Early Alzheimer's disease pathology in human cortex involves transient cell states.
| Publication Type | Academic Article |
| Authors | Gazestani V, Kamath T, Nadaf N, Dougalis A, Burris S, Rooney B, Junkkari A, Vanderburg C, Pelkonen A, Gomez-Budia M, Välimäki N, Rauramaa T, Therrien M, Koivisto A, Tegtmeyer M, Herukka S, Abdulraouf A, Marsh S, Hiltunen M, Nehme R, Malm T, Stevens B, Leinonen V, Macosko E |
| Journal | Cell |
| Volume | 186 |
| Issue | 20 |
| Pagination | 4438-4453.e23 |
| Date Published | 09/28/2023 |
| ISSN | 1097-4172 |
| Keywords | Alzheimer Disease, Microglia, Neurons, Frontal Lobe |
| Abstract | 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. |
| DOI | 10.1016/j.cell.2023.08.005 |
| PubMed ID | 37774681 |
| PubMed Central ID | PMC11107481 |