Implicating Calpain in Tau-Mediated Toxicity In Vivo

Abstract

Alzheimer's disease and other related neurodegenerative disorders known as tauopathies are characterized by the accumulation of abnormally phosphorylated and aggregated forms of the microtubule-associated protein tau. Several laboratories have identified a 17 kD proteolytic fragment of tau in degenerating neurons and in numerous cell culture models that is generated by calpain cleavage and speculated to contribute to tau toxicity. In the current study, we employed a Drosophila tauopathy model to investigate the importance of calpain-mediated tau proteolysis in contributing to tau neurotoxicity in an animal model of human neurodegenerative disease. We found that mutations that disrupted endogenous calpainA or calpainB activity in transgenic flies suppressed tau toxicity. Expression of a calpain-resistant form of tau in Drosophila revealed that mutating the putative calpain cleavage sites that produce the 17 kD fragment was sufficient to abrogate tau toxicity in vivo. Furthermore, we found significant toxicity in the fly retina associated with expression of only the 17 kD tau fragment. Collectively, our data implicate calpain-mediated proteolysis of tau as an important pathway mediating tau neurotoxicity in vivo.

Tau immunotherapy for Alzheimer's disease

“…Recently, an additional N-terminal fragment (residues 1-224) was identified in CSF from patients with AD and PSP, and has been hypothesized to be an early marker of disease and particularly pathogenic [35,36]. A similar calpain-cleaved fragment was reported by other groups [37,38].…”

Lysine methylation is an endogenous post-translational modification of tau protein in human brain and a modulator of aggregation propensity

“…In the projection domain, methylation sites K24 and K44 lie adjacent to putative caspase and calpain cleavage sites, respectively. The latter cleavage event is reportedly associated with toxicity in biological models [44, 58– 60]. In the MTBR, where the majority of Lys methylation was found, sites overlapped with three of five reported ubiquitylation sites on AD-derived filamentous tau.…”

Passive immunization targeting the N-terminal projection domain of tau decreases tau pathology and improves cognition in a transgenic mouse model of Alzheimer disease and tauopathies

“…Although the role of tau in regulating microtubule dynamics is extensively established, much less is known about the functional role of the N-terminal domain of tau on neuron survival. A 17-kD N-terminal tau fragment generated by calpain cleavage, comprising residues amino acid 45-230, was proposed to mediate Ab-induced toxicity (Park and Ferreira 2005), and mediate tau neurotoxicity in Drosophila tauopathy model (Reinecke et al 2011). However, the toxicity and in vivo relevance of this 17 kD fragment are debated.…”