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.

Calpain inhibition rescues troponin T3 fragmentation, increases Cav1.1 , and enhances skeletal muscle force in aging sedentary mice

“…BDA‐410 is a synthetic Leu‐Leu peptidomimetic that significantly attenuates various disease conditions (Carragher, 2006), including memory and synaptic transmission in a mouse model of Alzheimer disease and signs of premature aging in a mouse model of kotho deficiency (Manya et al ., 2002; Trinchese et al ., 2008). BDA‐410 strongly and reversibly inhibits cysteine proteases but not serine or aspartic proteinases.…”

Loss-of-function of inositol polyphosphate-4-phosphatase reversibly increases the severity of allergic airway inflammation

“…As an increase in the intracellular free calcium is known to activate the calpain family of proteases 30 , and abnormal calcium homeostasis has been observed in asthma 31,32 , it is very likely to be one of the underlying mechanisms for calpain-mediated INPP4A degradation. Various types of calpain inhibitors have been known to alleviate a myriad of disorders 33,34 . We selected calpeptin, as it was found to be the most potent among various calpain inhibitors, and also because of its potent cell penetrative nature in in vitro studies 35 .…”

Synaptic Therapy in Alzheimer's Disease: A CREB-centric Approach

“…Enhanced calpain activation produces augmented APP processing via BACE activation and augmented Aβ deposit [161], increases tau-mediated neuropathology [162], and disrupts the functionality of kinases such as CDK5 by pushing the cleavage of the CDK5 activator p35 [163], but also induces microgliosis, somatodendritic dystrophy, and increased mortality while the endogenous calpain inhibitor calpastatin is knocked down in animal models of AD [164]. This evidence supports the possible use of calpain inhibitors as a therapeutic treatment in AD [153][154][155]. The field of medicinal chemistry is currently engaged in producing a variety of molecules as possible calpain inhibitor candidates [165,166].…”

“…Calpain-cleaved CREB preserves serine 133 phosphorylation and recognizes cAMP response element sequences on DNA while losing its major influence in activating the transcription process [144,145]. However, when calpains are overactivated in response to overshoots of calcium influx, such as in neurodegenerative disease like AD or ischemic insults [136,[147][148][149][150][151][152][153], phosphorylated CREB levels decrease and the phenomenon is accompanied by a decline of both synaptic plasticity and memory [154].…”