Plaque-independent disruption of neural circuits in Alzheimer’s disease mouse models

Plaque-independent disruption of neural circuits in Alzheimer’s disease mouse models

Departments of ^*Cellular and Molecular Pharmacology, ^†Physiology, ^**Psychiatry, and ^††Neurology, University of California at San Francisco, San Francisco, CA 94143-0450; ^§Departments of Neurosciences and Pathology, University of California at San Diego, La Jolla, CA 92093-0624; ^¶Elan Pharmaceuticals, South San Francisco, CA 94080; and ^‖Gladstone Institute of Neurological Disease, San Francisco, CA 94141-9100

Contributed by Roger A. Nicoll

Abstract

Autosomal dominant forms of familial Alzheimer’s disease (FAD) are associated with increased production of the amyloid β peptide, Aβ42, which is derived from the amyloid protein precursor (APP). In FAD, as well as in sporadic forms of the illness, Aβ peptides accumulate abnormally in the brain in the form of amyloid plaques. Here, we show that overexpression of FAD(717_V→F)-mutant human APP in neurons of transgenic mice decreases the density of presynaptic terminals and neurons well before these mice develop amyloid plaques. Electrophysiological recordings from the hippocampus revealed prominent deficits in synaptic transmission, which also preceded amyloid deposition by several months. Although in young mice, functional and structural neuronal deficits were of similar magnitude, functional deficits became predominant with advancing age. Increased Aβ production in the context of decreased overall APP expression, achieved by addition of the Swedish FAD mutation to the APP transgene in a second line of mice, further increased synaptic transmission deficits in young APP mice without plaques. These results suggest a neurotoxic effect of Aβ that is independent of plaque formation.

Footnotes

↵ ‡ Present address: Centre National de la Recherche Scientifique, Institut Alfred Fessard, Avenue de la Terrasse, 91198 Gif-Yvette, France.
↵ ‡‡ To whom reprint requests should be addressed at: Gladstone Institute of Neurological Disease, P.O. Box 41900, San Francisco, CA 94141-9100. e-mail: Lmucke{at}gladstone.ucsf.edu.
ABBREVIATIONS:

AD,

Alzheimer’s disease;

APP,

amyloid protein precursor;

FAD,

familial AD;

PDGF,

platelet-derived growth factor;

RPA,

RNase protection assay;

FL,

full-length;

NMDA,

N-methyl-d-aspartate;

AMPA,

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

EPSC,

excitatory postsynaptic current;

hAPP,

human APP;

EPSP,

excitatory postsynaptic potential;

LTP,

long-term potentiation;

nt,

nucleotides