Isoform-specific hyperactivation of calpain-2 occurs presymptomatically at the synapse in Alzheimer’s disease mice and correlates with memory deficits in human subjects

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.

Deletion of the Capn1 Gene Results in Alterations in Signaling Pathways Related to Alzheimer’s Disease, Protein Quality Control and Synaptic Plasticity in Mouse Brain

“…On the other hand, since calpain has been implicated in the etiology of AD, our result would suggest that calpain-2 rather than calpain-1 might be implicated in AD. This fits well with a recent report indicating that calpain-2 is overactivated in pre-symptomatic AD (Ahmad et al, 2018). Alterations in the circadian rhythm, including sleep disorders, have been implicated in the development of neurodegenerative disorders, including AD (Hood and Amir, 2017;Wall et al, 2018).…”

Age-dependent ataxia and neurodegeneration caused by an αII spectrin mutation with impaired regulation of its calpain sensitivity

“…Neurodegenerative disorders such as Alzheimer’s dementia, Parkinson’s disease, traumatic encephalopathy, and hereditary ataxias exhibit slowly-progressive neuronal death, neuroinflammation, and a notable loss in proteostasis. Inappropriate activation of calpains is one event postulated to accompany neurodegeneration 1 , 2 . Calpains regulate many cellular processes including neurite outgrowth, synaptic remodeling, autophagy control, learning and memory.…”

Calpain-1 and Calpain-2 in the Brain: New Evidence for a Critical Role of Calpain-2 in Neuronal Death

“…Similarly, calpain inhibitors promoted mTOR-independent autophagy and rescued Huntington’s disease phenotypes in zebrafish [ 71 ]. In Alzheimer’s disease (AD), calpain-2 was found to be hyper-activated in synaptosomes in presymptomatic AD, and the activation was correlated with a decline in cognitive function and an increase in levels of β-amyloid deposits [ 72 ]. Calpain activation has also been shown to switch cellular programs from autophagy to apoptosis in various preparations [ 73 , 74 , 75 ].…”