Early Alzheimer's disease pathology in human cortex is associated with a transient phase of distinct cell states.

Autor: Gazestani V; Broad Institute of MIT and Harvard, Cambridge, MA 02142 USA., Kamath T; Broad Institute of MIT and Harvard, Cambridge, MA 02142 USA.; Harvard Graduate Program in Biophysics and Harvard/MIT MD-PhD Program, Harvard University, Cambridge, MA 02139 USA., Nadaf NM; Broad Institute of MIT and Harvard, Cambridge, MA 02142 USA., Burris SJ; Broad Institute of MIT and Harvard, Cambridge, MA 02142 USA., Rooney B; Program in Neuroscience, Harvard Medical School, Boston, MA 02115 USA., Junkkari A; Institute of Clinical Medicine, Unit of Pathology, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.; Department of Neurosurgery, Kuopio University Hospital, Kuopio, Finland., Vanderburg C; Broad Institute of MIT and Harvard, Cambridge, MA 02142 USA., Rauramaa T; Institute of Clinical Medicine, Unit of Pathology, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.; Department of Pathology, Kuopio University Hospital, Kuopio, Finland., Therrien M; Broad Institute of MIT and Harvard, Cambridge, MA 02142 USA., Tegtmeyer M; Broad Institute of MIT and Harvard, Cambridge, MA 02142 USA., Herukka SK; Institute of Clinical Medicine, Unit of Pathology, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.; Department of Neurology, Kuopio University Hospital, Kuopio, Finland., Abdulraouf A; Broad Institute of MIT and Harvard, Cambridge, MA 02142 USA., Marsh S; F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115 USA., Malm T; A.I. Virtanen Institute for Molecular Sciences, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland., Hiltunen M; Institute of Biomedicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland., Nehme R; Broad Institute of MIT and Harvard, Cambridge, MA 02142 USA., Stevens B; Broad Institute of MIT and Harvard, Cambridge, MA 02142 USA.; F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115 USA.; Howard Hughes Medical Institute (HHMI), Boston, MA 02115 USA., Leinonen V; Institute of Clinical Medicine, Unit of Pathology, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.; Department of Neurosurgery, Kuopio University Hospital, Kuopio, Finland., Macosko EZ; Broad Institute of MIT and Harvard, Cambridge, MA 02142 USA.; Massachusetts General Hospital, Department of Psychiatry, Boston, MA 02114 USA.
Jazyk: angličtina
Zdroj: BioRxiv : the preprint server for biology [bioRxiv] 2023 Jun 05. Date of Electronic Publication: 2023 Jun 05.
DOI: 10.1101/2023.06.03.543569
Abstrakt: Cellular perturbations underlying Alzheimer's disease 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 Alzheimer's disease 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 transient state of hyperactivity preceding loss of excitatory neurons, which correlated with the selective loss of layer 1 inhibitory neurons. Microglia overexpressing neuroinflammatory-related processes also expanded as AD pathological burden increased. Lastly, both oligodendrocytes and pyramidal neurons upregulated genes associated with amyloid beta 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.
Databáze: MEDLINE