Calpastatin modulates APP processing in the brains of β-amyloid depositing but not wild-type mice

NEUROBIOLOGY OF AGING

卷:33

Article

Morales-Corraliza, Jose^1,2  Berger, Jason D.¹  Mazzella, Matthew J.¹  Veeranna^1,2  Neubert, Thomas A.²  Ghiso, Jorge²  Rao, Mala V.^1,2  Staufenbiel, Matthias³  Nixon, Ralph A.^1,2  Mathews, Paul M.^1,2 

[1] Nathan S Kline Inst Psychiat Res, Orangeburg, NY 10962 USA

[2] NYU, Sch Med, New York, NY USA

[3] Nervous Syst Res, Novartis Inst Biomed Res, Basel, Switzerland

关键词: Calpain;    Calpastatin;    APP;    A beta;    Alzheimer's disease;   

DOI  :  10.1016/j.neurobiolaging.2011.11.023

来源: Elsevier

【 摘 要 】

We report that neuronal overexpression of the endogenous inhibitor of calpains, calpastatin (CAST), in a mouse model of human Alzheimer's disease (AD) beta-amyloidosis, the APP23 mouse, reduces beta-amyloid (A beta) pathology and A beta levels when comparing aged, double transgenic (tg) APP23/CAST with APP23 mice. Concurrent with A beta plaque deposition, aged APP23/CAST mice show a decrease in the steady-state brain levels of the amyloid precursor protein (APP) and APP C-terminal fragments (CTFs) when compared with APP23 mice. This CAST-dependent decrease in APP metabolite levels was not observed in single tg CAST mice expressing endogenous APP or in younger, A beta plaque predepositing APP23/CAST mice. We also determined that the CAST-mediated inhibition of calpain activity in the brain is greater in the CAST mice with A beta pathology than in non-APP tg mice, as demonstrated by a decrease in calpain-mediated cytoskeleton protein cleavage. Moreover, aged APP23/CAST mice have reduced extracellular signal-regulated kinase 1/2 (ERK1/2) activity and tau phosphorylation when compared with APP23 mice. In summary, in vivo calpain inhibition mediated by CAST transgene expression reduces A beta pathology in APP23 mice, with our findings further suggesting that APP metabolism is modified by CAST overexpression as the mice develop A beta pathology. Our results indicate that the calpain system in neurons is more responsive to CAST inhibition under conditions of A beta pathology, suggesting that in the disease state neurons may be more sensitive to the therapeutic use of calpain inhibitors. (C) 2012 Elsevier Inc. All rights reserved.

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