| First Author | Mao P | Year | 2012 |
| Journal | Hum Mol Genet | Volume | 21 |
| Issue | 13 | Pages | 2973-90 |
| PubMed ID | 22492996 | Mgi Jnum | J:184612 |
| Mgi Id | MGI:5425174 | Doi | 10.1093/hmg/dds128 |
| Citation | Mao P, et al. (2012) Mitochondria-targeted catalase reduces abnormal APP processing, amyloid beta production and BACE1 in a mouse model of Alzheimer's disease: implications for neuroprotection and lifespan extension. Hum Mol Genet 21(13):2973-90 |
| abstractText | The purpose of this study was to investigate the protective effects of the mitochondria-targeted antioxidant catalase (MCAT) and lifespan extension in mice that express amyloid beta (Abeta). Using immunoblotting and immunostaining analyses, we measured the production of full-length amyloid precursor protein (APP), soluble APPalpha, C-terminal fragments CTF99 and CTF83, monomeric and oligomeric Abeta, Abeta deposits and beta site amyloid precursor protein cleaving enzyme 1 (BACE1), in different stages of disease progression in MCAT/AbetaPP and AbetaPP mice. Using quantitative reverse transcriptase polymerase chain reaction and immunostaining analyses, we studied the expression of catalase, BACE1, the Alzheimer's disease (AD) markers, synaptophysin, APP, neprilysin, insulin-degrading enzyme and transthyretin in MCAT, AbetaPP, MCAT/AbetaPP and wild-type (WT) mice. Using the high pressure liquid chromatography analysis of 8-hydroxy-2-deoxyguanosine, we measured oxidative DNA damage in the cerebral cortical tissues from MCAT, AbetaPP, MCAT/AbetaPP and WT mice. We found that the AbetaPP transgenic mice that carried the human MCAT gene lived 5 months longer than did the AbetaPP mice. We also found that the overexpression of MCAT in the brain sections from the MCAT/AbetaPP transgenic mice significantly correlated with a reduction in the levels of full-length APP, CTF99, BACE1, Abeta levels (40 and 42), Abeta deposits and oxidative DNA damage relative to the brain sections from the AbetaPP mice. Interestingly, we found significantly increased levels of soluble APPalpha and CTF83 in the MCAT/AbetaPP mice, relative to the AbetaPP mice. These data provide direct evidence that oxidative stress plays a primary role in AD etiopathology and that in MCAT mice express Abeta, MCAT prevents abnormal APP processing, reduces Abeta levels and enhances Abeta-degrading enzymes in mice at different ages, corresponding to different stages of disease progression. These findings indicate that mitochondria-targeted molecules may be an effective therapeutic approach to treat patients with AD. |
