title: 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.
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.affiliation: Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, 505 NW185th Avenue, Beaverton, OR 97006, USA.
authors.forename: Peizhong
authors.initials: P
authors.lastname: Mao
authors.forename: Maria
authors.initials: M
authors.lastname: Manczak
authors.forename: Marcus J
authors.initials: MJ
authors.lastname: Calkins
authors.forename: Quang
authors.initials: Q
authors.lastname: Truong
authors.forename: Tejaswini P
authors.initials: TP
authors.lastname: Reddy
authors.forename: Arubala P
authors.initials: AP
authors.lastname: Reddy
authors.forename: Ulziibat
authors.initials: U
authors.lastname: Shirendeb
authors.forename: Herng-Hsiang
authors.initials: HH
authors.lastname: Lo
authors.forename: Peter S
authors.initials: PS
authors.lastname: Rabinovitch
authors.forename: P Hemachandra
authors.initials: PH
authors.lastname: Reddy
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000096:biosynthesis*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000096:biosynthesis*; D001921:Brain / Q000473:pathology; D002374:Catalase / Q000235:genetics / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D004249:DNA Damage / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D007339:Insulysin / Q000096:biosynthesis / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D015260:Neprilysin / Q000096:biosynthesis; D018696:Neuroprotective Agents / Q000378:metabolism; D018384:Oxidative Stress; D011228:Prealbumin / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D011897:Random Allocation; D016708:Synaptophysin / Q000096:biosynthesis
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D018696:Neuroprotective Agents; D011228:Prealbumin; D012333:RNA, Messenger; D016708:Synaptophysin; D002374:Catalase; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse; D015260:Neprilysin; D007339:Insulysin