Abstract
Alzheimer's Disease (AD) is characterized by cerebral accumulation of β-amyloid peptides (Aβ), which are proteolytically derived from β-amyloid precursor protein (βAPP). βAPP metabolism is highly regulated via various signal transduction systems, e.g., several serine/threonine kinases and phosphatases. Several growth factors known to act via receptor tyrosine kinases also have been demonstrated to regulate sβAPP secretion. Among these receptors, insulin and insulin-like growth factor-1 receptors are highly expressed in brain, especially in hippocampus and cortex. Emerging evidence indicates that insulin has important functions in brain regions involved in learning and memory. Here we present evidence that insulin significantly reduces intracellular accumulation of Aβ and that it does so by accelerating βAPP/Aβ trafficking from the trans-Golgi network, a major cellular site for Aβ generation, to the plasma membrane. Furthermore, insulin increases the extracellular level of Aβ both by promoting its secretion and by inhibiting its degradation via insulin-degrading enzyme. The action of insulin on βAPP metabolism is mediated via a receptor tyrosine kinase/mitogen-activated protein (MAP) kinase kinase pathway. The results suggest cell biological and signal transduction mechanisms by which insulin modulates βAPP and Aβ trafficking in neuronal cultures.
