INTRACELLULAR AND SECRETED ALZHEIMER BETA-AMYLOID SPECIES ARE GENERATED BY DISTINCT MECHANISMS IN CULTURED HIPPOCAMPAL-NEURONS

Cerebral plaques containing beta-amyloid (beta A4) represent an invari ant pathological feature of Alzheimer disease (AD). beta A4 is proteol ytically generated from its parent molecule, amyloid precursor protein (APP). In nonneuronal cells beta A4 has been shown to be secreted via a pH-sensitive and endocytosis-dependent pathway, and this process, w hen occurring in the brain, is considered to play an important role in AD. In neurons the mechanisms of beta A4 production are not known. He re we have analyzed these mechanisms by expressing human APP and its m utant versions in hippocampal neurons using the Semliki forest virus s ystem. We show that these cells initially generate two pools of beta A 4, an extracellular and an intracellular, and only the extracellular p ool is produced via a pH-sensitive and endocytosis-dependent pathway. Thus, hippocampal neurons are able to utilize an alternate pathway to produce intracellular beta A4. We also show that a common feature of t wo types of APP mutations (''Swedish'' and ''London'') implicated in e arly-onset AD is their increased production of C-terminally elongated beta A4 (beta(42)), both intra- and extracellularly. Since neurons are the only cells that produce substantial levels of intracellular beta A4 and also the main victims in AD, these findings may provide an impo rtant link between beta A4 and neurodegeneration.