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 ◽  
...  

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.

2019 ◽  
Vol 15 ◽  
pp. P1260-P1260
Author(s):  
Carl Grant Mangleburg ◽  
Ying-Wooi Wan ◽  
Rami Al-Ouran ◽  
Tom V. Lee ◽  
Katherine S. Allison ◽  
...  

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Natasha Andressa Nogueira Jorge ◽  
Uwe Ueberham ◽  
Mara Knobloch ◽  
Peter F. Stadler ◽  
Jörg Fallmann ◽  
...  

2019 ◽  
Author(s):  
Makis Tzioras ◽  
Michael J.D. Daniels ◽  
Declan King ◽  
Karla Popovic ◽  
Rebecca K. Holloway ◽  
...  

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


Cell Reports ◽  
2020 ◽  
Vol 32 (2) ◽  
pp. 107908 ◽  
Author(s):  
Ying-Wooi Wan ◽  
Rami Al-Ouran ◽  
Carl G. Mangleburg ◽  
Thanneer M. Perumal ◽  
Tom V. Lee ◽  
...  

2021 ◽  
pp. 1-14
Author(s):  
Pan Liu ◽  
Qian Yang ◽  
Ning Yu ◽  
Yan Cao ◽  
Xue Wang ◽  
...  

Background: Alzheimer’s disease (AD) is one of the most challenging diseases causing an increasing burden worldwide. Although the neuropathologic diagnosis of AD has been established for many years, the metabolic changes in neuropathologic diagnosed AD samples have not been fully investigated. Objective: To elucidate the potential metabolism dysregulation in the postmortem human brain samples assessed by AD related pathological examination. Methods: We performed untargeted and targeted metabolomics in 44 postmortem human brain tissues. The metabolic differences in the hippocampus between AD group and control (NC) group were compared. Results: The results show that a pervasive metabolic dysregulation including phenylalanine metabolism, valine, leucine, and isoleucine biosynthesis, biotin metabolism, and purine metabolism are associated with AD pathology. Targeted metabolomics reveal that phenylalanine, phenylpyruvic acid, and N-acetyl-L-phenylalanine are upregulated in AD samples. In addition, the enzyme IL-4I1 catalyzing transformation from phenylalanine to phenylpyruvic acid is also upregulated in AD samples. Conclusion: There is a pervasive metabolic dysregulation in hippocampus with AD-related pathological changes. Our study suggests that the dysregulation of phenylalanine metabolism in hippocampus may be an important pathogenesis for AD pathology formation.


2013 ◽  
Vol 106 ◽  
pp. 57-67 ◽  
Author(s):  
Chun-Ming Wang ◽  
Ming-Yan Liu ◽  
Fang Wang ◽  
Min-Jie Wei ◽  
Shuang Wang ◽  
...  

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