AMPA Receptor Activation Promotes Non-Amyloidogenic Amyloid Precursor Protein Processing and Suppresses Neuronal Amyloid-β ProductionReport as inadecuate




AMPA Receptor Activation Promotes Non-Amyloidogenic Amyloid Precursor Protein Processing and Suppresses Neuronal Amyloid-β Production - Download this document for free, or read online. Document in PDF available to download.

Soluble oligomeric amyloid β peptide Aβ generated from processing of the amyloid precursor protein APP plays a central role in the pathogenesis of Alzheimer-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 Aβ levels through an ERK-dependent increase in α-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, Aβ levels, and cleavage of an APP-GAL4 reporter protein. We report that direct stimulation of AMPAR increases non-amyloidogenic α-secretase-mediated APP processing and inhibits Aβ 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 Aβ pathology in AD.



Author: Sarah E. Hoey, Federica Buonocore, Carla J. Cox, Victoria J. Hammond, Michael S. Perkinton, Robert J. Williams

Source: http://plos.srce.hr/



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