Integrated multimodal cell atlas of Alzheimer's disease.

Autor:	Gabitto MI; Allen Institute for Brain Science, Seattle, WA, 98109., Travaglini KJ; Allen Institute for Brain Science, Seattle, WA, 98109., Rachleff VM; Allen Institute for Brain Science, Seattle, WA, 98109.; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98104., Kaplan ES; Allen Institute for Brain Science, Seattle, WA, 98109., Long B; Allen Institute for Brain Science, Seattle, WA, 98109., Ariza J; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98104., Ding Y; Allen Institute for Brain Science, Seattle, WA, 98109., Mahoney JT; Allen Institute for Brain Science, Seattle, WA, 98109., Dee N; Allen Institute for Brain Science, Seattle, WA, 98109., Goldy J; Allen Institute for Brain Science, Seattle, WA, 98109., Melief EJ; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98104., Brouner K; Allen Institute for Brain Science, Seattle, WA, 98109., Campos J; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98104., Carr AJ; Chan Zuckerberg Initiative, Redwood City, CA 94063., Casper T; Allen Institute for Brain Science, Seattle, WA, 98109., Chakrabarty R; Allen Institute for Brain Science, Seattle, WA, 98109., Clark M; Allen Institute for Brain Science, Seattle, WA, 98109., Compos J; Allen Institute for Brain Science, Seattle, WA, 98109., Cool J; Chan Zuckerberg Initiative, Redwood City, CA 94063., Valera Cuevas NJ; Allen Institute for Brain Science, Seattle, WA, 98109., Dalley R; Allen Institute for Brain Science, Seattle, WA, 98109., Darvas M; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98104., Ding SL; Allen Institute for Brain Science, Seattle, WA, 98109., Dolbeare T; Allen Institute for Brain Science, Seattle, WA, 98109., Mac Donald CL; Department of Neurological Surgery, University of Washington, Seattle, WA 98104., Egdorf T; Allen Institute for Brain Science, Seattle, WA, 98109., Esposito L; Allen Institute for Brain Science, Seattle, WA, 98109., Ferrer R; Allen Institute for Brain Science, Seattle, WA, 98109., Gala R; Allen Institute for Brain Science, Seattle, WA, 98109., Gary A; Allen Institute for Brain Science, Seattle, WA, 98109., Gloe J; Allen Institute for Brain Science, Seattle, WA, 98109., Guilford N; Allen Institute for Brain Science, Seattle, WA, 98109., Guzman J; Allen Institute for Brain Science, Seattle, WA, 98109., Ho W; Allen Institute for Brain Science, Seattle, WA, 98109., Jarksy T; Allen Institute for Brain Science, Seattle, WA, 98109., Johansen N; Allen Institute for Brain Science, Seattle, WA, 98109., Kalmbach BE; Allen Institute for Brain Science, Seattle, WA, 98109., Keene LM; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98104., Khawand S; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98104., Kilgore M; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98104., Kirkland A; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98104., Kunst M; Allen Institute for Brain Science, Seattle, WA, 98109., Lee BR; Allen Institute for Brain Science, Seattle, WA, 98109., Malone J; Allen Institute for Brain Science, Seattle, WA, 98109., Maltzer Z; Allen Institute for Brain Science, Seattle, WA, 98109., Martin N; Allen Institute for Brain Science, Seattle, WA, 98109., McCue R; Allen Institute for Brain Science, Seattle, WA, 98109., McMillen D; Allen Institute for Brain Science, Seattle, WA, 98109., Meyerdierks E; Allen Institute for Brain Science, Seattle, WA, 98109., Meyers KP; Kaiser Permanente Washington Research Institute, Seattle, WA, 98101., Mollenkopf T; Allen Institute for Brain Science, Seattle, WA, 98109., Montine M; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98104., Nolan AL; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98104., Nyhus J; Allen Institute for Brain Science, Seattle, WA, 98109., Olsen PA; Allen Institute for Brain Science, Seattle, WA, 98109., Pacleb M; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98104., Pham T; Allen Institute for Brain Science, Seattle, WA, 98109., Pom CA; Allen Institute for Brain Science, Seattle, WA, 98109., Postupna N; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98104., Ruiz A; Allen Institute for Brain Science, Seattle, WA, 98109., Schantz AM; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98104., Sorensen SA; Allen Institute for Brain Science, Seattle, WA, 98109., Staats B; Allen Institute for Brain Science, Seattle, WA, 98109., Sullivan M; Allen Institute for Brain Science, Seattle, WA, 98109., Sunkin SM; Allen Institute for Brain Science, Seattle, WA, 98109., Thompson C; Allen Institute for Brain Science, Seattle, WA, 98109., Tieu M; Allen Institute for Brain Science, Seattle, WA, 98109., Ting J; Allen Institute for Brain Science, Seattle, WA, 98109., Torkelson A; Allen Institute for Brain Science, Seattle, WA, 98109., Tran T; Allen Institute for Brain Science, Seattle, WA, 98109., Wang MQ; Allen Institute for Brain Science, Seattle, WA, 98109., Waters J; Allen Institute for Brain Science, Seattle, WA, 98109., Wilson AM; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98104., Haynor D; Department of Radiology, University of Washington, Seattle, WA 98014., Gatto N; Kaiser Permanente Washington Research Institute, Seattle, WA, 98101., Jayadev S; Department of Neurology, University of Washington, Seattle, WA 98104., Mufti S; Allen Institute for Brain Science, Seattle, WA, 98109., Ng L; Allen Institute for Brain Science, Seattle, WA, 98109., Mukherjee S; Department of Medicine, University of Washington, Seattle, WA 98104., Crane PK; Department of Medicine, University of Washington, Seattle, WA 98104., Latimer CS; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98104., Levi BP; Allen Institute for Brain Science, Seattle, WA, 98109., Smith K; Allen Institute for Brain Science, Seattle, WA, 98109., Close JL; Allen Institute for Brain Science, Seattle, WA, 98109., Miller JA; Allen Institute for Brain Science, Seattle, WA, 98109., Hodge RD; Allen Institute for Brain Science, Seattle, WA, 98109., Larson EB; Department of Medicine, University of Washington, Seattle, WA 98104., Grabowski TJ; Department of Radiology, University of Washington, Seattle, WA 98014., Hawrylycz M; Allen Institute for Brain Science, Seattle, WA, 98109., Keene CD; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98104., Lein ES; Allen Institute for Brain Science, Seattle, WA, 98109.
Jazyk:	angličtina
Zdroj:	Research square [Res Sq] 2023 May 23. Date of Electronic Publication: 2023 May 23.
DOI:	10.21203/rs.3.rs-2921860/v1
Abstrakt:	Alzheimer's disease (AD) is the most common cause of dementia in older adults. Neuropathological and imaging studies have demonstrated a progressive and stereotyped accumulation of protein aggregates, but the underlying molecular and cellular mechanisms driving AD progression and vulnerable cell populations affected by disease remain coarsely understood. The current study harnesses single cell and spatial genomics tools and knowledge from the BRAIN Initiative Cell Census Network to understand the impact of disease progression on middle temporal gyrus cell types. We used image-based quantitative neuropathology to place 84 donors spanning the spectrum of AD pathology along a continuous disease pseudoprogression score and multiomic technologies to profile single nuclei from each donor, mapping their transcriptomes, epigenomes, and spatial coordinates to a common cell type reference with unprecedented resolution. Temporal analysis of cell-type proportions indicated an early reduction of Somatostatin-expressing neuronal subtypes and a late decrease of supragranular intratelencephalic-projecting excitatory and Parvalbumin-expressing neurons, with increases in disease-associated microglial and astrocytic states. We found complex gene expression differences, ranging from global to cell type-specific effects. These effects showed different temporal patterns indicating diverse cellular perturbations as a function of disease progression. A subset of donors showed a particularly severe cellular and molecular phenotype, which correlated with steeper cognitive decline. We have created a freely available public resource to explore these data and to accelerate progress in AD research at SEA-AD.org. Competing Interests: Additional Declarations: There is NO Competing Interest.
Databáze:	MEDLINE
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