In:
eLife, eLife Sciences Publications, Ltd, Vol. 6 ( 2017-07-06)
Abstract:
The amyloid precursor protein (APP) harbors physiological roles at synapses and is central to Alzheimer’s disease (AD) pathogenesis. Evidence suggests that APP intracellular domain (AICD) could regulate synapse function, but the underlying molecular mechanisms remain unknown. We addressed AICD actions at synapses, per se, combining in vivo AICD expression, ex vivo AICD delivery or APP knock-down by in utero electroporation of shRNAs with whole-cell electrophysiology. We report a critical physiological role of AICD in controlling GluN2B-containing NMDA receptors (NMDARs) at immature excitatory synapses, via a transcription-dependent mechanism. We further show that AICD increase in mature neurons, as reported in AD, alters synaptic NMDAR composition to an immature-like GluN2B-rich profile. This disrupts synaptic signal integration, via over-activation of SK channels, and synapse plasticity, phenotypes rescued by GluN2B antagonism. We provide a new physiological role for AICD, which becomes pathological upon AICD increase in mature neurons. Thus, AICD could contribute to AD synaptic failure.
Type of Medium:
Online Resource
ISSN:
2050-084X
DOI:
10.7554/eLife.25659.001
DOI:
10.7554/eLife.25659.002
DOI:
10.7554/eLife.25659.003
DOI:
10.7554/eLife.25659.004
DOI:
10.7554/eLife.25659.005
DOI:
10.7554/eLife.25659.006
DOI:
10.7554/eLife.25659.007
DOI:
10.7554/eLife.25659.008
DOI:
10.7554/eLife.25659.009
DOI:
10.7554/eLife.25659.010
DOI:
10.7554/eLife.25659.011
DOI:
10.7554/eLife.25659.012
DOI:
10.7554/eLife.25659.013
DOI:
10.7554/eLife.25659.014
DOI:
10.7554/eLife.25659.015
Language:
English
Publisher:
eLife Sciences Publications, Ltd
Publication Date:
2017
detail.hit.zdb_id:
2687154-3