Trafficking and Proteolytic Processing of APP

Accumulations of insoluble deposits of amyloid beta-peptide are major pathological hallmarks of Alzheimer disease. Amyloid beta-peptide is derived by sequential proteolytic processing from a large type I trans-membrane protein, the beta-amyloid precursor protein. The proteolytic enzymes involved in its processing are named secretases. beta- and gamma-secretase liberate by sequential cleavage the neurotoxic amyloid beta-peptide, whereas alpha-secretase prevents its generation by cleaving within the middle of the amyloid domain. In this chapter we describe the cell biological and biochemical characteristics of the three secretase activities involved in the proteolytic processing of the precursor protein. In addition we outline how the precursor protein maturates and traffics through the secretory pathway to reach the subcellular locations where the individual secretases are preferentially active. Furthermore, we illuminate how neuronal activity and mutations which cause familial Alzheimer disease affect amyloid beta-peptide generation and therefore disease onset and progression.