The adipocyte differentiation protein APMAP is an endogenous suppressor of Ab production in the brain

The deposition of amyloid-beta (Ab) aggregates in the brain is a major pathological hallmark of Alzheimer’s disease (AD). Ab is generated from the cleavage of C-terminal fragments of the amyloid precursor protein (APP-CTFs) by g-secretase, an intramembrane-cleaving protease with multiple substrates, including the Notch receptors. Endogenous modulation of g-secretase is pointed to be implicated in the sporadic, agedependent form of AD. Moreover, specifically modulating Abproduction has become a priority for the safe treatment of AD because the inhibition of g-secretase results in adverse effects that are related to impaired Notch cleavage. Here, we report the identification of the adipocyte differentiation protein APMAP as a novel endogenous suppressor of Ab generation. We found that APMAP interacts physically with g-secretase and its substrate APP. In cells, the partial depletion of APMAP drastically increased the levels of APP-CTFs, as well as uniquely affecting their stability, with the consequence being increased secretion of Ab. In wild-type and APP/ presenilin 1 transgenic mice, partial adeno-associated virus-mediated APMAP knockdown in the hippocampus increased Ab production by ∼20 and ∼55%, respectively. Together, our data demonstrate that APMAP is a negative regulator of Abproduction through its interaction with APP andg-secretase. All observed APMAP phenotypes can be explained by an impaired degradation of APP-CTFs, likely caused by an altered substrate transport capacity to the lysosomal/autophagic system.