Stimulation of β-amyloid precursor protein trafficking by insulin reduces intraneuronal β-amyloid and requires mitogen-activated protein kinase signaling

Alzheimer's Disease (AD) is characterized by cerebral accumulation of beta -amyloid peptides (A beta), which are proteolytically derived from beta -amyloid precursor protein (beta APP). beta APP 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 s beta APP 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 A beta and that it does so by accelerating beta APP/A beta trafficking from the transGolgi network, a major cellular site for A beta generation, to the plasma membrane. Furthermore, insulin increases the extracellular level of A beta both by promoting its secretion and by inhibiting its degradation via insulin-degrading enzyme. The action of insulin on beta APP 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 beta APP and A beta trafficking in neuronal cultures.