PHYSIOLOGICAL AND PATHOLOGICAL INTERRELATIONSHIPS OF AMYLOID-BETA PEPTIDE AND THE AMYLOID PRECURSOR PROTEIN

Amyloid beta peptide (beta A4) accumulates as plaques in the brains of individuals with Alzheimer's disease and Down's syndrome, and may con tribute to the cognitive decline that is a feature of these diseases. beta A4 is a normal product of cell metabolism, derived from the amylo id precursor protein (APP), but the biological functions of these mole cules are not fully known. A hypothetical, descriptive model of the bi ological interrelationships between beta A4 and APP is presented. APPs , the soluble form of APP, which is released at the neuronal surface, and beta A4 are envisaged as physiological ligands which have reciproc al paracrine effects on neuronal growth and neurite extension. Differe ntial expression of these factors, manifest as changes in the APPs:bet a A4 ratio, may therefore have growth-promoting or growth-inhibiting e ffects on neurons. These effects may be mediated through separate cell -surface interactions but common intracellular effector systems, such as calcium and protein kinase C. In turn, the intracellular events may control the relative production of each ligand from APP through negat ive feedback loops. Disturbances of these control mechanisms may permi t pathological overproduction, and hence accumulation, of beta A4. Suc h a model may also have therapeutic implications.