The amyloid precursor protein: a biochemical enigma in brain development, function and disease.

For 20 years the amyloid cascade hypothesis of Alzheimer disease (AD) has placed the amyloid-β peptide (Aβ), formed from the amyloid precursor protein (APP), centre stage in the process of neurodegeneration. However, no new therapeutic agents have reached the clinic through exploitation of the hypothesis. The APP metabolites, including Aβ, generated by its proteolytic processing, have distinct physiological functions. In particular, the cleaved intracellular domain of APP (AICD) regulates expression of several genes, including APP itself, the β-secretase BACE-1 and the Aβ-degrading enzyme, neprilysin and this transcriptional regulation involves direct promoter binding of AICD. Of the three major splice isoforms of APP (APP695, APP751, APP770), APP695 is the predominant neuronal form, from which Aβ and transcriptionally-active AICD are preferentially generated by selective processing through the amyloidogenic pathway. Despite intensive research, the normal functions of the APP isoforms remain an enigma. APP plays an important role in brain development, memory and synaptic plasticity and secreted forms of APP are neuroprotective. A fuller understanding of the physiological and pathological actions of APP and its metabolic and gene regulatory network could provide new therapeutic opportunities in neurodegeneration, including AD.