Integrated multimodal cell atlas of Alzheimer's disease
Integrated multimodal cell atlas of Alzheimer's disease
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. Pseudo-progression analysis showed two major epochs corresponding with a slow early increase in pathology and a later exponential increase that correlated with cognitive decline. The early phase included inflammatory microglial and reactive astrocyte component, as well as a selective loss of Sst+ inhibitory neuron types in superficial cortical layers, loss of myelinating oligodendrocytes, and up-regulation of a re-myelination program by OPCs. The later phase involved loss of excitatory neurons and Pvalb and Vip neuron subtypes also predominantly in superficial layers. These cell vulnerabilities were also seen in prefrontal cortex and replicated by other independent studies when integrated with the BRAIN Initiative reference. Study data and exploratory tools are freely available to accelerate progress in AD research at SEA-AD.org.
Keene C. Dirk、Ng Lydia、Sorensen Staci A.、Sullivan Matt、Sunkin Susan M.、Tieu Michael、Levi Boaz P.、Waters Jack、Wilson Angela M.、Haynor David、Jayadev Suman、Mufti Shoaib、Mukherjee Shubhabrata、Larson Eric B.、Lee Brian R.、Grabowski Thomas J.、Hawrylycz Michael、Pham Trangthanh、Pom Christina A.、Rimorin Christine、Ruiz Augustin、Shapovalova Nadiya V.、Chakrabarty Rushil、Clark Michael、Cool Jonah、Dalley Rachel、Egdorf Tom、Fleckenstein Lynn E、Gloe Jessica、Guzman Junitta、Kalmbach Brian E.、Keene Lisa M.、Agrawal Anamika、Kana Omar、Zhen Xingjian、Brouner Krissy、Carr Ambrose J.、Travaglini Kyle J.、Rachleff Victoria M.、Ariza Jeanelle、Ding Yi、Dee Nick、Goldy Jeff、Casper Tamara、Campos John、Malone Jocelin、Maltzer Zoe、Martin Naomi、McMillen Delissa、Mena Gonzalo、Nyhus Julie、Olsen Paul A.、Campos Jazmin、Johansen Nelson、Miller Jeremy A.、Mac Donald Christine L.、Tran Tracy、Leytze Mckaila、Postupna Nadia、Latimer Caitlin S.、Barlow Samuel T.、Thompson Carol、Crane Paul K.、Ding Song-Lin、Pacleb Maiya、Meyerdierks Emma、Pagan Chelsea M、Torkelson Amy、Khawand Sarah、Pena Nicholas、Kilgore Mitch、Hodge Rebecca D.、Wang Ming-Qiang、Ferrer Rebecca、Walling-Bell Sarah、Dolbeare Tim、Meyers Kelly P.、Staats Brian、Esposito Luke、Nolan Amber L.、Darvas Martin、Long Brian、Ting Jonathan、Mollenkopf Tyler、Saldi Giuseppe A.、Kunst Michael、Melief Erica J.、Gatto Nicole M.、Gary Amanda、Guilford Nathan、Gala Rohan、Mahoney Joseph T.、Ho Windy、Hirschstein Daniel、Hupp Madison、Gabitto Mariano I.、Lein Ed S.、Jarksy Tim、Montine Mark、Valera Cuevas Nasmil J.、McCue Rachel、Kirkland Amanda、Gelfand Emily、Kaplan Eitan S.、Schantz Aimee M.、Close Jennie L.、Smith Kimberly
神经病学、精神病学基础医学生物科学研究方法、生物科学研究技术
Keene C. Dirk,Ng Lydia,Sorensen Staci A.,Sullivan Matt,Sunkin Susan M.,Tieu Michael,Levi Boaz P.,Waters Jack,Wilson Angela M.,Haynor David,Jayadev Suman,Mufti Shoaib,Mukherjee Shubhabrata,Larson Eric B.,Lee Brian R.,Grabowski Thomas J.,Hawrylycz Michael,Pham Trangthanh,Pom Christina A.,Rimorin Christine,Ruiz Augustin,Shapovalova Nadiya V.,Chakrabarty Rushil,Clark Michael,Cool Jonah,Dalley Rachel,Egdorf Tom,Fleckenstein Lynn E,Gloe Jessica,Guzman Junitta,Kalmbach Brian E.,Keene Lisa M.,Agrawal Anamika,Kana Omar,Zhen Xingjian,Brouner Krissy,Carr Ambrose J.,Travaglini Kyle J.,Rachleff Victoria M.,Ariza Jeanelle,Ding Yi,Dee Nick,Goldy Jeff,Casper Tamara,Campos John,Malone Jocelin,Maltzer Zoe,Martin Naomi,McMillen Delissa,Mena Gonzalo,Nyhus Julie,Olsen Paul A.,Campos Jazmin,Johansen Nelson,Miller Jeremy A.,Mac Donald Christine L.,Tran Tracy,Leytze Mckaila,Postupna Nadia,Latimer Caitlin S.,Barlow Samuel T.,Thompson Carol,Crane Paul K.,Ding Song-Lin,Pacleb Maiya,Meyerdierks Emma,Pagan Chelsea M,Torkelson Amy,Khawand Sarah,Pena Nicholas,Kilgore Mitch,Hodge Rebecca D.,Wang Ming-Qiang,Ferrer Rebecca,Walling-Bell Sarah,Dolbeare Tim,Meyers Kelly P.,Staats Brian,Esposito Luke,Nolan Amber L.,Darvas Martin,Long Brian,Ting Jonathan,Mollenkopf Tyler,Saldi Giuseppe A.,Kunst Michael,Melief Erica J.,Gatto Nicole M.,Gary Amanda,Guilford Nathan,Gala Rohan,Mahoney Joseph T.,Ho Windy,Hirschstein Daniel,Hupp Madison,Gabitto Mariano I.,Lein Ed S.,Jarksy Tim,Montine Mark,Valera Cuevas Nasmil J.,McCue Rachel,Kirkland Amanda,Gelfand Emily,Kaplan Eitan S.,Schantz Aimee M.,Close Jennie L.,Smith Kimberly.Integrated multimodal cell atlas of Alzheimer's disease[EB/OL].(2025-03-28)[2025-05-17].https://www.biorxiv.org/content/10.1101/2023.05.08.539485.点此复制
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