivermead Paragraph Recall Test and CERAD-Word List Test), when detecting mild cognitive impairment of suspected Alzheimer’s disease etiology (MCI-AD) (N = 19) from normal controls (NC) (N = 21). Statistical analyses showed high discriminatory capacity of the PM task for detecting MCI-AD. The Non-Specific-Non-Salient condition proved particularly useful in detecting MCI-AD, possibly reflecting the difficulty of the task, requiring more strategic attentional resources to monitor for the PM cue. With a cutoff score of <4/10, the Non-Specific-Non-Salient condition achieved a sensitivity = 84%, and a specificity = 95%, superior to the most discriminative RM test used (CERAD-Total Learning: sensitivity = 83%; specificity = 76%). Results suggest that PM is an early sign of memory failure in MCI-AD and may be a more pronounced deficit than retrospective failure, probably reflecting the greater self-initiated retrieval demands involved in the PM task used. Limitations include the relatively small sample size, and the use of a convenience sample (i.e. memory clinic attenders and healthy active volunteers), reducing the generalizability of the results, which should be regarded as preliminary. (JINS, 2009, 15, 154–159.)

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Human Leukocyte Antigens: The missing link in Alzheimer’s disease etiology

10.32907/ro-120-150153 ◽

2021 ◽

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Human Leukocyte ◽

Human Leukocyte Antigens ◽

Disease Etiology ◽

Missing Link ◽

Leukocyte Antigens

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From reaction kinetics to dementia: A simple dimer model of Alzheimer’s disease etiology

PLoS Computational Biology ◽

10.1371/journal.pcbi.1009114 ◽

2021 ◽

Vol 17 (7) ◽

pp. e1009114

Author(s):

Michael R. Lindstrom ◽

Manuel B. Chavez ◽

Elijah A. Gross-Sable ◽

Eric Y. Hayden ◽

David B. Teplow

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neuronal Degeneration ◽

Theoretical Calculations ◽

Disease Incidence ◽

Current Model ◽

Protein A ◽

Science Data ◽

Disease Etiology ◽

Model Of Alzheimer’S Disease

Oligomers of the amyloid β-protein (Aβ) have been implicated in the pathogenesis of Alzheimer’s disease (AD) through their toxicity towards neurons. Understanding the process of oligomerization may contribute to the development of therapeutic agents, but this has been difficult due to the complexity of oligomerization and the metastability of the oligomers thus formed. To understand the kinetics of oligomer formation, and how that relates to the progression of AD, we developed models of the oligomerization process. Here, we use experimental data from cell viability assays and proxies for rate constants involved in monomer-dimer-trimer kinetics to develop a simple mathematical model linking Aβ assembly to oligomer-induced neuronal degeneration. This model recapitulates the rapid growth of disease incidence with age. It does so through incorporation of age-dependent changes in rates of Aβ monomer production and elimination. The model also describes clinical progression in genetic forms of AD (e.g., Down’s syndrome), changes in hippocampal volume, AD risk after traumatic brain injury, and spatial spreading of the disease due to foci in which Aβ production is elevated. Continued incorporation of clinical and basic science data into the current model will make it an increasingly relevant model system for doing theoretical calculations that are not feasible in biological systems. In addition, terms in the model that have particularly large effects are likely to be especially useful therapeutic targets.

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Transcriptional dysregulation study reveals a core network involving the genesis for Alzheimer’s disease

10.1101/240002 ◽

2017 ◽

Author(s):

Guofeng Meng ◽

Hongkang Mei

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Synaptic Function ◽

Core Network ◽

Disease Etiology ◽

Transcriptional Dysregulation ◽

Disease States ◽

Human And Mouse

AbstractBackgroundThe pathogenesis of Alzheimer’s disease is associated with dysregulation at different levels from transcriptome to cellular functioning. Such complexity necessitates investigations of disease etiology to be carried out considering multiple aspects of the disease and the use of independent strategies. The established works more emphasized on the structural organization of gene regulatory network while neglecting the internal regulation changes.MethodsApplying a strategy different from popularly used co-expression network analysis, this study investigated the transcriptional dysregulations during the transition from normal to disease states.Results97 genes were predicted as dysregulated genes, which were also associated with clinical outcomes of Alzheimer’s disease. Both the co-expression and differential co-expression analysis suggested these genes to be interconnected as a core network and that their regulations were strengthened during the transition to disease states. Functional studies suggested the dysregulated genes to be associated with aging and synaptic function. Further, we checked the evolutionary conservation of the gene co-expression and found that human and mouse brain might have divergent transcriptional co-regulation even when they had conserved gene expression profiles.ConclusionOverall, our study reveals a profile of transcriptional dysregulation in the genesis of Alzheimer’s disease by forming a core network with altered regulation; the core network is associated with Alzheimer’s diseases by affecting the aging and synaptic functions related genes; the gene regulation in brain may not be conservative between human and mouse.

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Age-Associated Epigenetic Alterations, Somatic Mutations, and Their Crosstalk in Alzheimer’s Disease

Innovation in Aging ◽

10.1093/geroni/igab046.2404 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. 636-637

Author(s):

Yaroslav Markov ◽

Kyra Thrush ◽

Morgan Levine

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Risk Factor ◽

Somatic Mutations ◽

Brain Regions ◽

Major Risk Factor ◽

Postmortem Brain ◽

Biological Aging ◽

Learning Approaches ◽

Age Related

Abstract Aging is the major risk factor for Alzheimer’s Disease (AD), and as life expectancy increases, neurodegeneration will continue to afflict an ever-increasing proportion of the population. While numerous theories are attempting to explain the drivers behind AD pathology, what unites them is the observation that AD is reliably associated with a progressive buildup of age-related molecular changes. Because of the varying clinical presentations of AD in patients with similar genetic backgrounds, it has been postulated that epigenetics may be implicated in its etiology. Building on our prior work showing that AD pathology is linked to alterations in age-related DNA CpG methylation (DNAme) across various brain regions, we use state-of-the-art machine learning approaches to identify patterns of molecular damage in postmortem brain samples. We show that alterations in DNAme are associated with accelerated biological aging, AD, and the APOE e4 genotype, which is a major risk factor for AD. We also demonstrate that these associations are present in the PFC but not cerebellum -- in line with the current understanding of AD progression in the brain. Finally, we perform whole-exome sequencing and protein mass spectrometry on the same brain samples to test our hypothesis as to whether AD-associated alterations of DNAme are linked with the accumulation of somatic mutations that affect the structural and binding properties of protein epigenetic regulators.

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