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Early Alzheimer’s disease pathology in human cortex involves transient cell states

Cellular perturbations underlying Alzheimer’s disease (AD) are primarily studied in human postmortem samples and model organisms. Here, we generated a single-nucleus atlas from a rare cohort of cortical biopsies from living individuals with varying degrees of AD pathology. We next performed a system...

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Published in:Cell 2023-09, Vol.186 (20), p.4438-4453.e23
Main Authors: Gazestani, Vahid, Kamath, Tushar, Nadaf, Naeem M., Dougalis, Antonios, Burris, S.J., Rooney, Brendan, Junkkari, Antti, Vanderburg, Charles, Pelkonen, Anssi, Gomez-Budia, Mireia, Välimäki, Nelli-Noora, Rauramaa, Tuomas, Therrien, Martine, Koivisto, Anne M., Tegtmeyer, Matthew, Herukka, Sanna-Kaisa, Abdulraouf, Abdulraouf, Marsh, Samuel E., Hiltunen, Mikko, Nehme, Ralda, Malm, Tarja, Stevens, Beth, Leinonen, Ville, Macosko, Evan Z.
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Language:English
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Summary:Cellular perturbations underlying Alzheimer’s disease (AD) are primarily studied in human postmortem samples and model organisms. Here, we generated a single-nucleus atlas from a rare cohort of cortical biopsies from living individuals with varying degrees of AD pathology. We next performed a systematic cross-disease and cross-species integrative analysis to identify a set of cell states that are specific to early AD pathology. These changes—which we refer to as the early cortical amyloid response—were prominent in neurons, wherein we identified a transitional hyperactive state preceding the loss of excitatory neurons, which we confirmed by acute slice physiology on independent biopsy specimens. Microglia overexpressing neuroinflammatory-related processes also expanded as AD pathology increased. Finally, both oligodendrocytes and pyramidal neurons upregulated genes associated with β-amyloid production and processing during this early hyperactive phase. Our integrative analysis provides an organizing framework for targeting circuit dysfunction, neuroinflammation, and amyloid production early in AD pathogenesis. [Display omitted] •Single-nucleus profiling of human cortex biopsies uncovers amyloid-associated states•Upper-layer pyramidal neurons show hyperactivity prior to degeneration•Microglial states correlate with pathological and clinical progression•Signatures of amyloid production identified in both neurons and oligodendrocytes Generating single-nucleus atlas from cortical biopsies of living individuals at early stage of Alzheimer’s disease, cell states of neurons, microglia, and oligodendrocytes associated with AD pathology are identified.
ISSN:0092-8674
1097-4172
1097-4172
DOI:10.1016/j.cell.2023.08.005