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 3

Calpain inhibition reestablished normal synaptic function following Aβ elevation.

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Calpain inhibition reestablished normal spatial-working memory and assoc...
(A) E64 improved BST at the CA3-CA1 connection of hippocampal slices from 7-month-old APP/PS1 mice treated for 5 months (10 slices from 9 E64-treated APP/PS1 mice, 7 slices from 7 vehicle-treated APP/PS1 mice, 8 slices from 8 vehicle-treated WT mice; P < 0.01 comparing E64- and vehicle-treated APP/PS1 slices with 2-way ANOVA). BST was not affected in E64-treated WT animals (6 slices from 6 mice; P > 0.05). (B) BDA-410 reestablished normal BST in APP/PS1 mice treated with inhibitor between 8 weeks and 7 months of age (7 slices from 7 BDA-410–treated APP/PS1 mice, 9 slices from 8 vehicle-treated APP/PS1 mice, 8 slices from 7 vehicle-treated WT mice; P < 0.01 comparing BDA-410– and vehicle-treated APP/PS1 slices). BDA-410 did not affect BST in WT littermates (11 slices from 9 mice; P > 0.05). (C) E64 was beneficial against LTP impairment at the same synapses as in A (vehicle-treated APP/PS1 mice versus vehicle-treated WT mice, P < 0.01 with 2-way ANOVA; E64-treated APP/PS1 mice versus vehicle-treated APP/PS1 mice, P < 0.01). The inhibitor did not affect LTP in WT mice (P > 0.05). (D) BDA-410 reestablished normal LTP in APP/PS1 mice treated between 8 weeks and 7 months of age (BDA-410–treated APP/PS1 mice versus vehicle-treated APP/PS1 mice; P < 0.01; same synapses as in B). BDA-410 did not affect LTP in WT littermates (P > 0.05). (E) BDA-410 reestablished normal LTP in APP mice treated between 8 and 11 to 12 months of age (P < 0.05 in 6 slices from 6 BDA-410–treated APP mice versus 7 slices from 7 vehicle-treated APP mice; 7 slices from 7 vehicle-treated WT littermates). BDA-410 did not affect LTP in slices from WT littermates (7 slices from 7 mice; P > 0.05). BST did not vary among the 4 groups of mice (data not shown). (F) BDA-410 reestablished normal LTP in Aβ42-perfused slices (6 slices treated with BDA-410 plus Aβ versus 8 Aβ-treated slices, P < 0.05; 6 vehicle-treated slices versus 7 BDA-410–treated slices). The bar indicates the perfusion with Aβ42.