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

Autor:	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
Jazyk:	angličtina
Rok vydání:	2019
Předmět:	0301 basic medicine Apolipoprotein E genetics [Plaque Amyloid] Mutant microglia genetics [Alzheimer Disease] Plaque Amyloid metabolism [Microglia] metabolism [Apolipoproteins E] pathology [Alzheimer Disease] Amyloid beta-Protein Precursor Mice 0302 clinical medicine genetics [Membrane Glycoproteins] pathology [Brain] metabolism [Amyloid beta-Protein Precursor] TREM2 genetics [Amyloid beta-Peptides] genetics [Receptors Immunologic] Receptors Immunologic Receptor 610 Medicine & health Membrane Glycoproteins Microglia Chemistry General Neuroscience neurodegeneration pathology [Microglia] metabolism [Receptors Immunologic] Brain amyloid plaque seeding medicine.anatomical_structure genetics [Amyloid beta-Protein Precursor] Seeding physiology [Phagocytosis] Alzheimer’s disease metabolism [Alzheimer Disease] ApoE Amyloid medicine.medical_specialty Genotype metabolism [Amyloid beta-Peptides] Mice Transgenic Article 03 medical and health sciences Trem2 protein mouse Apolipoproteins E Phagocytosis Alzheimer Disease ddc:570 Internal medicine medicine Animals Humans pathology [Plaque Amyloid] metabolism [Amyloid] Amyloid beta-Peptides metabolism [Plaque Amyloid] Disease Models Animal 030104 developmental biology Endocrinology metabolism [Brain] metabolism [Membrane Glycoproteins] 030217 neurology & neurosurgery Function (biology)
Zdroj:	Nature neuroscience Nature reviews / Neuroscience 22(2), 191-204 (2019). doi:10.1038/s41593-018-0296-9 Nature Neuroscience
DOI:	10.7892/boris.125653
Popis:	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.
Databáze:	OpenAIRE
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