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The amyloid precursor protein (APP) undergoes constitutive shedding by a protease activity called a-secretase. This is considered an important mechanism preventing the generation of the Alzheimer's disease amyloid-b peptide (Ab). a-Secretase appears to be a metalloprotease of the ADAM family, but its identity remains to be established. Using a novel a-secretase-cleavage site-specific antibody, we found that RNAi-mediated knockdown of ADAM10, but surprisingly not of ADAM9 or 17, completely suppressed APP a-secretase cleavage in different cell lines and in primary murine neurons. Other proteases were not able to compensate for this loss of a-cleavage. This finding was further confirmed by mass-spectrometric detection of APPcleavage fragments. Surprisingly, in different cell lines, the reduction of a-secretase cleavage was not paralleled by a corresponding increase in the Ab-generating b-secretase cleavage, revealing that both proteases do not always compete for APP as a substrate. Instead, our data suggest a novel pathway for APP processing, in which ADAM10 can partially compete with c-secretase for the cleavage of a C-terminal APP fragment generated by b-secretase. We conclude that ADAM10 is the physiologically relevant, constitutive a-secretase of APP.

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.