Amyloid Precursor Protein Processing and Alzheimer’s Disease.pdfVIP

NIH Public Access Author Manuscript Annu Rev Neurosci . Author manuscript; available in PMC 2011 September 15. N Published in final edited form as: I H Annu Rev Neurosci. 2011 ; 34: 185–204. doi:10.1146/annurev-neuro-061010-113613. - P A A u Amyloid Precursor Protein Processing and Alzheimer’s Disease t h o r 1 2 Richard J. O’Brien and Philip C. Wong M a Richard J. O’Brien: robrien@ n 1 u Department of Neurology, Johns Hopkins Bayview Medical Center s c 2 r Department of Pathology, Johns Hopkins University School of Medicine i p t Abstract Alzheimer’s disease (AD), the leading cause of dementia worldwide, is characterized by the accumulation of the β-amyloid peptide (Aβ) 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 Aβ peptide from sequential amyloid N precursor protein (APP) proteolysis is the crucial step in the development of AD. APP is a single- I H pass transmembrane protein expressed at high levels in the brain and metabolized in a rapid and - P highly complex fashion by a series of sequential proteases, including the intramembranous γ- A secretase complex, which also process other key regulatory molecules. Why Aβ accumulates in A the brains of elderly individuals is unclear but could relate to changes in APP metabolism or Aβ u t h elimination. Lessons l