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.
Human molecular genetics 2012 Apr 5; In press
Mao P, Manczak M, Calkins MJ, Truong Q, Reddy TP, Reddy AP, Shirendeb U, Lo HH, Rabinovitch PS, Reddy PH
Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, 505 NW 185 Avenue, Beaverton, OR 97006.
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 Aβ. Using immunoblotting and immunostaining analyses, we measured the production of full-length APP, soluble APPα, C-terminal fragments CTF99 and CTF83, monomeric and oligomeric Aβ, Aβ deposits, BACE1, in different stages of disease progression in MCAT/AβPP and AβPP mice. Using qRT-PCR, and immunostaining analyses, we studied the expression of catalase, BACE1, and the AD markers, synaptophysin, APP, neprilysin, insulin degrading enzyme, transthyretin in MCAT, AβPP, MCAT/AβPP, and wild-type mice. Using HPLC analysis of 8-hydroxy-deoxyguanosine, we measured oxidative DNA damage in the cerebral cortical tissues from MCAT, AβPP, MCAT/AβPP, and wild-type mice. We found that the AβPP transgenic mice that carried the human MCAT gene lived 3.5 months longer than did the AβPP mice. We also found that the overexpression of MCAT in brain sections from the MCAT/AβPP transgenic mice significantly correlated with a reduction in the levels of full-length APP, CTF99, BACE1, Aβ levels (40 & 42), Aβ deposits, and oxidative DNA damage in brain sections from the AβPP mice. Interestingly, we found significantly increased levels of soluble APPα and CTF83 in the MCAT/AβPP, mice relative to the AβPP mice. These data provide direct evidence that oxidative stress plays a primary role in AD etiopathology, and that in MCAT mice that express Aβ, MCAT prevents abnormal APP processing, reduces Aβ levels, and enhances Aβ-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.