Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE

Parhizkar, Samira; Arzberger, Thomas; Brendel, Matthias; Kleinberger, Gernot; Deussing, Maximilian; Focke, Carola; Nuscher, Brigitte; Xiong, Monica; Ghasemigharagoz, Alireza; Katzmarski, Natalie; Krasemann, Susanne; Lichtenthaler, Stefan F.; Müller, Stephan A.; Colombo, Alessio; Monasor, Laura Sebastian; Tahirovic, Sabina; Herms, Jochen; Willem, Michael; Pettkus, Nadine; Butovsky, Oleg; ... (2019). Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE. Nature neuroscience, 22(2), pp. 191-204. Nature America 10.1038/s41593-018-0296-9

Text Parhizkar_2019_Nat_Neurosci.pdf - Published Version Restricted to registered users only Available under License Publisher holds Copyright. Download (4MB) | Request a copy

Coding variants in the triggering receptor expressed on myeloid cells 2 (TREM2) are associated with late-onset Alzheimer's disease (AD). We demonstrate that amyloid plaque seeding is increased in the absence of functional Trem2. Increased seeding is accompanied by decreased microglial clustering around newly seeded plaques and reduced plaque-associated apolipoprotein E (ApoE). Reduced ApoE deposition in plaques is also observed in brains of AD patients carrying TREM2 coding variants. Proteomic analyses and microglia depletion experiments revealed microglia as one origin of plaque-associated ApoE. Longitudinal amyloid small animal positron emission tomography demonstrates accelerated amyloidogenesis in Trem2 loss-of-function mutants at early stages, which progressed at a lower rate with aging. These findings suggest that in the absence of functional Trem2, early amyloidogenesis is accelerated due to reduced phagocytic clearance of amyloid seeds despite reduced plaque-associated ApoE.

Interest & Impact

Downloads

1 since deposited on 06 May 2019
0 in the past 12 months

Citations

5 Citations in Web of Science ®
6 Citations in Scopus

Search

in Google Scholar™

Services

Actions (login required)

Edit item

Actions (login required)

Edit item