Project DetailsToo much of beta-amyloid (ABeta) protein in the brain is believed to initiate the pathological cascade culminating in Alzheimer's disease (AD) - the most common form of dementia. ABeta is derived from the proteolytic cleavage of beta-amyloid precursor protein by beta- and gamma-secretase activities. Inhibiting either secretase is a major goal in AD therapeutics. The gamma-secretase, which determines the generation of the toxic form of ABeta, can be regulated by many factors or genetic pathways. Because gamma-secretase can also cleave a variety of membrane proteins, which are important for normal physiological activities, significant unwanted effects may appear if we could develop drugs to inhibit the gamma-secretase. In this proposal, we utilized a technology called Random Homozygous Knockout to identify genes that can inhibit the gamma-secretase activity and hence reduce brain ABeta levels. Through years of intensive research, we have found a novel gene, FG01, that can significantly reduce ABeta without affecting the action of gamma-secretase toward other important proteins when it is expressed in mouse and human neuron-like cells. We will continue to characterize the functions of this gene to understand its mechanism of action, which may eventually be applied to develop therapeutic interventions specifically inhibiting ABeta without unwanted side-effects.