Ludwig-Maximilians-Universität, Chair of Metabolic Biochemistry

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

Nat Neurosci. 2019 Feb;22(2):191-204

Authors/Editors: Samira Parhizkar
Thomas Arzberger
Matthias Brendel
Gernot Kleinberger
Maximilian Deussing
Carola Focke
Brigitte Nuscher
Monica Xiong
Alireza Ghasemigharagoz
Natalie Katzmarski
Susanne Krasemann
Stefan F. Lichtenthaler
Stephan A. Müller
Alessio Colombo
Laura Sebastian Monasor
Sabina Tahirovic
Jochen Herms
Michael Willem
Nadine Pettkus
Oleg Butovsky
Peter Bartenstein
Dieter Edbauer
Axel Rominger
Ali Ertürk
Stefan A. Grathwohl
Jonas J. Neher
David M. Holtzman
Melanie Meyer-Luehmann
Christian Haass
Publication Date: 2019
Type of Publication: Journal Article


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.

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