Inhibition of calpains improves memory and synaptic transmission in a mouse model of Alzheimer disease
Fabrizio Trinchese, … , Ralph A. Nixon, Ottavio Arancio
Fabrizio Trinchese, … , Ralph A. Nixon, Ottavio Arancio
Published July 1, 2008
Citation Information: J Clin Invest. 2008;118(8):2796-2807. https://doi.org/10.1172/JCI34254.
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Research Article Neuroscience

Inhibition of calpains improves memory and synaptic transmission in a mouse model of Alzheimer disease

Abstract

Calpains are calcium-dependent enzymes that determine the fate of proteins through regulated proteolytic activity. Calpains have been linked to the modulation of memory and are key to the pathogenesis of Alzheimer disease (AD). When abnormally activated, calpains can also initiate degradation of proteins essential for neuronal survival. Here we show that calpain inhibition through E64, a cysteine protease inhibitor, and the highly specific calpain inhibitor BDA-410 restored normal synaptic function both in hippocampal cultures and in hippocampal slices from the APP/PS1 mouse, an animal model of AD. Calpain inhibition also improved spatial-working memory and associative fear memory in APP/PS1 mice. These beneficial effects of the calpain inhibitors were associated with restoration of normal phosphorylation levels of the transcription factor CREB and involved redistribution of the synaptic protein synapsin I. Thus, calpain inhibition may prove useful in the alleviation of memory loss in AD.

Authors

Fabrizio Trinchese, Mauro Fa’, Shumin Liu, Hong Zhang, Ariel Hidalgo, Stephen D. Schmidt, Hisako Yamaguchi, Narihiko Yoshii, Paul M. Mathews, Ralph A. Nixon, Ottavio Arancio

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Figure 2

The highly selective calpain inhibitor BDA-410 reestablished normal basal frequency of spontaneous neurotransmitter release and rescued impairment of synaptic plasticity in APP/PS1 mouse cultures.

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The highly selective calpain inhibitor BDA-410 reestablished normal basa...
(A) Chemical structure of BDA-410. (B) Vehicle-treated APP/PS1 cultures showed approximately 2-fold increase of spontaneous mEPSC frequency (n = 7) compared with vehicle-treated WT cultures (n = 8; P < 0.01 with 1-way ANOVA). BDA-410 did not affect average basal mEPSC frequency in WT cultures (n = 7) and reestablished normal basal frequency of spontaneous neurotransmitter release in APP/PS1 cultures (n = 8; P < 0.01). (C) Application of glutamate (200 μM) did not enhance mEPSC frequency in cultures from APP/PS1 mice compared with cultures from WT mice (n = 7 in APP/PS1 cultures; n = 8 in WT littermate cultures; P < 0.01 with 2-way ANOVA). mEPSC amplitude values were not affected by glutamate (data not shown). Block of calpain activity through BDA-410 was beneficial against the impairment of long-lasting enhancement of synaptic transmission (n = 8; P < 0.01 compared with vehicle-treated APP/PS1 cultures), without affecting it in WT cultures (P > 0.05 compared with vehicle-treated WT cultures).