TY  - JOUR
AU  - Parhizkar, Samira
AU  - Arzberger, Thomas
AU  - Brendel, Matthias
AU  - Kleinberger, Gernot
AU  - Deussing, Maximilian
AU  - Focke, Carola
AU  - Nuscher, Brigitte
AU  - Xiong, Monica
AU  - Ghasemigharagoz, Alireza
AU  - Katzmarski, Natalie
AU  - Krasemann, Susanne
AU  - Lichtenthaler, Stefan F
AU  - Müller, Stephan A
AU  - Colombo, Alessio
AU  - Sebastian Monasor, Laura
AU  - Tahirovic, Sabina
AU  - Herms, Jochen
AU  - Willem, Michael
AU  - Pettkus, Nadine
AU  - Butovsky, Oleg
AU  - Bartenstein, Peter
AU  - Edbauer, Dieter
AU  - Rominger, Axel
AU  - Ertürk, Ali
AU  - Grathwohl, Stefan A
AU  - Neher, Jonas J
AU  - Holtzman, David M
AU  - Meyer-Luehmann, Melanie
AU  - Haass, Christian
TI  - Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE.
JO  - Nature reviews / Neuroscience
VL  - 22
IS  - 2
SN  - 1097-6256
CY  - London
PB  - Nature Publ. Group58142
M1  - DZNE-2020-06770
SP  - 191-204
PY  - 2019
AB  - 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.
KW  - Alzheimer Disease: genetics
KW  - Alzheimer Disease: metabolism
KW  - Alzheimer Disease: pathology
KW  - Amyloid: metabolism
KW  - Amyloid beta-Peptides: genetics
KW  - Amyloid beta-Peptides: metabolism
KW  - Amyloid beta-Protein Precursor: genetics
KW  - Amyloid beta-Protein Precursor: metabolism
KW  - Animals
KW  - Apolipoproteins E: metabolism
KW  - Brain: metabolism
KW  - Brain: pathology
KW  - Disease Models, Animal
KW  - Genotype
KW  - Humans
KW  - Membrane Glycoproteins: genetics
KW  - Membrane Glycoproteins: metabolism
KW  - Mice
KW  - Mice, Transgenic
KW  - Microglia: metabolism
KW  - Microglia: pathology
KW  - Phagocytosis: physiology
KW  - Plaque, Amyloid: genetics
KW  - Plaque, Amyloid: metabolism
KW  - Plaque, Amyloid: pathology
KW  - Receptors, Immunologic: genetics
KW  - Receptors, Immunologic: metabolism
KW  - Amyloid (NLM Chemicals)
KW  - Amyloid beta-Peptides (NLM Chemicals)
KW  - Amyloid beta-Protein Precursor (NLM Chemicals)
KW  - Apolipoproteins E (NLM Chemicals)
KW  - Membrane Glycoproteins (NLM Chemicals)
KW  - Receptors, Immunologic (NLM Chemicals)
KW  - Trem2 protein, mouse (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:30617257
C2  - pmc:PMC6417433
DO  - DOI:10.1038/s41593-018-0296-9
UR  - https://pub.dzne.de/record/140448
ER  -