Format

Send to

Choose Destination
See comment in PubMed Commons below
J Neurosci. 2014 Jul 9;34(28):9222-34. doi: 10.1523/JNEUROSCI.1132-14.2014.

Specific calpain inhibition by calpastatin prevents tauopathy and neurodegeneration and restores normal lifespan in tau P301L mice.

Author information

1
Center for Dementia Research and Departments of Psychiatry and rao@nki.rfmh.org.
2
Center for Dementia Research and.
3
Division of Neurochemistry, Nathan Kline Institute, Orangeburg, New York 10962.
4
Center for Dementia Research and Departments of Psychiatry and.
5
Eli Lilly and Company, Indianapolis, Indiana 46285.
6
Center for Dementia Research and Departments of Psychiatry and Cell Biology, New York University Langone Medical Center, New York, New York 10016, and.

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.

KEYWORDS:

ambulatory movements; calcium; fractionation; insoluble extracts; nesting behavior

PMID:
25009256
PMCID:
PMC4087203
DOI:
10.1523/JNEUROSCI.1132-14.2014
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Support Center