Amyloid Precursor Protein Processing and Alzheimer's Disease

Alzheimer's disease (AD), the leading cause of dementia worldwide, is characterized by the accumulation of the beta-amyloid peptide (A beta) within the brain along with hyperphosphorylated and cleaved forms of the microtubule-associated protein tau. Genetic, biochemical, and behavioral research suggest that physiologic generation of the neurotoxic A beta peptide from sequential amyloid precursor protein (APP) proteolysis is the crucial step in the development of AD. APP is a single-pass transmembrane protein expressed at high levels in the brain and metabolized in a rapid and highly complex fashion by a series of sequential proteases, including the intramembranous gamma-secretase complex, which also process other key regulatory molecules. Why A beta accumulates in the brains of elderly individuals is unclear but could relate to changes in APP metabolism or A beta elimination. Lessons learned from biochemical and genetic studies of APP processing will be crucial to the development of therapeutic targets to treat AD.