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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 Article has an altmetric score of 21

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

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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 1

The calpain inhibitor E64 reestablished normal synaptic function in APP/PS1 mouse hippocampal cultures.

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The calpain inhibitor E64 reestablished normal synaptic function in APP/...
(A) Calpain 1 immunoreactivity colocalized with immunofluorescence for the presynaptic protein, synapsin I. Calpain 1–immunoreactive puncta (left panel). Synapsin I–immunoreactive puncta (middle panel). Colocalization of calpain-immunoreactive puncta with synapsin I–immunoreactive puncta (so that the puncta appear yellow) (right panel). Scale bar: 15 μm. (B) Western blot demonstrated that E64 annulled calpain cleavage of spectrin to its 150-kDa fragment (n = 5 per group). (C) Quantitative western blot analysis of the 150-kDa fragment showed a 32% increase in APP/PS1 cultures compared with WT cultures (n = 5 for both; P < 0.05; data normalized against α-tubulin). (D) Vehicle-treated (veh-treated) APP/PS1 cultures showed approximately 2-fold increase of spontaneous mEPSC frequency (n = 10) compared with vehicle-treated WT cultures (n = 10; P < 0.01, with 1-way ANOVA). E64 did not affect average basal mEPSC frequency in WT cultures (n = 10; P > 0.05 with t test) but reestablished normal basal frequency of spontaneous neurotransmitter release in APP/PS1 cultures (n = 6). (E) Application of glutamate no longer enhanced mEPSC frequency in cultures from vehicle-treated APP/PS1 mice compared with cultures from vehicle-treated WT mice (n = 10 in APP/PS1 cultures; n = 10 in WT littermate cultures; P < 0.01 with 2-way ANOVA) without affecting mEPSC amplitude in either genotype (data not shown). Block of calpain activity through E64 ameliorated the deficit in long-lasting enhancement of synaptic transmission (n = 10; P < 0.01 compared with vehicle-treated APP/PS1 cultures), without affecting it in WT cultures (n = 10; P > 0.05 compared with vehicle-treated WT cultures).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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