Amyloid precursor protein overexpression depresses excitatory transmission through both presynaptic and postsynaptic mechanisms

doi:10.1073/pnas.0608807104

Amyloid precursor protein overexpression depresses excitatory transmission through both presynaptic and postsynaptic mechanisms

Department of *Physiology and Biophysics,
^‡Medicine, and
^§Pharmacology and
^†Graduate Program in Neurobiology and Behavior, University of Washington School of Medicine, Seattle, WA 98195; and
^¶Veterans Affairs Medical Center Geriatric Research Education and Clinical Center, Seattle, WA 98108

Edited by Richard L. Huganir, Johns Hopkins University School of Medicine, Baltimore, MD, and approved November 7, 2006 (received for review October 4, 2006)

Abstract

Overexpression of the amyloid precursor protein (APP) in hippocampal neurons leads to elevated β-amyloid peptide (Aβ) production and consequent depression of excitatory transmission. The precise mechanisms underlying APP-induced synaptic depression are poorly understood. Uncovering these mechanisms could provide insight into how neuronal function is compromised before cell death during the early stages of Alzheimer's disease. Here we verify that APP up-regulation leads to depression of transmission in cultured hippocampal autapses; and we perform whole-cell recording, FM imaging, and immunocytochemistry to identify the specific mechanisms accounting for this depression. We find that APP overexpression leads to postsynaptic silencing through a selective reduction of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated currents. This effect is likely mediated by Aβ because expression of mutant APP incapable of producing Aβ did not depress transmission. In addition, although we eliminate presynaptic silencing as a mechanism underlying APP-mediated inhibition of transmission, we did observe an Aβ-induced presynaptic deficit in vesicle recycling with sustained stimulation. These findings demonstrate that APP elevation disrupts both presynaptic and postsynaptic compartments.

Footnotes

^‖To whom correspondence should be addressed at:
Department of Physiology and Biophysics, University of Washington School of Medicine, Box 357290, Seattle, WA 98195.
E-mail: jmsull{at}u.washington.edu
Author contributions: J.T.T. and B.G.K. contributed equally to this work; J.T.T., B.G.K., and J.M.S. designed research; J.T.T., B.G.K., T.J.L., D.G.C., and J.M.S. performed research; J.T.T., B.G.K., T.J.L., D.G.C., and J.M.S. analyzed data; and J.T.T., B.G.K., and J.M.S. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS direct submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0608807104/DC1.
Abbreviations:

Aβ,

β-amyloid peptide;

AD,

Alzheimer's disease;

AMPA,

α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid;

AMPAR,

AMPA receptor;

APP,

amyloid precursor protein;

APPΔBACE,

APPM596V point mutant;

BACE,

β-APP-cleaving enzyme 1;

CNQX,

6-cyano-7-nitroquinoxaline-2,3-dione;

EPSC,

excitatory postsynaptic current;

FM1-43FX,

fixable variant of FM1-43;

IRES,

internal ribosomal entry site;

mEPSC,

miniature excitatory postsynaptic current;

NMDAR,

NMDA receptor;

PPR,

paired-pulse ratio;

RRP,

readily releasable pool;

SFV,

Semliki Forest virus.