On of calcium signalling [6, 34, 37, 65, 66, 70]. Activation of calpain-1 was used as a marker for calcium dysregulation in this study. Calpain-1 is an intracellular cysteine protease that is activated upon autoproteolytic cleavage of the inactive precursor at its N-terminus in low micromolar (M) concentrations of calcium. Increased truncation and activation of calpain-1 has previously been reported in late stage (Braak V-VI) AD brain [2, 25, 32, 61]. In addition, biomarker studies have recently demonstrated increased calpain activity in cerebrospinal fluid, and corresponding reductions of calpain activity in serum and plasma, in AD patients relative to non-cognitively impaired controls [39]. This is not surprising since calpain-mediated proteolysis has been implicated in many neurodegenerative pathways including the processing of amyloid precursor protein to generate A species and resulting synaptic dysfunction [45, 72], cleavage and phosphorylation of tau by cdk5, GSK-3 and dual specificity tyrosine-phosphorylation regulated kinase 1A DYRK1A [25, 32, 50, 71], and altered learning and memory abilities via processing of synaptic proteins and suppression of LTP [33, 41]. In addition, recent evidence has implicated the calpain substrate and endogenous inhibitor, calpastatin in a novel autodestruction pathway linked to neurodegeneration [80, 81]. Rapid Wallerian degeneration of injured axons was shown to occur following activation of calpain alongside depletion of calpastatin inhibitory activity [31]. Induction of this calpain-calpastatin-mediated degeneration pathway was subsequently shown to occur downstream of nicotinamide mononucleotide adenylyltransferase 1mediated changes in Sarm1 and mitogen activated protein kinase activities, and depletion of ATP [21, 32]. In addition to playing an important role in pruning processes duringneuronal development [31], this pathway is likely to be involved in a wide spectrum of neurodegenerative diseases. Subsequent investigations will likely provide more insight into the importance of this signalling cascade for AD. Another area in which dysregulation of calcium and/or calpain signalling is likely to be an important influence is the prion-like propagation of protein aggregates, a topic of intensive research in neurodegenerative disease research. Both A and tau aggregates are reported to be transmitted through AD brain along anatomically connected pathways [82]. Although all of the mechanisms underlying pathology spread are not completely understood, stimulating electrical activity, or activating calcium-dependent NMDA and AMPA receptors, was shown PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/16989806 to induce the release of tau from neurons in primary culture and in mouse models of disease [9, 58, 79]. Thus, it is possible that dysregulation of calcium-calpain pathways may contribute to tau spread in neurodegenerative tauopathies, including AD. There are several questions raised by experimental models that were not addressed in this study. For example, calpain-mediated cleavage of the NR2B subunit of NMDARs has been shown to give rise to active NMDAR forms that could exacerbate excitotoxicity [22, 64]. We did not observe calpain-cleaved NR2B fragments in this study, which could Capecitabine have been due to the effects of postmortem degradation of rapidly turned over proteins, or the levels of these fragments being below detectable levels. The transient increase in NR2B holoprotein that we observe at Braak stage II-III in supernatant fractions could imply that cal.