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The Journal of Neuroscience, November 19, 2008, 28(47):12241-12254; doi:10.1523/JNEUROSCI.4119-08.2008

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Neurobiology of Disease
Marked Calpastatin (CAST) Depletion in Alzheimer's Disease Accelerates Cytoskeleton Disruption and Neurodegeneration: Neuroprotection by CAST Overexpression

Mala V. Rao,^1,2 * Panaiyur S. Mohan,^1,2 * Corrinne M. Peterhoff,¹ Dun-Sheng Yang,^1,2 Stephen D. Schmidt,¹ Philip H. Stavrides,¹ Jabbar Campbell,¹ Yuanxin Chen,¹ Ying Jiang,¹ Peter A. Paskevich,^5,6,7 Anne M. Cataldo,^5,6,7 Vahram Haroutunian,⁸ and Ralph A. Nixon^1,2,3,4

¹Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, New York 10962, Departments of ²Psychiatry, ³Cell Biology, and ⁴Pathology, New York University School of Medicine, New York, New York 10016, Departments of ⁵Psychiatry and ⁶Neuropathology and ⁷McLean Hospital, Harvard Medical School, Belmont, Massachusetts 02478, and ⁸Department of Psychiatry, Mount Sinai School of Medicine, New York, New York 10029

Correspondence should be addressed to Dr. Ralph A. Nixon, Nathan S. Kline Institute, 140 Old Orangeburg Road, Orangeburg, NY 10962. Email: Nixon{at}nki.rfmh.org

Increased activity of calpains is implicated in synaptic dysfunction and neurodegeneration in Alzheimer's disease (AD). The molecular mechanisms responsible for increased calpain activity in AD are not known. Here, we demonstrate that disease progression is propelled by a marked depletion of the endogenous calpain inhibitor, calpastatin (CAST), from AD neurons, which is mediated by caspase-1, caspase-3, and calpains. Initial CAST depletion focally along dendrites coincides topographically with calpain II and ERK 1/2 activation, tau cleavage by caspase-3, and tau and neurofilament hyperphosphorylation. These same changes, together with cytoskeletal proteolysis and neuronal cell death, accompany CAST depletion after intrahippocampal kainic acid administration to mice, and are substantially reduced in mice overexpressing human CAST. Moreover, CAST reduction by shRNA in neuronal cells causes calpain-mediated death at levels of calcium-induced injury that are sublethal to cells normally expressing CAST. Our results strongly support a novel hypothesis that CAST depletion by multiple abnormally activated proteases accelerates calpain dysregulation in AD leading to cytoskeleton disruption and neurodegeneration. CAST mimetics may, therefore, be neuroprotective in AD.

Key words: apoptosis; caspase; calpain; tau; cdk5; ERK

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Received Aug. 28, 2008; accepted Oct. 2, 2008.

Correspondence should be addressed to Dr. Ralph A. Nixon, Nathan S. Kline Institute, 140 Old Orangeburg Road, Orangeburg, NY 10962. Email: Nixon{at}nki.rfmh.org

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