| First Author | Morales-Corraliza J | Year | 2012 |
| Journal | Neurobiol Aging | Volume | 33 |
| Issue | 6 | Pages | 1125.e9-18 |
| PubMed ID | 22206846 | Mgi Jnum | J:188315 |
| Mgi Id | MGI:5440157 | Doi | 10.1016/j.neurobiolaging.2011.11.023 |
| Citation | Morales-Corraliza J, et al. (2012) Calpastatin modulates APP processing in the brains of beta-amyloid depositing but not wild-type mice. Neurobiol Aging 33(6):1125.e9-18 |
| abstractText | 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 (Abeta) pathology and Abeta levels when comparing aged, double transgenic (tg) APP23/CAST with APP23 mice. Concurrent with Abeta 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, Abeta 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 Abeta 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 Abeta pathology in APP23 mice, with our findings further suggesting that APP metabolism is modified by CAST overexpression as the mice develop Abeta pathology. Our results indicate that the calpain system in neurons is more responsive to CAST inhibition under conditions of Abeta pathology, suggesting that in the disease state neurons may be more sensitive to the therapeutic use of calpain inhibitors. |
