The amyloid precursor protein of Alzheimer's disease and the A beta peptide

Alzheimer's disease is characterized by the accumulation of beta amyloid pe ptides in plaques and vessel walls and by the intraneuronal accumulation of paired helical filaments composed of hyperphosphorylated tau. In this revi ew, we concentrate on the biology of amyloid precursor protein, and on the central role of amyloid in the pathogenesis of Alzheimer's disease, Amyloid precursor protein (APP) is part of a super-family of transmembrane and sec reted proteins. It appears to have a number of roles, including regulation of haemostasis and mediation of neuroprotection. APP also has potentially i mportant metal and heparin-binding properties, and the current challenge is to synthesize all these varied activities into a coherent view of its func tion. Cleavage of amyloid precursor protein by beta- and gamma-secretases r esults in the generation of the A beta (beta A4) peptide, whereas alpha-sec retase cleaves within the AP sequence and prevents formation from APP. Rece nt findings indicate that the site of gamma-secretase cleavage is critical to the development of amyloid deposits; A beta(1-42) is much more amyloidog enic than A beta(1-40). A beta(1-42) formation is favoured by mutations in the two presenilin genes (PS1 and PS2), and by the commonest amyloid precur sor protein mutations. Transgenic mouse models of Alzheimer's disease incor porating various mutations in the presenilin gene now exist, and have shown amyloid accumulation and cognitive impairment. Neurofibrillary tangles hav e not been reproduced in these models, however. While aggregated A beta is neurotoxic, perhaps via an oxidative mechanism, the relationship between su ch toxicity and neurofibrillary tangle formation remains a subject of ongoi ng research.