期刊
CELL REPORTS
卷 37, 期 13, 页码 -出版社
CELL PRESS
DOI: 10.1016/j.celrep.2021.110182
关键词
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类别
资金
- NIH [AG034618, AG035015, P30AG066462, NS056049, AG051556]
- Alz-heimer's Disease Neuroimaging Initiative (ADNI) (NIH) [U01 AG024904]
- Department of Defense ADNI [W81XWH-12-2-0012]
- National Institute on Aging
- National Institute of Biomedical Imaging and Bioengineering
- AbbVie
- Alzheimer's Association
- Alzheimer's Drug Discovery Foundation
- Araclon Biotech
- BioClinica, Inc.
- Biogen
- Bristol-Myers Squibb Company
- CereSpir, Inc.
- Cogstate
- Eisai Inc.
- Elan Pharmaceuticals, Inc.
- Eli Lilly and Company
- EuroImmun
- F. Hoffmann-La Roche, Ltd.
- Genentech, Inc.
- Fujirebio
- GE Healthcare
- IXICO, Ltd.
- Janssen Alzheimer Immunotherapy Research & Development, LLC.
- Johnson & Johnson Pharmaceutical Research & Development, LLC.
- Lumosity
- Lund-beck
- Merck Co., Inc.
- Meso Scale Diagnostics, LLC.
- NeuroRx Research
- Neurotrack Technologies
- Novartis Pharmaceuticals Corporation
- Pfizer, Inc.
- Piramal Imaging
- Servier
- Takeda Pharmaceutical Company
- Transi-tion Therapeutics
- Canadian Institutes of Health Research
The study reveals a potential general mechanism that can explain the regional vulnerability of Alzheimer's disease, linking pathogenic disruptions in endosomal trafficking to its anatomical vulnerability, particularly in the trans-entorhinal cortex. VPS26b is found to mediate regionally selective synaptic dysfunction and SORL1 deficiency, providing insights into the pathogenesis of AD.
Whether and how the pathogenic disruptions in endosomal trafficking observed in Alzheimer's disease (AD) are linked to its anatomical vulnerability remain unknown. Here, we began addressing these questions by showing that neurons are enriched with a second retromer core, organized around VPS26b, differentially dedicated to endosomal recycling. Next, by imaging mouse models, we show that the trans-entorhinal cortex, a region most vulnerable to AD, is most susceptible to VPS26b depletion-a finding validated by electrophysiology, immunocytochemistry, and behavior. VPS26b was then found enriched in the trans-entorhinal cortex of human brains, where both VPS26b and the retromer-related receptor SORL1 were found deficient in AD. Finally, by regulating glutamate receptor and SORL1 recycling, we show that VPS26b can mediate regionally selective synaptic dysfunction and SORL1 deficiency. Together with the trans-entorhinal's unique network properties, hypothesized to impose a heavy demand on endosomal recycling, these results suggest a general mechanism that can explain AD's regional vulnerability.
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