BACE overexpression alters the subcellular processing of APP and inhibits A[beta] deposition in vivo

Introducing mutations within the amyloid precursor protein (APP) that affect [beta]- and [gamma]-secretase cleavages results in amyloid plaque formation in vivo. However, the relationship between [beta]-amyloid deposition and the subcellular site of A[beta] production is unknown. To determine the effect of increasing [beta]-secretase (BACE) activity on A[beta] deposition, we generated transgenic mice overexpressing human BACE. Although modest overexpression enhanced amyloid deposition, high BACE overexpression inhibited amyloid formation despite increased [beta]-cleavage of APP. However, high BACE expression shifted the subcellular location of APP cleavage to the neuronal perikarya early in the secretory pathway. These results suggest that the production, clearance, and aggregation of A[beta] peptides are highly dependent on the specific neuronal subcellular domain wherein A[beta] is generated and highlight the importance of perikaryal versus axonal APP proteolysis in the development of A[beta] amyloid pathology in Alzheimer's disease.