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

被引：85

作者：

Gazestani, Vahid ^{[1
]}

Kamath, Tushar ^{[1
,2
]}

Nadaf, Naeem M. ^{[1
]}

Dougalis, Antonios ^{[3
]}

Burris, S. J.

Rooney, Brendan

Junkkari, Antti ^{[5
,6
]}

Vanderburg, Charles ^{[1
]}

Pelkonen, Anssi ^{[3
]}

Gomez-Budia, Mireia ^{[3
]}

Valimaki, Nelli-Noora ^{[3
]}

Rauramaa, Tuomas ^{[5
,7
]}

Therrien, Martine ^{[1
]}

Koivisto, Anne M. ^{[4
,5
,8
,9
,10
]}

Tegtmeyer, Matthew ^{[1
]}

Herukka, Sanna-Kaisa ^{[5
,8
]}

Abdulraouf, Abdulraouf ^{[1
]}

Marsh, Samuel E.

Hiltunen, Mikko ^{[12
]}

Nehme, Ralda ^{[1
]}

Malm, Tarja

Stevens, Beth ^{[1
,11
,13
]}

Leinonen, Ville ^{[5
,6
]}

Macosko, Evan Z. ^{[1
,14
]}

机构：

[1] Broad Inst & Harvard, Cambridge, MA 02142 USA

[2] Harvard Univ, Harvard Grad Program Biophys & Harvard, MD PhD Program, Cambridge, MA 02139 USA

[3] Univ Eastern Finland, AI Virtanen Inst Mol Sci, Kuopio, Finland

[4] Harvard Med Sch, Program Neurosci, Boston, MA 02115 USA

[5] Univ Eastern Finland, Inst Clin Med, Kuopio, Finland

[6] Kuopio Univ Hosp, Dept Neurosurg, Kuopio, Finland

[7] Kuopio Univ Hosp, Dept Pathol, Kuopio, Finland

[8] Kuopio Univ Hosp, Dept Neurol, FIN-70211 Kuopio, Finland

[9] Univ Helsinki, Dept Neurosci, Helsinki, Finland

[10] Helsinki Univ Hosp, Dept Geriatr, Helsinki, Finland

[11] Boston Childrens Hosp, FM Kirby Neurobiol Ctr, Boston, MA 02115 USA

[12] Univ Eastern Finland, Inst Biomed, Kuopio, Finland

[13] Howard Hughes Med Inst HHMI, Boston, MA 02115 USA

[14] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA

来源：

CELL | 2023年 / 186卷 / 20期

基金：

芬兰科学院;

关键词：

NORMAL-PRESSURE HYDROCEPHALUS; RISK LOCI; RNA-SEQ; BRAIN; NEURONS; MOUSE; ATLAS; DEATH; INDIVIDUALS; MODULATION;

D O I：

10.1016/j.cell.2023.08.005

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 neuroin-flammatory-related processes also expanded as AD pathology increased. Finally, both oligodendrocytes and pyramidal neurons upregulated genes associated with b-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.

引用

页码：4438 / +

页数：40

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