期刊
ALZHEIMERS & DEMENTIA
卷 18, 期 10, 页码 1919-1929出版社
WILEY
DOI: 10.1002/alz.12531
关键词
Alzheimer's disease; cathepsin; high molecular weight kininogen; microglia; phagocytosis
资金
- PHS contract [HHSN-271-2013-00030C]
This study found increased accumulation of high molecular weight kininogen (HK) in the hippocampus of Alzheimer's disease (AD) patients, which may affect the uptake and degradation of Aβ fibrils by microglia, leading to microglial dysfunction in AD.
Increased activation of the contact system protein high molecular weight kininogen (HK) has been shown in plasma and cerebrospinal fluid of Alzheimer's disease (AD) patients, but its potential role in the brain has not been explored. We assessed HK levels in brain tissue from 20 AD patients and controls and modeled the effects of HK on microglia-like cells in culture. We show increased levels of HK in the hippocampus of AD patients, which colocalized with amyloid beta (A beta) deposits and activated microglia. Treatment of microglia with HK led to cell clustering and elevated levels of phagocytosed A beta. We demonstrate that microglia internalize HK and traffic it to lysosomes, which is accompanied by reduced activity of lysosomal cathepsins L and S. Our results suggest that HK accumulation in the AD hippocampus may alter microglial uptake and degradation of A beta fibrils, possibly contributing to microglial dysfunction in AD.
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