Frontiers in Aging Neuroscience (Jun 2024)
In-vivo neuronal dysfunction by Aβ and tau overlaps with brain-wide inflammatory mechanisms in Alzheimer’s disease
- Lazaro M. Sanchez-Rodriguez,
- Lazaro M. Sanchez-Rodriguez,
- Lazaro M. Sanchez-Rodriguez,
- Ahmed F. Khan,
- Ahmed F. Khan,
- Ahmed F. Khan,
- Quadri Adewale,
- Quadri Adewale,
- Quadri Adewale,
- Gleb Bezgin,
- Gleb Bezgin,
- Gleb Bezgin,
- Gleb Bezgin,
- Joseph Therriault,
- Joseph Therriault,
- Joseph Therriault,
- Jaime Fernandez-Arias,
- Jaime Fernandez-Arias,
- Jaime Fernandez-Arias,
- Stijn Servaes,
- Stijn Servaes,
- Stijn Servaes,
- Nesrine Rahmouni,
- Nesrine Rahmouni,
- Nesrine Rahmouni,
- Cécile Tissot,
- Cécile Tissot,
- Cécile Tissot,
- Cécile Tissot,
- Jenna Stevenson,
- Jenna Stevenson,
- Jenna Stevenson,
- Hongxiu Jiang,
- Hongxiu Jiang,
- Xiaoqian Chai,
- Xiaoqian Chai,
- Felix Carbonell,
- Pedro Rosa-Neto,
- Pedro Rosa-Neto,
- Pedro Rosa-Neto,
- Yasser Iturria-Medina,
- Yasser Iturria-Medina,
- Yasser Iturria-Medina
Affiliations
- Lazaro M. Sanchez-Rodriguez
- Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada
- Lazaro M. Sanchez-Rodriguez
- McConnell Brain Imaging Centre, Montreal Neurological Institute, Montreal, QC, Canada
- Lazaro M. Sanchez-Rodriguez
- Ludmer Centre for Neuroinformatics and Mental Health, Montreal, QC, Canada
- Ahmed F. Khan
- Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada
- Ahmed F. Khan
- McConnell Brain Imaging Centre, Montreal Neurological Institute, Montreal, QC, Canada
- Ahmed F. Khan
- Ludmer Centre for Neuroinformatics and Mental Health, Montreal, QC, Canada
- Quadri Adewale
- Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada
- Quadri Adewale
- McConnell Brain Imaging Centre, Montreal Neurological Institute, Montreal, QC, Canada
- Quadri Adewale
- Ludmer Centre for Neuroinformatics and Mental Health, Montreal, QC, Canada
- Gleb Bezgin
- Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada
- Gleb Bezgin
- McConnell Brain Imaging Centre, Montreal Neurological Institute, Montreal, QC, Canada
- Gleb Bezgin
- Ludmer Centre for Neuroinformatics and Mental Health, Montreal, QC, Canada
- Gleb Bezgin
- McGill University Research Centre for Studies in Aging, Douglas Research Centre, Montreal, QC, Canada
- Joseph Therriault
- Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada
- Joseph Therriault
- McConnell Brain Imaging Centre, Montreal Neurological Institute, Montreal, QC, Canada
- Joseph Therriault
- McGill University Research Centre for Studies in Aging, Douglas Research Centre, Montreal, QC, Canada
- Jaime Fernandez-Arias
- Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada
- Jaime Fernandez-Arias
- McConnell Brain Imaging Centre, Montreal Neurological Institute, Montreal, QC, Canada
- Jaime Fernandez-Arias
- McGill University Research Centre for Studies in Aging, Douglas Research Centre, Montreal, QC, Canada
- Stijn Servaes
- Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada
- Stijn Servaes
- McConnell Brain Imaging Centre, Montreal Neurological Institute, Montreal, QC, Canada
- Stijn Servaes
- McGill University Research Centre for Studies in Aging, Douglas Research Centre, Montreal, QC, Canada
- Nesrine Rahmouni
- Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada
- Nesrine Rahmouni
- McConnell Brain Imaging Centre, Montreal Neurological Institute, Montreal, QC, Canada
- Nesrine Rahmouni
- McGill University Research Centre for Studies in Aging, Douglas Research Centre, Montreal, QC, Canada
- Cécile Tissot
- Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada
- Cécile Tissot
- McConnell Brain Imaging Centre, Montreal Neurological Institute, Montreal, QC, Canada
- Cécile Tissot
- McGill University Research Centre for Studies in Aging, Douglas Research Centre, Montreal, QC, Canada
- Cécile Tissot
- Lawrence Berkeley National Laboratory, Berkeley, CA, United States
- Jenna Stevenson
- Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada
- Jenna Stevenson
- McConnell Brain Imaging Centre, Montreal Neurological Institute, Montreal, QC, Canada
- Jenna Stevenson
- McGill University Research Centre for Studies in Aging, Douglas Research Centre, Montreal, QC, Canada
- Hongxiu Jiang
- Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada
- Hongxiu Jiang
- McConnell Brain Imaging Centre, Montreal Neurological Institute, Montreal, QC, Canada
- Xiaoqian Chai
- Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada
- Xiaoqian Chai
- McConnell Brain Imaging Centre, Montreal Neurological Institute, Montreal, QC, Canada
- Felix Carbonell
- Biospective Inc., Montreal, QC, Canada
- Pedro Rosa-Neto
- Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada
- Pedro Rosa-Neto
- McConnell Brain Imaging Centre, Montreal Neurological Institute, Montreal, QC, Canada
- Pedro Rosa-Neto
- McGill University Research Centre for Studies in Aging, Douglas Research Centre, Montreal, QC, Canada
- Yasser Iturria-Medina
- Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada
- Yasser Iturria-Medina
- McConnell Brain Imaging Centre, Montreal Neurological Institute, Montreal, QC, Canada
- Yasser Iturria-Medina
- Ludmer Centre for Neuroinformatics and Mental Health, Montreal, QC, Canada
- DOI
- https://doi.org/10.3389/fnagi.2024.1383163
- Journal volume & issue
-
Vol. 16
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 < 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.
Keywords
- Alzheimer’s disease
- neuronal dysfunctions and alterations
- whole-brain modeling
- transcriptomics
- amyloid – beta
- tau and phospho-tau protein
