Abstract
Calpain hyperactivation is implicated in late-stages of neurodegenerative diseases including Alzheimer’s disease (AD). However, calpains are also critical for synaptic function and plasticity, and hence memory formation and learning. Since synaptic deficits appear early in AD pathogenesis prior to appearance of overt disease symptoms, we examined if localized dysregulation of calpain-1 and/or 2 contributes to early synaptic dysfunction in AD. Increased activity of synaptosomal calpain-2, but not calpain-1 was observed in presymptomatic 1 month old APPswe/PS1ΔE9 mice (a mouse model of AD) which have no evident pathological or behavioural hallmarks of AD and persisted up to 10 months of age. However, total cellular levels of calpain-2 remained unaffected. Moreover, synaptosomal calpain-2 was hyperactivated in frontal neocortical tissue samples of post-mortem brains of AD-dementia subjects and correlated significantly with decline in tests for cognitive and memory functions, and increase in levels of β-amyloid deposits in brain. We conclude that isoform-specific hyperactivation of calpain-2, but not calpain-1 occurs at the synapse early in the pathogenesis of AD potentially contributing to the deregulation of synaptic signaling in AD. Our findings would be important in paving the way for potential therapeutic strategies for amelioration of cognitive deficits observed in ageing-related dementia disorders like AD.
Highlights
Alzheimer’s disease is one of the major causes of dementia in elderly across the world with no cures available currently
We examined the status of calpains 1 and 2 in an isoform-specific manner in the synapse during early stage of Alzheimer’s disease (AD) pathogenesis using APPswe/PS1ΔE9 mice, a well characterized mouse model of AD14 and used post mortem human brain samples to determine if these observations seen in mouse model of AD could be extrapolated to AD as seen in human subjects
We demonstrate using a mouse model of AD (APPSwe/PS1ΔE9 mice) that calpain-2 but not calpain-1 is hyperactivated in cortical synaptosomes as early as 1 month of age, much before the onset of the behavioral symptoms and β-amyloid pathology
Summary
Alzheimer’s disease is one of the major causes of dementia in elderly across the world with no cures available currently. Synaptic dysfunction is evident in early stages of AD when there is little β-amyloid deposition or neuronal death[1,2]. In spite of evidence for early synaptic deficits in AD and the critical roles played by calpains in synapse physiology it is surprising that synapse-specific deregulation of calpains has not been studied in detail in AD pathology. This is of critical importance since synapse-specific dysregulation of calpains could potentially contribute as an early pathogenic event in AD, and can be exploited as a target for potential disease-modifying therapeutic measures. We examined the status of calpains 1 and 2 in an isoform-specific manner in the synapse during early stage of AD pathogenesis using APPswe/PS1ΔE9 mice, a well characterized mouse model of AD14 and used post mortem human brain samples to determine if these observations seen in mouse model of AD could be extrapolated to AD as seen in human subjects
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