Editors' ChoiceNeuroscience

Three risk factors, one mechanism

Sci. Signal.  26 Jul 2016:
Vol. 9, Issue 438, pp. ec171
DOI: 10.1126/scisignal.aah6246

Late-onset Alzheimer’s disease (AD) accounts for the majority of AD cases. A characteristic feature of AD is the accumulation of β-amyloid (Aβ) plaques in the brain. Several mutations are associated with risk for late-onset AD, particularly mutations in the genes encoding apolipoproteins APOE4 and clusterin (also known as APOJ), which alter the metabolism and impair the clearance of Aβ. Mutations in the gene encoding TREM2 (triggering receptor expressed on myeloid cells 2), a protein with a single transmembrane domain that is present in microglia in the brain, are also associated with increased risk of AD. Yeh et al. found that the three risk factors are mechanistically linked. A protein microarray screen using a library of secreted ligands immobilized on glass slides and a fusion antibody construct containing the extracellular domain of TREM2 or TREM1 identified various lipoproteins as potential selective ligands of TREM2. These included low-density lipoprotein, lipidated APOE and lapidated clusterin, which are the physiologically functional forms of these molecules. Constructs of any of the three AD-associated variants of TREM2 had reduced binding capacity for LDL, lipidated APOE, and lipidated clusterin. Compared with cells expressing wild-type TREM2, human embryonic kidney 293 (HEK293) cells expressing mutant TREM2 had a reduced rate of uptake of lipidated APOE and lipidated clusterin, as well as a reduction in the total amount of these lipoproteins that accumulated in the cells. Primary microglia from mice lacking TREM2 had decreased uptake of clusterin from astrocyte-conditioned medium. Step gradient density ultracentrifugation revealed that fluorescein-labeled Aβ aggregates migrated at the same density as LDL and lipidated clusterin. Microglia from wild-type but not Trem2-knockout mice took up more of the Aβ-LDL and Aβ-clusterin complexes than they did of the free Aβ from these gradient-purified fractions. The amount of Aβ-LDL and Aβ-clusterin uptake by microglia from Trem2 heterozygous (HET) mice was intermediate between that of microglia from wild-type and homozygous knockout mice, suggesting a gene dosage effect could have physiological relevance. After uptake, the degradation of free Aβ did not differ but that of Aβ-LDL was slower in Trem2-knockout microglia than in wild-type microglia. This effect on degradation suggested that TREM2-mediated uptake may engage more efficient degradative pathway in microglia than occurs through TREM2-independent mechanisms of uptake. Macrophages from human subjects carrying one allele of an AD-associated TREM2 mutant took up less Aβ-LDL than did those from age-, gender-, and ethnicity-matched control subjects. The findings suggest that as ligands of TREM2, lipidated clusterin and LDL (and potentially lipidated APOE) facilitate the uptake and clearance of Aβ by microglia, thus explaining how mutations in any of these molecules can increase Aβ accumulation and the associated risk for AD.

F. L. Yeh, Y. Wang, I. Tom, L. C. Gonzalez, M. Sheng, TREM2 binds to apolipoproteins, including APOE and CLU/APOJ, and thereby facilitates uptake of amyloid-beta by microglia. Neuron 91, 328–340 (2016). [Online Journal]