The pathological hallmark of Alzheimer's disease (AD) is accumulation of misfolded amyloid-beta peptides and hyperphosphorylated tau protein in the brain. Increasing evidence suggests that serine-aspartyl proteases-caspases are activated in the AD brain. Previous studies identified a caspase-3 cleavage site within the amyloid-beta precursor protein, and a caspase-3 cleavage of tau as the mechanisms involved in the development of A beta and tau neuropathology, respectively. However, the potential role that caspase-3 could have on tau metabolism remains unknown. In the current studies, we provide experimental evidence that caspase-3 directly and specifically regulates tau phosphorylation, and demonstrate that this effect is mediated by the GSK3 beta kinase pathway via a caspase-3-dependent cleavage of the protein kinase B (also known as Akt). In addition, we confirm these results in vivo by using a transgenic mouse model of AD. Collectively, our findings demonstrate a new role for caspase-3 in the neurobiology of tau, and suggest that therapeutic strategies aimed at inhibiting this protease-dependent cleavage of Akt may prove beneficial in preventing tau hyperphosphorylation and subsequent neuropathology in AD and related tauopathies.
机构:
Buck Inst Age Res, Novato, CA 94945 USA
Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USABuck Inst Age Res, Novato, CA 94945 USA
Bredesen, Dale E.
;
John, Varghese
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Buck Inst Age Res, Novato, CA 94945 USABuck Inst Age Res, Novato, CA 94945 USA
John, Varghese
;
Galvan, Veronica
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机构:
Univ Texas Hlth Sci Ctr San Antonio, Dept Physiol, San Antonio, TX 78284 USA
Univ Texas Hlth Sci Ctr San Antonio, Sam & Ann Barshop Inst Longev & Aging Studies, San Antonio, TX USABuck Inst Age Res, Novato, CA 94945 USA
机构:
Reg Acad Hlth Ctr Edinburg E RAHC, Div Med Res, Edinburg, TX 78541 USA
Univ Texas Hlth Sci Ctr San Antonio, Dept Cellular & Struct Biol, San Antonio, TX 78229 USAReg Acad Hlth Ctr Edinburg E RAHC, Div Med Res, Edinburg, TX 78541 USA
Cheng, Benxu
;
Martinez, Alex Anthony
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Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, San Antonio, TX 78229 USAReg Acad Hlth Ctr Edinburg E RAHC, Div Med Res, Edinburg, TX 78541 USA
Martinez, Alex Anthony
;
Morado, Jacob
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机构:
Univ Texas Pan Amer, Cooperat Pharm Program, Edinburg, TX 78541 USAReg Acad Hlth Ctr Edinburg E RAHC, Div Med Res, Edinburg, TX 78541 USA
Morado, Jacob
;
Scofield, Virginia
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Reg Acad Hlth Ctr Edinburg E RAHC, Div Med Res, Edinburg, TX 78541 USAReg Acad Hlth Ctr Edinburg E RAHC, Div Med Res, Edinburg, TX 78541 USA
Scofield, Virginia
;
Roberts, James L.
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机构:
Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, San Antonio, TX 78229 USA
Trinity Univ, Dept Biol, Div Neurosci, San Antonio, TX 78212 USAReg Acad Hlth Ctr Edinburg E RAHC, Div Med Res, Edinburg, TX 78541 USA
Roberts, James L.
;
Maffi, Shivani Kaushal
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机构:
Reg Acad Hlth Ctr Edinburg E RAHC, Div Med Res, Edinburg, TX 78541 USA
Univ Texas Hlth Sci Ctr San Antonio, Dept Mol Med, San Antonio, TX 78245 USAReg Acad Hlth Ctr Edinburg E RAHC, Div Med Res, Edinburg, TX 78541 USA
机构:
Buck Inst Age Res, Novato, CA 94945 USA
Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USABuck Inst Age Res, Novato, CA 94945 USA
Bredesen, Dale E.
;
John, Varghese
论文数: 0引用数: 0
h-index: 0
机构:
Buck Inst Age Res, Novato, CA 94945 USABuck Inst Age Res, Novato, CA 94945 USA
John, Varghese
;
Galvan, Veronica
论文数: 0引用数: 0
h-index: 0
机构:
Univ Texas Hlth Sci Ctr San Antonio, Dept Physiol, San Antonio, TX 78284 USA
Univ Texas Hlth Sci Ctr San Antonio, Sam & Ann Barshop Inst Longev & Aging Studies, San Antonio, TX USABuck Inst Age Res, Novato, CA 94945 USA
机构:
Reg Acad Hlth Ctr Edinburg E RAHC, Div Med Res, Edinburg, TX 78541 USA
Univ Texas Hlth Sci Ctr San Antonio, Dept Cellular & Struct Biol, San Antonio, TX 78229 USAReg Acad Hlth Ctr Edinburg E RAHC, Div Med Res, Edinburg, TX 78541 USA
Cheng, Benxu
;
Martinez, Alex Anthony
论文数: 0引用数: 0
h-index: 0
机构:
Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, San Antonio, TX 78229 USAReg Acad Hlth Ctr Edinburg E RAHC, Div Med Res, Edinburg, TX 78541 USA
Martinez, Alex Anthony
;
Morado, Jacob
论文数: 0引用数: 0
h-index: 0
机构:
Univ Texas Pan Amer, Cooperat Pharm Program, Edinburg, TX 78541 USAReg Acad Hlth Ctr Edinburg E RAHC, Div Med Res, Edinburg, TX 78541 USA
Morado, Jacob
;
Scofield, Virginia
论文数: 0引用数: 0
h-index: 0
机构:
Reg Acad Hlth Ctr Edinburg E RAHC, Div Med Res, Edinburg, TX 78541 USAReg Acad Hlth Ctr Edinburg E RAHC, Div Med Res, Edinburg, TX 78541 USA
Scofield, Virginia
;
Roberts, James L.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, San Antonio, TX 78229 USA
Trinity Univ, Dept Biol, Div Neurosci, San Antonio, TX 78212 USAReg Acad Hlth Ctr Edinburg E RAHC, Div Med Res, Edinburg, TX 78541 USA
Roberts, James L.
;
Maffi, Shivani Kaushal
论文数: 0引用数: 0
h-index: 0
机构:
Reg Acad Hlth Ctr Edinburg E RAHC, Div Med Res, Edinburg, TX 78541 USA
Univ Texas Hlth Sci Ctr San Antonio, Dept Mol Med, San Antonio, TX 78245 USAReg Acad Hlth Ctr Edinburg E RAHC, Div Med Res, Edinburg, TX 78541 USA