scholarly journals Altered synaptic ingestion by human microglia in Alzheimer’s disease

2019 ◽  
Author(s):  
Makis Tzioras ◽  
Michael J.D. Daniels ◽  
Declan King ◽  
Karla Popovic ◽  
Rebecca K. Holloway ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Human Brain ◽  
Mouse Models ◽  
Disease Risk ◽  
Synaptic Proteins ◽  
Postmortem Brain ◽  
Human Microglia ◽  
Human Postmortem Brain ◽  
Synapse Loss

AbstractSynapse loss correlates strongly with cognitive decline in Alzheimer’s disease, but the mechanisms underpinning this phenomenon remain unclear. Recent evidence from mouse models points to microglial cells as mediators of synapse removal, and human genetic evidence implicates microglia in disease risk. Here we demonstrate that microglia from human postmortem brain contain synaptic proteins and that greater amounts are observed in microglia from Alzheimer’s compared to non-diseased brain tissue. Further, we observe that primary human adult microglia phagocytose synapses isolated from human brain, and that AD brain-derived synapses are phagocytosed more rapidly and abundantly than controls. Together, these data show that synapses in the human AD brain are more prone to ingestion by microglia. Our findings provide evidence from human tissue implicating altered microglial-mediated synaptic uptake in AD pathobiology.One Sentence SummaryAD alters synapse ingestion by microglia

The Correlations between Postmortem Brain Pathologies and Cognitive Dysfunction in Aging and Alzheimer's Disease

2018 ◽  
Vol 15 (5) ◽  
pp. 462-473 ◽  
Author(s):  
Wen-Ying Qiu ◽  
Qian Yang ◽  
Wanying Zhang ◽  
Naili Wang ◽  
Di Zhang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Human Brain ◽  
Amyloid Β ◽  
Cognitive Status ◽  
Postmortem Brain ◽  
Braak Stage ◽  
Brain Bank ◽  
General Linear Multivariate Model ◽  
Human Brains

Background: The pathological diagnostic criteria for Alzheimer's disease (AD) updated by the National Institute on Aging-Alzheimer's Association (NIA-AA) in 2012 has been widely adopted, but the clinicopathological relevance remained obscure in Chinese population. Objective: This study aims to investigate the correlations between the antemortem clinical cognitive performances and the postmortem neuropathological changes in the aging and AD brains collected in a human brain bank in China. Method: A total of 52 human brains with antemortem cognitive status information [Everyday Cognition (ECog)] were collected through the willed donation program by CAMS/PUMC Human Brain Bank. Pathological changes were evaluated with the “ABC” score following the guidelines of NIA-AA. The clinicopathological relationship was analyzed with correlation analysis and general linear multivariate model. Results: The general ABC score has a significant correlation with global ECog score (r=0.37, p=0.014) and most of ECog domains. The CERAD score of neuritic plaques (C score) has a significant correlation with global ECog score (r=0.40, p=0.007) and the majority of ECog domains, such as memory (r=0.50, p=0.001), language (r=0.45, p=0.002), visuospatial functions (r=0.31, p=0.040), planning (r=0.35, p=0.021) and organization (r=0.39, p=0.010). The Braak stage of neurofibrillary tangles (NFTs) (B score) has a moderate correlation with memory (r=0.32, p=0.035). The Thal phases of amyloid-β (Aβ) deposits (A score) present no significant correlation with any of ECog domains. Conclusion: In this study, we verified the correlation of postmortem C and B scores, but not the A score with cognition performance in a collection of samples from the Chinese human brain bank.

scholarly journals Genetics of the human microglia regulome refines Alzheimer's disease risk loci

2021 ◽  
Author(s):  
Roman Kosoy ◽  
John Fullard ◽  
Biao Zeng ◽  
Jaroslav Bendl ◽  
Pengfei Dong ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Regulatory Networks ◽  
Disease Risk ◽  
Single Gene ◽  
Critical Role ◽  
Chromatin Accessibility ◽  
Human Microglia ◽  
Mapping Analysis ◽  
Regulatory Landscape

Microglia are brain resident myeloid cells that play a critical role in neuroimmunity and the etiology of Alzheimer's Disease (AD). Yet our understanding of how the genetic regulatory landscape controls microglial function and contributes to disease is limited. Here, we performed transcriptome and chromatin accessibility profiling in primary human microglia from 150 donors to identify genetically-driven variation and cell-specific enhancer-promoter interactions. Integrative fine-mapping analysis identified putative regulatory mechanisms for 21 AD risk loci, of which 18 were refined to a single gene, including 3 novel genes (KCNN4, FIBP and LRRC25). Transcription factor regulatory networks captured AD risk variation and identified SPI1 as a key regulator of microglia expression and AD risk. This comprehensive resource capturing variation in the human microglia regulome provides novel insights into the etiology of neurodegenerative disease.

scholarly journals Functional dissection of Alzheimer’s disease brain gene expression signatures in humans and mouse models

2019 ◽  
Author(s):  
Ying-Wooi Wan ◽  
Rami Al-Ouran ◽  
Carl Grant Mangleburg ◽  
Tom V. Lee ◽  
Katherine Allison ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Human Brain ◽  
Mouse Models ◽  
Neurofibrillary Tangle ◽  
Differentially Expressed Gene ◽  
Experimental Models ◽  
Genetic Manipulations ◽  
Brain Gene Expression ◽  
The Unfolded Protein Response

SUMMARYHuman brain transcriptomes can highlight biological pathways associated with Alzheimer’s disease (AD); however, challenges remain to link expression changes with causal triggers. We have examined 30 AD-associated, gene coexpression modules from human brains for overlap with 251 differentially-expressed gene sets from mouse brain RNA-sequencing experiments, including from models of AD and other neurodegenerative disorders. Human-mouse overlaps highlight responses to amyloid versus neurofibrillary tangle pathology and further reveal age- and sex-dependent expression signatures for AD progression. Human coexpression modules enriched for neuronal and/or microglial genes overlap broadly with signatures from mouse models of AD, Huntington’s disease, Amyotrophic Lateral Sclerosis, and also aging. Several human AD coexpression modules, including those implicated in the unfolded protein response and oxidative phosphorylation, were not activated in AD models, but instead were detected following other, unexpected mouse genetic manipulations. Our results comprise a powerful, cross-species resource and pinpoint experimental models for diverse features of AD pathophysiology from human brain transcriptomes.

scholarly journals Cell type‐specific enhancer‐promoter connectivity maps in the human brain and associations with Alzheimer’s disease risk

2020 ◽  
Vol 16 (S3) ◽  
Author(s):  
Alexi Nott ◽  
Inge Holtman ◽  
Nicole Coufal ◽  
Johannes CM Schlachetzki ◽  
Miao Yu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Human Brain ◽  
Disease Risk ◽  
Cell Type ◽  
Cell Type Specific

Alzheimer’s Disease Risk Variant rs2373115 Regulates GAB2 and NARS2 Expression in Human Brain Tissues

2018 ◽  
Vol 66 (1) ◽  
pp. 37-43 ◽  
Author(s):  
Guiyou Liu ◽  
Tao Wang ◽  
Rui Tian ◽  
Yang Hu ◽  
Zhifa Han ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Human Brain ◽  
Disease Risk ◽  
Risk Variant ◽  
Brain Tissues

scholarly journals Tau-mediated Disruption of the Spliceosome Triggers Cryptic RNA-splicing and Neurodegeneration in Alzheimer’s Disease

2019 ◽  
Author(s):  
Yi-Chen Hsieh ◽  
Caiwei Guo ◽  
Hari K. Yalamanchili ◽  
Measho Abreha ◽  
Rami Al-Ouran ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Rna Splicing ◽  
Intron Retention ◽  
Neurofibrillary Tangle ◽  
Neuronal Loss ◽  
Mrna Splicing ◽  
Postmortem Brain ◽  
Loss Of Function ◽  
Human Postmortem Brain

SUMMARYIn Alzheimer’s disease (AD), spliceosomal proteins with critical roles in RNA processing aberrantly aggregate and mislocalize to Tau neurofibrillary tangles. We test the hypothesis that Tau-spliceosome interactions disrupt pre-mRNA splicing in AD. In human postmortem brain with AD pathology, Tau coimmunoprecipitates with spliceosomal core components. In Drosophila models, pan-neuronal Tau expression triggers reductions in core and U1-specific spliceosomal proteins, and genetic disruption of these factors, including SmB, U1-70K, and U1A, enhances Tau-mediated neurodegeneration. We further show that loss-of-function in SmB, encoding a core spliceosomal protein, causes decreased survival, progressive locomotor impairment, and neuronal loss, independent of Tau toxicity. Lastly, RNA-sequencing reveals a similar profile of mRNA splicing errors in SmB mutant and Tau transgenic flies, including intron retention and non-annotated cryptic splice junctions. In human brains, we confirm cryptic splicing errors in association with neurofibrillary tangle pathologic burden. Our results implicate spliceosome disruption and perturbations of the neuronal transcriptome in Tau-mediated neurodegeneration in AD.

scholarly journals Synaptic Loss in Alzheimer's Disease: Mechanistic Insights Provided by Two-Photon in vivo Imaging of Transgenic Mouse Models

2020 ◽  
Vol 14 ◽  
Author(s):  
Jaichandar Subramanian ◽  
Julie C. Savage ◽  
Marie-Ève Tremblay
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Models ◽  
Synaptic Loss ◽  
Two Photon ◽  
Synapse Loss ◽  
Disease Mutations ◽  
The Brain

Synapse loss is the strongest correlate for cognitive decline in Alzheimer's disease. The mechanisms underlying synapse loss have been extensively investigated using mouse models expressing genes with human familial Alzheimer's disease mutations. In this review, we summarize how multiphoton in vivo imaging has improved our understanding of synapse loss mechanisms associated with excessive amyloid in the living animal brain. We also discuss evidence obtained from these imaging studies for the role of cell-intrinsic calcium dyshomeostasis and cell-extrinsic activities of microglia, which are the immune cells of the brain, in mediating synapse loss.

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