Recent studies suggest that cholesterol may modulate pathogenesis of Alzheimer's disease (AD) by modulating processing of the β-amyloid precursor protein (APP) and formation of amyloid-β (Aβ) peptide, a causative factor of AD. The link between cholesterol and Alzheimer's disease has also been revealed in a non-AD disorder with altered cholesterol metabolism, a Niemann Pick type C disease (NPC), which shows increased formation of Aβ. However, the exact molecular mechanism of cholesterol-effect on Aβ still remains to be determined. This project aims to analyze whether the molecular mechanisms of the cholesterol effect on APP and Aβ may involve APP-family members, APLP1 and APLP2.  We will elucidate whether cholesterol affects processing of APLP1 and APLP2, like APP, and whether the cholesterol effect on APP is mediated by APLP1/2-regulated trafficking of APP. Since APLPs, the two APP homologues, are processed in a manner analogous to APP and were previously shown also to modulate APP processing/endocytosis, we speculate that cholesterol-mediated alterations of APP cleavage/trafficking and formation of Aβ may involve APLP1 and/or APLP2. We envisage that proposed studies will add to the mechanism of cholesterol-effect in the pathogenesis of AD. Finding that cholesterol affects other APP family members, in addition to APP, will help elucidating whether cholesterol lowering drugs may potentially be used to treat Alzheimer's disease.