Mitochondria-targeted catalase reduces abnormal APP processing, amyloid β production and BACE1 in a mouse model of Alzheimer's disease: Implications for neuroprotection and lifespan extension

Peizhong Mao, Maria Manczak, Marcus J. Calkins, Quang Truong, Tejaswini P. Reddy, Arubala Reddy, Ulziibat Shirendeb, Herng Hsiang Lo, Peter S. Rabinovitch, P (Hemachandra) Reddy

    Research output: Contribution to journalArticle

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    Abstract

    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 (Aβ). Using immunoblotting and immunostaining analyses, we measured the production of full-length amyloid precursor protein (APP), soluble APPα, C-terminal fragments CTF99 and CTF83, monomeric and oligomeric Aβ, Aβ deposits and beta site amyloid precursor protein cleaving enzyme 1 (BACE1), in different stages of disease progression in MCAT/AβPP and AβPP 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, AβPP, MCAT/AβPP 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, AβPP, MCAT/AβPP and WT mice. We found that the AβPP transgenic mice that carried the human MCAT gene lived 5 months longer than did the AβPP mice. We also found that the overexpression of MCAT in the 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 and 42), Aβ deposits and oxidative DNA damage relative to the 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 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.

    Original languageEnglish (US)
    Article numberdds128
    Pages (from-to)2973-2990
    Number of pages18
    JournalHuman Molecular Genetics
    Volume21
    Issue number13
    DOIs
    StatePublished - Jul 2012

    Fingerprint

    Amyloid beta-Protein Precursor
    Amyloid
    Catalase
    Alzheimer Disease
    Mitochondria
    Enzymes
    Antioxidants
    Neuroprotection
    Transgenic Mice
    DNA Damage
    Disease Progression
    Insulysin
    Neprilysin
    Synaptophysin

    ASJC Scopus subject areas

    • Genetics
    • Genetics(clinical)
    • Molecular Biology

    Cite this

    Mitochondria-targeted catalase reduces abnormal APP processing, amyloid β production and BACE1 in a mouse model of Alzheimer's disease : Implications for neuroprotection and lifespan extension. / Mao, Peizhong; Manczak, Maria; Calkins, Marcus J.; Truong, Quang; Reddy, Tejaswini P.; Reddy, Arubala; Shirendeb, Ulziibat; Lo, Herng Hsiang; Rabinovitch, Peter S.; Reddy, P (Hemachandra).

    In: Human Molecular Genetics, Vol. 21, No. 13, dds128, 07.2012, p. 2973-2990.

    Research output: Contribution to journalArticle

    Mao, P, Manczak, M, Calkins, MJ, Truong, Q, Reddy, TP, Reddy, A, Shirendeb, U, Lo, HH, Rabinovitch, PS & Reddy, PH 2012, 'Mitochondria-targeted catalase reduces abnormal APP processing, amyloid β production and BACE1 in a mouse model of Alzheimer's disease: Implications for neuroprotection and lifespan extension', Human Molecular Genetics, vol. 21, no. 13, dds128, pp. 2973-2990. https://doi.org/10.1093/hmg/dds128
    Mao, Peizhong ; Manczak, Maria ; Calkins, Marcus J. ; Truong, Quang ; Reddy, Tejaswini P. ; Reddy, Arubala ; Shirendeb, Ulziibat ; Lo, Herng Hsiang ; Rabinovitch, Peter S. ; Reddy, P (Hemachandra). / Mitochondria-targeted catalase reduces abnormal APP processing, amyloid β production and BACE1 in a mouse model of Alzheimer's disease : Implications for neuroprotection and lifespan extension. In: Human Molecular Genetics. 2012 ; Vol. 21, No. 13. pp. 2973-2990.
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    AU - Reddy, Arubala

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