Specific Calpain Inhibition by Calpastatin Prevents Tauopathy and Neurodegeneration and Restores Normal Lifespan in Tau P301L Mice

Abstract

Tau pathogenicity in Alzheimer's disease and other tauopathies is thought to involve the generation of hyperphosphorylated, truncated, and oligomeric tau species with enhanced neurotoxicity, although the generative mechanisms and the implications for disease therapy are not well understood. Here, we report a striking rescue from mutant tau toxicity in the JNPL3 mouse model of tauopathy. We show that pathological activation of calpains gives rise to a range of potentially toxic forms of tau, directly, and by activating cdk5. Calpain overactivation in brains of these mice is accelerated as a result of the marked depletion of the endogenous calpain inhibitor, calpastatin. When levels of this inhibitor are restored in neurons of JNPL3 mice by overexpressing calpastatin, tauopathy is prevented, including calpain-mediated breakdown of cytoskeletal proteins, cdk5 activation, tau hyperphosphorylation, formation of potentially neurotoxic tau fragments by either calpain or caspase-3, and tau oligomerization. Calpastatin overexpression also prevents loss of motor axons, delays disease onset, and extends survival of JNPL3 mice by 3 months to within the range of normal lifespan. Our findings support the therapeutic promise of highly specific calpain inhibition in the treatment of tauopathies and other neurodegenerative states.

Blast waves from detonated military explosive reduce GluR1 and synaptophysin levels in hippocampal slice cultures

“…In the current study, RDX detonations did not produce the cytoskeletal damage and cellular degeneration found subsequent to AMPA-mediated excitotoxicity, and a similar AMPA insult in hippocampal slices resulted in a tight association between GluR1 loss, generated spectrin breakdown products, and neuronal death (Bahr et al, 2002). Since RDX blasts do not exhibit calpain-mediated spectrin breakdown and do not align well with the slow synaptic decline profile linked to protein accumulation stress, it is of particular interest that calpain, with the use of inhibitors in Alzheimer's disease models, has been implicated in Alzheimer-type protein accumulation pathology (Trinchese et al, 2008; Hook et al, 2011; Rao et al, 2014). It should be noted that protein accumulation events involving Aβ and tau have been linked to brain trauma including a TBI model with a compressed-gas blast tube (see Goldstein et al, 2012; Du et al, 2016; Scott et al, 2016).…”

Prions and Protein Assemblies that Convey Biological Information in Health and Disease

“…In these studies, α-synuclein prions were delivered directly to the cytosol via transfection reagents, and thus the precise role of cathepsin B remains unknown for physiological uptake and seeding. Multiple studies also support a central role for toxic tau fragments, based on proteolytic processing by cathepsin L, asparagine endopeptidase (AEP), and calpain, as inhibition of these proteases reduces tau phosphorylation, neurofibrillary tangle pathology, and neurodegeneration (Basurto-Islas et al, 2013; Rao et al, 2014; Wang et al, 2009; Zhang et al, 2014). Notably, AEP generates a tau fragment reminiscent of the tau repeat domain (Wischik et al, 1988) that is prone to fibril formation (Zhang et al, 2014).…”

Heart mitochondria and calpain 1: Location, function, and targets

“…activities, including in mitochondria, can be regulated by genetic knockout of calpain 4 [58] or overexpression of calpastatin [59]. Calpain 10 is an atypical calpain [6], and its activity is not subject to regulation by calpain 4 and calpastatin.…”