Single-cell atlas reveals correlates of high cognitive function, dementia, and resilience to Alzheimer's disease pathology.

Autor:	Mathys H; Picower Institute for Learning and Memory, MIT, Cambridge, MA 02139, USA; Department of Brain and Cognitive Sciences, MIT, Cambridge, MA 02139, USA; University of Pittsburgh Brain Institute and Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA. Electronic address: mathysh@pitt.edu., Peng Z; Picower Institute for Learning and Memory, MIT, Cambridge, MA 02139, USA; Department of Brain and Cognitive Sciences, MIT, Cambridge, MA 02139, USA., Boix CA; Computer Science and Artificial Intelligence Laboratory, MIT, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Victor MB; Picower Institute for Learning and Memory, MIT, Cambridge, MA 02139, USA; Department of Brain and Cognitive Sciences, MIT, Cambridge, MA 02139, USA., Leary N; Picower Institute for Learning and Memory, MIT, Cambridge, MA 02139, USA; Department of Brain and Cognitive Sciences, MIT, Cambridge, MA 02139, USA., Babu S; University of Pittsburgh Brain Institute and Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA., Abdelhady G; University of Pittsburgh Brain Institute and Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA., Jiang X; Picower Institute for Learning and Memory, MIT, Cambridge, MA 02139, USA; Department of Brain and Cognitive Sciences, MIT, Cambridge, MA 02139, USA., Ng AP; Picower Institute for Learning and Memory, MIT, Cambridge, MA 02139, USA; Department of Brain and Cognitive Sciences, MIT, Cambridge, MA 02139, USA., Ghafari K; University of Pittsburgh Brain Institute and Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA., Kunisky AK; University of Pittsburgh Brain Institute and Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA., Mantero J; Computer Science and Artificial Intelligence Laboratory, MIT, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Galani K; Computer Science and Artificial Intelligence Laboratory, MIT, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Lohia VN; University of Pittsburgh Brain Institute and Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA., Fortier GE; University of Pittsburgh Brain Institute and Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA., Lotfi Y; University of Pittsburgh Brain Institute and Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA., Ivey J; University of Pittsburgh Brain Institute and Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA., Brown HP; University of Pittsburgh Brain Institute and Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA., Patel PR; University of Pittsburgh Brain Institute and Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA., Chakraborty N; University of Pittsburgh Brain Institute and Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA., Beaudway JI; University of Pittsburgh Brain Institute and Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA., Imhoff EJ; University of Pittsburgh Brain Institute and Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA., Keeler CF; University of Pittsburgh Brain Institute and Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA., McChesney MM; University of Pittsburgh Brain Institute and Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA., Patel HH; University of Pittsburgh Brain Institute and Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA., Patel SP; University of Pittsburgh Brain Institute and Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA., Thai MT; University of Pittsburgh Brain Institute and Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA., Bennett DA; Rush Alzheimer's Disease Center, Chicago, IL 60612, USA., Kellis M; Computer Science and Artificial Intelligence Laboratory, MIT, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: manoli@mit.edu., Tsai LH; Picower Institute for Learning and Memory, MIT, Cambridge, MA 02139, USA; Department of Brain and Cognitive Sciences, MIT, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: lhtsai@mit.edu.
Jazyk:	angličtina
Zdroj:	Cell [Cell] 2023 Sep 28; Vol. 186 (20), pp. 4365-4385.e27.
DOI:	10.1016/j.cell.2023.08.039
Abstrakt:	Alzheimer's disease (AD) is the most common cause of dementia worldwide, but the molecular and cellular mechanisms underlying cognitive impairment remain poorly understood. To address this, we generated a single-cell transcriptomic atlas of the aged human prefrontal cortex covering 2.3 million cells from postmortem human brain samples of 427 individuals with varying degrees of AD pathology and cognitive impairment. Our analyses identified AD-pathology-associated alterations shared between excitatory neuron subtypes, revealed a coordinated increase of the cohesin complex and DNA damage response factors in excitatory neurons and in oligodendrocytes, and uncovered genes and pathways associated with high cognitive function, dementia, and resilience to AD pathology. Furthermore, we identified selectively vulnerable somatostatin inhibitory neuron subtypes depleted in AD, discovered two distinct groups of inhibitory neurons that were more abundant in individuals with preserved high cognitive function late in life, and uncovered a link between inhibitory neurons and resilience to AD pathology. Competing Interests: Declaration of interests L.-H.T. is a member of the Scientific Advisory Boards of Cognito Therapeutics, 4M Therapeutics, Cell Signaling Technology, and Souvien Therapeutics, which have no association to the work described in this manuscript. (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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