Single-cell multiregion dissection of Alzheimer's disease

被引：66

作者：

Mathys, Hansruedi ^{[1
,2
,3
,4
]}

Boix, Carles A. ^{[5
,6
,7
,8
]}

Akay, Leyla Anne ^{[1
,2
,13
]}

Xia, Ziting ^{[1
,2
,9
]}

Davila-Velderrain, Jose ^{[10
]}

Ng, Ayesha P. ^{[1
,2
]}

Jiang, Xueqiao ^{[1
,2
]}

Abdelhady, Ghada ^{[3
]}

Galani, Kyriaki ^{[6
,7
]}

Mantero, Julio ^{[6
,7
]}

Band, Neil ^{[6
,7
]}

James, Benjamin T. ^{[6
,7
]}

Babu, Sudhagar ^{[3
]}

Galiana-Melendez, Fabiola ^{[1
,2
]}

Louderback, Kate ^{[1
,2
]}

Prokopenko, Dmitry ^{[11
]}

Tanzi, Rudolph E. ^{[11
]}

Bennett, David A. ^{[12
]}

Tsai, Li-Huei ^{[1
,2
,7
]}

Kellis, Manolis ^{[6
,7
]}

机构：

[1] MIT, Picower Inst Learning & Memory, 77 Massachusetts Ave, Cambridge, MA 02139 USA

[2] MIT, Dept Brain & Cognit Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA

[3] Univ Pittsburgh, Inst Brain, Sch Med, Pittsburgh, PA USA

[4] Univ Pittsburgh, Sch Med, Dept Neurobiol, Pittsburgh, PA USA

[5] MIT, Comp Sci & Artificial Intelligence Lab, 77 Massachusetts Ave, Cambridge, MA 02139 USA

[6] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[7] MIT, Computat & Syst Biol Program, 77 Massachusetts Ave, Cambridge, MA 02139 USA

[8] MIT, Harvard MIT Hlth Sci & Technol Program, 77 Massachusetts Ave, Cambridge, MA 02139 USA

[9] Human Technopole, Milan, Italy

[10] Massachusetts Gen Hosp, Dept Neurol, McCance Ctr Brain Hlth, Genet & Aging Res Unit, Boston, MA 02114 USA

[11] Harvard Med Sch, Boston, MA 02115 USA

[12] Rush Alzheimers Dis Ctr, Chicago, IL USA

[13] Stanford Univ, Dept Comp Sci, Stanford, CA 94305 USA

来源：

NATURE | 2024年 / 632卷 / 8026期

基金：

瑞士国家科学基金会;

关键词：

ENTORHINAL CORTEX NEURONS; GENOME-WIDE ASSOCIATION; NUCLEUS RNA-SEQ; HUMAN-BRAIN; COGNITIVE PERFORMANCE; MEMORY; ATLAS; CHOLINE; ARCHITECTURE; INDIVIDUALS;

D O I：

10.1038/s41586-024-07606-7

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Alzheimer's disease is the leading cause of dementia worldwide, but the cellular pathways that underlie its pathological progression across brain regions remain poorly understood(1-3). Here we report a single-cell transcriptomic atlas of six different brain regions in the aged human brain, covering 1.3million cells from 283 post-mortem human brain samples across 48 individuals with and without Alzheimer's disease. We identify 76 cell types, including region-specific subtypes of astrocytes and excitatory neurons and an inhibitory interneuron population unique to the thalamus and distinct from canonical inhibitory subclasses. We identify vulnerable populations of excitatory and inhibitory neurons that are depleted in specific brain regions in Alzheimer's disease, and provide evidence that the Reelin signalling pathway is involved in modulating the vulnerability of these neurons. We develop a scalable method for discovering gene modules, which we use to identify cell-type-specific and region-specific modules that are altered in Alzheimer's disease and to annotate transcriptomic differences associated with diverse pathological variables. We identify an astrocyte program that is associated with cognitive resilience to Alzheimer's disease pathology, tying choline metabolism and polyamine biosynthesis in astrocytes to preserved cognitive function late in life. Together, our study develops a regional atlas of the ageing human brain and provides insights into cellular vulnerability, response and resilience to Alzheimer's disease pathology.

引用

页码：858 / +

页数：35

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