Mechanisms of Signal Transduction
The Effects of Amyloid Precursor Protein on Postsynaptic Composition and Activity*

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The amyloid precursor protein (APP) is cleaved to produce the Alzheimer disease-associated peptide Aβ, but the normal functions of uncleaved APP in the brain are unknown. We found that APP was present in the postsynaptic density of central excitatory synapses and coimmunoprecipitated with N-methyl-d-aspartate receptors (NMDARs). The presence of APP in the postsynaptic density was supported by the observation that NMDARs regulated trafficking and processing of APP; overexpression of the NR1 subunit increased surface levels of APP, whereas activation of NMDARs decreased surface APP and promoted production of Aβ. We transfected APP or APP RNA interference into primary neurons and used electrophysiological techniques to explore the effects of APP on postsynaptic function. Reduction of APP decreased (and overexpression of APP increased) NMDAR whole cell current density and peak amplitude of spontaneous miniature excitatory postsynaptic currents. The increase in NMDAR current by APP was due to specific recruitment of additional NR2B-containing receptors. Consistent with these findings, immunohistochemical experiments demonstrated that APP increased the surface levels and decreased internalization of NR2B subunits. These results demonstrate a novel physiological role of postsynaptic APP in enhancing NMDAR function.

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The abbreviations used are: AD, Alzheimer disease; APP, amyloid precursor protein; NMDA, N-methyl-d-aspartate; NMDAR, NMDA receptor; RNAi, RNA interference; PSD, postsynaptic density; mEPSC, miniature excitatory postsynaptic current; GFP, green fluorescent protein; siRNA, small interfering RNA; β-ME, β-mercaptoethanol; PBS, phosphate-buffered saline; DIV, day(s) in vitro; CGC, cerebellar granule cell; pF, picofarads.

*

This work was supported, in whole or in part, by National Institutes of Health Grants AG14473 (to G. W. R.), NS48085 (to D. T. S. P.), NS047700 (to S. V.), AG12406 (to B. T. H.), AG032330 (to H. S. H.). This work is also supported by the Alzheimer’s Research Fund in memory of Bill and Marie Drach. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

1

Both of these authors contributed equally to this work.

2

Present address: Neurodegeneration Research, GlaxoSmith Kline, Shanghai 201203, China.

3

Investigator of the Howard Hughes Medical Institute.