In Vitro and In Vivo Analysis of APP Variants

Early-onset, familial forms of Alzheimer’s disease are caused by the inheritance of mutations in genes that code for amyloid precursor protein (APP) or presenilins (PS1 and PS2). The main pathological hallmark of Alzheimer’s disease is the presence of senile plaques composed of amyloid beta plaques that arise from the cleavage of amyloid precursor protein. Mutations in the amyloid precursor protein gene are located within or close to the sequence that codes for the amyloid beta peptide. Recently, Dr. Rudy Tanzi and colleagues have identified an additional mutation in the APP gene that causes familial Alzheimer’s disease. Of interest, this mutation is located far away from the other mutations typically seen next to the amyloid beta domain. We have examined the impact of this mutation on the production of amyloid beta plaques and have demonstrated, using two methods (cultured mammalian cells and mouse models of Alzheimer’s disease that carry this mutation), that levels of amyloid beta are increased. This proposal seeks to clarify the mechanism by which this mutation in amyloid precursor protein enhances amyloid beta production.