RT Journal Article
SR Electronic
T1 Specific Calpain Inhibition by Calpastatin Prevents Tauopathy and Neurodegeneration and Restores Normal Lifespan in Tau P301L Mice
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 9222
OP 9234
DO 10.1523/JNEUROSCI.1132-14.2014
VO 34
IS 28
A1 Mala V. Rao
A1 Mary Kate McBrayer
A1 Jabbar Campbell
A1 Asok Kumar
A1 Audrey Hashim
A1 Henry Sershen
A1 Philip H. Stavrides
A1 Masuo Ohno
A1 Michael Hutton
A1 Ralph A. Nixon
YR 2014
UL http://www.jneurosci.org/content/34/28/9222.abstract
AB 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.