In-vivo neuronal dysfunction by Aβ and tau overlaps with brain-wide inflammatory mechanisms in Alzheimer’s disease

Sanchez-Rodriguez, Lazaro M.; Khan, Ahmed F.; Adewale, Quadri; Bezgin, Gleb; Therriault, Joseph; Fernandez-Arias, Jaime; Servaes, Stijn; Rahmouni, Nesrine; Tissot, Cécile; Stevenson, Jenna; Jiang, Hongxiu; Chai, Xiaoqian; Carbonell, Felix; Rosa-Neto, Pedro; Iturria-Medina, Yasser

doi:10.3389/fnagi.2024.1383163

In-vivo neuronal dysfunction by Aβ and tau overlaps with brain-wide inflammatory mechanisms in Alzheimer’s disease

Journal Article · Tue Jun 18 00:00:00 EDT 2024 · Frontiers in aging neuroscience

DOI:https://doi.org/10.3389/fnagi.2024.1383163· OSTI ID:2405929

Sanchez-Rodriguez, Lazaro M. ^[1]; Khan, Ahmed F. ^[1]; Adewale, Quadri ^[1]; Bezgin, Gleb ^[2]; Therriault, Joseph ^[3]; Fernandez-Arias, Jaime ^[3]; Servaes, Stijn ^[3]; Rahmouni, Nesrine ^[3]; Tissot, Cécile ^[4]; Stevenson, Jenna ^[3]; Jiang, Hongxiu ^[5]; Chai, Xiaoqian ^[5]; Carbonell, Felix ^[6]; Rosa-Neto, Pedro ^[3]; Iturria-Medina, Yasser ^[1]

McGill University, Montreal, QC (Canada); McConnell Brain Imaging Centre, Montreal Neurological Institute, Montreal, QC (Canada); Ludmer Centre for Neuroinformatics and Mental Health, Montreal, QC (Canada)
McGill University, Montreal, QC (Canada); McConnell Brain Imaging Centre, Montreal Neurological Institute, Montreal, QC (Canada); Ludmer Centre for Neuroinformatics and Mental Health, Montreal, QC (Canada); McGill University Research Centre for Studies in Aging, Douglas Research Centre, Montreal, QC (Canada)
McGill University, Montreal, QC (Canada); McConnell Brain Imaging Centre, Montreal Neurological Institute, Montreal, QC (Canada); McGill University Research Centre for Studies in Aging, Douglas Research Centre, Montreal, QC (Canada)
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States); McGill University, Montreal, QC (Canada); McConnell Brain Imaging Centre, Montreal Neurological Institute, Montreal, QC (Canada); McGill University Research Centre for Studies in Aging, Douglas Research Centre, Montreal, QC (Canada)
McGill University, Montreal, QC (Canada); McConnell Brain Imaging Centre, Montreal Neurological Institute, Montreal, QC (Canada)
Biospective Inc., Montreal, QC (Canada)

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 < 0.001). These results further support the central role of the immune system and neuroinflammatory pathways in AD pathogenesis. Neuronal dysregulation by AD pathologies also associated with neurotypical synaptic and developmental processes. In addition, we identified drug candidates from the vast LINCS library to halt or reduce the observed Aβ-tau effects on neuronal activity. Top-ranked pharmacological interventions target inflammatory, cancer and cardiovascular pathways, including specific medications undergoing clinical evaluation in AD. Our findings, based on the examination of molecular-pathological-functional interactions in humans, may accelerate the process of bringing effective therapies into clinical practice.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 2405929

Journal Information:: Frontiers in aging neuroscience, Journal Name: Frontiers in aging neuroscience Vol. 16; ISSN 1663-4365

Publisher:: FrontiersCopyright Statement

Country of Publication:: United States

Language:: English

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The biological pathways of Alzheimer disease: a review Calabrò, Marco; Rinaldi, Carmela AIMS Neuroscience, Vol. 8, Issue 1 https://doi.org/10.3934/Neuroscience.2021005	journal	January 2021
Integrated transcriptomic and neuroimaging brain model decodes biological mechanisms in aging and Alzheimer’s disease Adewale, Quadri; Khan, Ahmed F.; Carbonell, Felix eLife, Vol. 10 https://doi.org/10.7554/eLife.62589	journal	May 2021

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60 APPLIED LIFE SCIENCES
Alzheimer’s disease
amyloid – beta
computational drug repurposing
inflammation
neuronal dysfunctions and alterations
tau and phospho-tau protein
transcriptomics
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In-vivo neuronal dysfunction by Aβ and tau overlaps with brain-wide inflammatory mechanisms in Alzheimer’s disease

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