TREM2 Binds to Apolipoproteins, Including APOE and CLU/APOJ, and Thereby Facilitates Uptake of Amyloid-Beta by Microglia

Genetic variants of TREM2, a protein expressed selectively by microglia in the brain, are associated with Alzheimer's disease (AD). Starting from an unbiased protein microarray screen, we identified a set of lipoprotein particles (including LDL) and apolipoproteins (including CLU/APOJ and APOE)...

Full description

Saved in:
Bibliographic Details
Published in:Neuron (Cambridge, Mass.) Vol. 91; no. 2; pp. 328 - 340
Main Authors: Yeh, Felix L, Wang, Yuanyuan, Tom, Irene, Gonzalez, Lino C, Sheng, Morgan
Format: Journal Article
Language:English
Published: United States 20.07.2016
Subjects:
Alzheimer Disease - metabolism
Amyloid beta-Peptides - metabolism
Apolipoproteins - metabolism
Brain - metabolism
Cell Line
Humans
Membrane Glycoproteins - genetics
Membrane Glycoproteins - metabolism
Microglia - metabolism
Protein Binding
Receptors, Immunologic - genetics
Receptors, Immunologic - metabolism
ISSN:1097-4199
Online Access:Get more information
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Genetic variants of TREM2, a protein expressed selectively by microglia in the brain, are associated with Alzheimer's disease (AD). Starting from an unbiased protein microarray screen, we identified a set of lipoprotein particles (including LDL) and apolipoproteins (including CLU/APOJ and APOE) as ligands of TREM2. Binding of these ligands by TREM2 was abolished or reduced by disease-associated mutations. Overexpression of wild-type TREM2 was sufficient to enhance uptake of LDL, CLU, and APOE in heterologous cells, whereas TREM2 disease variants were impaired in this activity. Trem2 knockout microglia showed reduced internalization of LDL and CLU. β-amyloid (Aβ) binds to lipoproteins and this complex is efficiently taken up by microglia in a TREM2-dependent fashion. Uptake of Aβ-lipoprotein complexes was reduced in macrophages from human subjects carrying a TREM2 AD variant. These data link three genetic risk factors for AD and reveal a possible mechanism by which mutant TREM2 increases risk of AD. VIDEO ABSTRACT.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1097-4199
DOI:10.1016/j.neuron.2016.06.015