1. In-vivo neuronal dysfunction by Aβ and tau overlaps with brain-wide inflammatory mechanisms in Alzheimer’s disease
- Author
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Lazaro M. Sanchez-Rodriguez, Ahmed F. Khan, Quadri Adewale, Gleb Bezgin, Joseph Therriault, Jaime Fernandez-Arias, Stijn Servaes, Nesrine Rahmouni, Cécile Tissot, Jenna Stevenson, Hongxiu Jiang, Xiaoqian Chai, Felix Carbonell, Pedro Rosa-Neto, and Yasser Iturria-Medina
- Subjects
Alzheimer’s disease ,neuronal dysfunctions and alterations ,whole-brain modeling ,transcriptomics ,amyloid – beta ,tau and phospho-tau protein ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
The molecular mechanisms underlying neuronal dysfunction in Alzheimer’s disease (AD) remain uncharacterized. Here, we identify genes, molecular pathways and cellular components associated with whole-brain dysregulation caused by amyloid-beta (Aβ) and tau deposits in the living human brain. We obtained in-vivo resting-state functional MRI (rs-fMRI), Aβ- and tau-PET for 47 cognitively unimpaired and 16 AD participants from the Translational Biomarkers in Aging and Dementia cohort. Adverse neuronal activity impacts by Aβ and tau were quantified with personalized dynamical models by fitting pathology-mediated computational signals to the participant’s real rs-fMRIs. Then, we detected robust brain-wide associations between the spatial profiles of Aβ-tau impacts and gene expression in the neurotypical transcriptome (Allen Human Brain Atlas). Within the obtained distinctive signature of in-vivo neuronal dysfunction, several genes have prominent roles in microglial activation and in interactions with Aβ and tau. Moreover, cellular vulnerability estimations revealed strong association of microglial expression patterns with Aβ and tau’s synergistic impact on neuronal activity (q
- Published
- 2024
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