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lüll Dual vulnerability of tau to calpains and caspase-3 proteolysis under neurotoxic and neurodegenerative conditions Liu MC; Kobeissy F; Zheng W; Zhang Z; Hayes RL; Wang KKASN Neuro 2011[Feb]; 3 (1): e00051Axonally specific microtubule-associated protein tau is an important component of neurofibrillary tangles found in AD (Alzheimer's disease) and other tauopathy diseases such as CTE (chronic traumatic encephalopathy). Such tau aggregate is found to be hyperphosphorylated and often proteolytically fragmented. Similarly, tau is degraded following TBI (traumatic brain injury). In the present study, we examined the dual vulnerability of tau to calpain and caspase-3 under neurotoxic and neurodegenerative conditions. We first identified three novel calpain cleavage sites in rat tau (four-repeat isoform) as Ser130 downward arrowLys131, Gly157 downward arrowAla158 and Arg380 downward arrowGlu381. Fragment-specific antibodies to target the major calpain-mediated TauBDP-35K (35 kDa tau-breakdown product) and the caspase-mediated TauBDP-45K respectively were developed. In rat cerebrocortical cultures treated with excitotoxin [NMDA (N-methyl-D-aspartate)], tau is significantly degraded into multiple fragments, including a dominant signal of calpain-mediated TauBDP-35K with minimal caspase-mediated TauBDP-45K. Following apoptosis-inducing EDTA treatment, tau was truncated only to TauBDP-48K/45K-exclusively by caspase. Cultures treated with another apoptosis inducer STS (staurosporine), dual fragmentation by calpain (TauBDP-35K) and caspase-3 (TauBDP-45K) was observed. Tau was also fragmented in injured rat cortex following TBI in vivo to BDPs of 45-42 kDa (minor), 35 kDa and 15 kDa, followed by TauBDP-25K. Calpain-mediated TauBDP-35K-specific antibody confirmed robust signals in the injured cortex, while caspase-mediated TauBDP-45K-specific antibody only detected faint signals. Furthermore, intravenous administration of a calpain-specific inhibitor SNJ-1945 strongly suppressed the TauBDP-35K formation. Taken together, these results suggest that tau protein is dually vulnerable to calpain and caspase-3 proteolysis under different neurotoxic and injury conditions.|Analysis of Variance[MESH]|Animals[MESH]|Animals, Newborn[MESH]|Brain Injuries/complications/pathology[MESH]|Brain/drug effects/metabolism[MESH]|Calpain/*metabolism[MESH]|Caspase 3/*metabolism[MESH]|Cells, Cultured[MESH]|Cerebral Cortex/cytology[MESH]|Disease Models, Animal[MESH]|Gene Expression Regulation/drug effects/physiology[MESH]|Male[MESH]|Molecular Weight[MESH]|N-Methylaspartate/toxicity[MESH]|Nerve Degeneration/etiology/*metabolism[MESH]|Neurons/drug effects/*metabolism[MESH]|Neurotoxicity Syndromes/*metabolism[MESH]|Neurotoxins/toxicity[MESH]|Peptide Hydrolases/pharmacology[MESH]|Protein Isoforms/metabolism[MESH]|Rats[MESH]|tau Proteins/*metabolism[MESH] |