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

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Radiology, Neuroradiology and Nuclear Medicine (DRNN) > Clinic of Nuclear Medicine

UniBE Contributor:

Rominger, Axel Oliver

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1097-6256

Publisher:

Nature America

Language:

English

Submitter:

Sabine Lanz

Date Deposited:

06 May 2019 13:34

Last Modified:

24 Oct 2019 02:17

Publisher DOI:

10.1038/s41593-018-0296-9

PubMed ID:

30617257

BORIS DOI:

10.7892/boris.125653

URI:

https://boris.unibe.ch/id/eprint/125653

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