Divergent Cellular Programs with a Pallial Division in Alzheimer’s Disease
Yining Hao1, Weishi Liu1, Jiahao Ji1, Yi Zhang1, Yu He1, Peng Yuan2, Jintai Yu1
1Department of Neurology and National Center for Neurological Diseases, Huashan Hospital, State Key Laboratory of Medical Neurobiology and Ministry of Education Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, 2Department of Rehabilitation Medicine, Huashan Hospital, State Key Laboratory of Medical Neurobiology, Institute for Translational Brain Research, MOE Frontiers Center for Brain Science, MOE Innovative Center for New Drug Development of Immune Inflammatory Diseases, Fudan University
Objective:
To address the knowledge gap on the variability in Alzheimer's disease (AD) pathology responses across different brain regions and to identify potential region-specific cellular mechanisms that confer differential susceptibility.
Background:
AD is the most common cause of dementia. While the key pathologies and hundreds of genetic risk factors are identified, the crucial mechanism underlying pathology-driven cognitive decline remains elusive, and no treatment is available to halt disease progression. An important yet poorly understood aspect of AD pathogenesis is whether different brain regions respond to the pathology in the same manner, or there are region-specific cellular programs that render some area more susceptible.
Design/Methods:
Aiming to fill this gap of knowledge, we undertook the largest spatial-temporal transcriptome study in 5×FAD mice. We collected forebrain and hindbrain sections from each mouse for spatial-transcriptomics and dissected 7 brain regions from adjacent slices for single-nuclei sequencing. This data set allowed us to depict the plaque-induced micro-environment in each brain region and contrast region-general and region-specific molecular programs at the level that was not possible before.
Results:
Importantly, we found that while microglia in all regions respond to plaque with a unified mode as previously reported, microglia in subpallial regions (striatum and basal forebrain) are more sensitive to amyloid and express high levels of neuroactive peptides and receptors. Concurrently, we discerned elevated density of subpallial-specific microglia encircling the cholinergic neurons and detected preliminary cholinergic apoptosis within both the murine and human AD basal forebrain.
Conclusions:
Our analysis revealed disproportional alteration in neuron-microglia interaction in sub-pallium regions that may affect the neuro-modulatory landscape throughout the brain, which was previously not appreciated. We have curated our dataset for the field to (re)evaluate plaque-induced brain response in a more holistic manner that might be a necessary step towards developing disease-modifying therapies.
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