Inhibition of calpains improves memory and synaptic transmission in a mouse model of Alzheimer disease
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
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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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 4

Calpain inhibition reestablished normal spatial-working memory and associative fear memory in APP/PS1 mice.

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Calpain inhibition reestablished normal synaptic function following Aβ e...
(A) In RAWM testing APP/PS1 mice treated with E64 for 5 months from 8 weeks of age made the same number of errors on the fourth acquisition (A4) and fifth retention trial (R) as vehicle-treated WT mice (n = 13; P < 0.05 compared with vehicle-treated APP/PS1 mice with 2-way ANOVA; planned comparisons at trial A4, P < 0.05, and trial R, P < 0.01), whereas vehicle-treated double transgenics made more errors than vehicle-treated WT mice (n = 7; P < 0.01 compared with vehicle-treated WT mice). E64 did not affect the performance of WT mice (n = 5; P > 0.05 compared with vehicle-treated WT mice). Visible platform task did not show any sensory-motor or motivational impairment in the same animals (data not shown). (B) BDA-410 reestablished normal spatial-working memory in APP/PS1 mice following 5 months of treatment from 8 weeks of age. BDA-410–treated double transgenics (n = 12) showed similar performance in the RAWM test as vehicle-treated WT littermates (n = 12), whereas vehicle-treated double transgenic mice (n = 11) showed abnormal learning and memory (P < 0.05 in BDA-410–treated APP/PS1 mice compared with vehicle-treated APP/PS1 mice; planned comparisons showed that the 2 groups were significantly different at trial A4, P < 0.05, and trial R, P < 0.01). The inhibitor did not affect the performance of WT mice (n = 14; P > 0.05 compared with vehicle-treated WT mice). The visible platform task did not show any sensory-motor or motivational impairment in all groups (data not shown). (C) BDA-410 reestablished normal contextual learning in APP/PS1 mice following 5 months of treatment from 8 weeks of age (P < 0.01 compared with vehicle-treated APP/PS1 mice). The inhibitor did not affect the performance of WT mice (P > 0.05).