EBP1 potentiates amyloid β pathology by regulating γ-secretase

Abstract

The abnormal deposition of amyloid beta (A beta), produced by proteolytic cleavage events of amyloid precursor protein involving the protease gamma-secretase and subsequent polymerization into amyloid plaques, plays a key role in the neuropathology of Alzheimer's disease (AD). Here we show that ErbB3 binding protein 1 (EBP1)/proliferation-associated 2G4 (PA2G4) interacts with presenilin, a catalytic subunit of gamma-secretase, inhibiting A beta production. Mice lacking forebrain Ebp1/Pa2g4 recapitulate the representative phenotypes of late-onset sporadic AD, displaying an age-dependent increase in A beta deposition, amyloid plaques and cognitive dysfunction. In postmortem brains of patients with AD and 5x-FAD mice, we found that EBP1 is proteolytically cleaved by asparagine endopeptidase at N84 and N204 residues, compromising its inhibitory effect on gamma-secretase, increasing A beta aggregation and neurodegeneration. Accordingly, injection of AAV2-Ebp1 wild-type or an asparagine endopeptidase-uncleavable mutant into the brains of 5x-FAD mice decreased A beta generation and alleviated the behavioral impairments. Thus, our study suggests that EBP1 acts as an inhibitor of gamma-secretase on amyloid precursor protein cleavage and preservation of functional EBP1 could be a therapeutic strategy for AD.