AMPA Receptor Activation Promotes Non-Amyloidogenic Amyloid Precursor Protein Processing and Suppresses Neuronal Amyloid-beta Production

作者:Hoey Sarah E; Buonocore Federica; Cox Carla J; Hammond Victoria J; Perkinton Michael S; Williams Robert J*
来源:PLos One, 2013, 8(10): e78155.
DOI:10.1371/journal.pone.0078155

摘要

Soluble oligomeric amyloid beta peptide (A beta) generated from processing of the amyloid precursor protein (APP) plays a central role in the pathogenesis of Alzheimer%26apos;s Disease (AD) and through actions at glutamatergic synapses affects excitability and plasticity. The physiological control of APP processing is not fully understood but stimulation of synaptic NMDA receptors (NMDAR) can suppress A beta levels through an ERK-dependent increase in alpha-secretase activity. AMPA-type glutamate receptors (AMPAR) couple to ERK phosphorylation independently of NMDAR activation raising the possibility that stimulation of AMPAR might similarly promote non-amyloidogenic APP processing. We have tested this hypothesis by investigating whether AMPAR directly regulate APP processing in cultured mouse cortical neurons, by analyzing APP C-terminal fragments (CTFs), soluble APP (sAPP), A beta levels, and cleavage of an APP-GAL4 reporter protein. We report that direct stimulation of AMPAR increases non-amyloidogenic alpha-secretase-mediated APP processing and inhibits A beta production. Processing was blocked by the matrix metalloproteinase inhibitor TAPI-1 but was only partially dependent on Ca2+ influx and ERK activity. AMPAR can therefore, be added to the repertoire of receptors that couple to non-amyloidogenic APP processing at glutamatergic synapses and thus pharmacological targeting of AMPAR could potentially influence the development and progression of A beta pathology in AD.

  • 出版日期2013-10-24