Amyloid beta (Aβ) is the main component of senile plaques, a distinct pathological hallmark in the brain of Alzheimer’s disease (AD) patients. Aβ is generated from amyloid precursor protein (APP) when cleaved by beta- and gamma-secretase enzymes. Instead, when APP is cleaved by alpha-secretase ADAM10 at the middle of the Aβ sequence, Aβ generation is prevented. Our previous studies of rare DNA mutations in ADAM10 and more recent large-scale genetic studies consistently showed that loss of ADAM10 function would increase the risk for AD. Beyond their central roles in Aβ generation, one prominent physiological function of both APP and ADAM10 in the brain is regulating neuronal adhesion to the extracellular matrix or different cells. In a preliminary study utilizing gene editing technology, we found an AD-causing mutation in APP at the exact ADAM10 cleavage site prevents the proteolytic process and significantly downregulates cell adhesion and migration. Together, these findings strongly support that ADAM10 plays an important role in AD through the cleavage of APP, and that increasing ADAM10 expression or activity is a promising avenue for AD therapy. In the proposed study, we aim to expand these findings and test the therapeutic possibility via three different approaches. First, we will test whether adeno-associated virus (AAV)-mediated increase of ADAM10 expression in adult brain decreases AD pathogenesis in a well-characterized AD mouse model. Second, we will develop an experimental antisense oligonucleotide drug that would increase ADAM10 expression and alleviate AD phenotypes. Third, we will make genetically engineered mice in which ADAM10-mediated cleavage of APP is specifically inhibited. We will examine the impact of reduced APP cleavage on brain physiology. We believe the research findings from the proposed study will accelerate drug development for AD and the research into a new direction based on the physiological functions of APP and ADAM10 in the brain.