Accumulation of high molecular weight kininogen in the brains of Alzheimer's disease patients may affect microglial function by altering phagocytosis and lysosomal cathepsin activity

• Published in: Alzheimer's & dementia Vol. 18; no. 10; pp. 1919 - 1929
• Main Authors: Zamolodchikov, Daria, Duffield, Michael, Macdonald, Lynn E., Alessandri‐Haber, Nicole
• Format: Journal Article
• Language: English
• Published: United States 01.10.2022
• Subjects: Alzheimer Disease - metabolism; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Brain - metabolism; cathepsin; Cathepsins - metabolism; Cathepsins - pharmacology; high molecular weight kininogen; Humans; Kininogen, High-Molecular-Weight - metabolism; Kininogen, High-Molecular-Weight - pharmacology; Lysosomes - metabolism; microglia; Microglia - metabolism; Phagocytosis; phagocytosis; cathepsin; Alzheimer's disease; microglia; high molecular weight kininogen
• ISSN: 1552-5260; 1552-5279
• DOI: 10.1002/alz.12531

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 (Aβ) deposits and activated microglia. Treatment of microglia with HK led to cell clustering and elevated levels of phagocytosed Aβ. 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 Aβ fibrils, possibly contributing to microglial dysfunction in AD.