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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.
Hum Mol Genet. 2012 Jul 01; 21(13):2973-90.HM

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.

Authors+Show Affiliations

Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, 505 NW185th Avenue, Beaverton, OR 97006, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22492996

Citation

Mao, Peizhong, et al. "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, 2012, pp. 2973-90.
Mao P, Manczak M, Calkins MJ, et al. 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. Hum Mol Genet. 2012;21(13):2973-90.
Mao, P., Manczak, M., Calkins, M. J., Truong, Q., Reddy, T. P., Reddy, A. P., Shirendeb, U., Lo, H. H., Rabinovitch, P. S., & Reddy, P. H. (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, 21(13), 2973-90. https://doi.org/10.1093/hmg/dds128
Mao P, et al. 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. Hum Mol Genet. 2012 Jul 1;21(13):2973-90. PubMed PMID: 22492996.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Mao,Peizhong, AU - Manczak,Maria, AU - Calkins,Marcus J, AU - Truong,Quang, AU - Reddy,Tejaswini P, AU - Reddy,Arubala P, AU - Shirendeb,Ulziibat, AU - Lo,Herng-Hsiang, AU - Rabinovitch,Peter S, AU - Reddy,P Hemachandra, Y1 - 2012/04/05/ PY - 2012/4/12/entrez PY - 2012/4/12/pubmed PY - 2012/12/14/medline SP - 2973 EP - 90 JF - Human molecular genetics JO - Hum. Mol. Genet. VL - 21 IS - 13 N2 - 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. SN - 1460-2083 UR - https://www.unboundmedicine.com/medline/citation/22492996/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_ L2 - https://academic.oup.com/hmg/article-lookup/doi/10.1093/hmg/dds128 DB - PRIME DP - Unbound Medicine ER -