Dataset Information

Swedish mutant APP-based BACE1 binding site peptide reduces APP ?-cleavage and cerebral A? levels in Alzheimer's mice.

ABSTRACT: BACE1 initiates amyloid-? (A?) generation and the resultant cerebral amyloidosis, as a characteristic of Alzheimer's disease (AD). Thus, inhibition of BACE1 has been the focus of a large body of research. The most recent clinical trials highlight the difficulty involved in this type of anti-AD therapy as evidenced by side effects likely due to the ubiquitous nature of BACE1, which cleaves multiple substrates. The human Swedish mutant form of amyloid protein precursor (APPswe) has been shown to possess a higher affinity for BACE1 compared to wild-type APP (APPwt). We pursued a new approach wherein harnessing this greater affinity to modulate BACE1 APP processing activity. We found that one peptide derived from APPswe, containing the ?-cleavage site, strongly inhibits BACE1 activity and thereby reduces A? production. This peptide, termed APPswe BACE1 binding site peptide (APPsweBBP), was further conjugated to the fusion domain of the HIV-1 Tat protein (TAT) at the C-terminus to facilitate its biomembrane-penetrating activity. APPwt and APPswe over-expressing CHO cells treated with this TAT-conjugated peptide resulted in a marked reduction of A? and a significant increase of soluble APP?. Intraperitoneal administration of this peptide to 5XFAD mice markedly reduced ?-amyloid deposits as well as improved hippocampal-dependent learning and memory.

SUBMITTER: Li S

PROVIDER: S-EPMC4473678 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Swedish mutant APP-based BACE1 binding site peptide reduces APP β-cleavage and cerebral Aβ levels in Alzheimer's mice.

Li Song S Hou Huayan H Mori Takashi T Sawmiller Darrell D Smith Adam A Tian Jun J Wang Yanjiang Y Giunta Brian B Sanberg Paul R PR Zhang Sheqing S Tan Jun J

Scientific reports 20150619

BACE1 initiates amyloid-β (Aβ) generation and the resultant cerebral amyloidosis, as a characteristic of Alzheimer's disease (AD). Thus, inhibition of BACE1 has been the focus of a large body of research. The most recent clinical trials highlight the difficulty involved in this type of anti-AD therapy as evidenced by side effects likely due to the ubiquitous nature of BACE1, which cleaves multiple substrates. The human Swedish mutant form of amyloid protein precursor (APPswe) has been shown to p ...[more]

PMID: 26091071

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Project description:Mutations in amyloid ? precursor protein (APP) gene alter APP processing, either causing familial Alzheimer's disease (AD) or protecting against dementia. Under normal conditions, ?-site APP cleaving enzyme 1 (BACE1) cleaves APP at minor Asp1 site to generate C99 for amyloid ? protein (A?) production, and predominantly at major Glu11 site to generate C89, resulting in truncated A? production. We discovered that A673V mutation, the only recessive AD-associated APP mutation, shifted the preferential ?-cleavage site of BACE1 in APP from the Glu11 site to the Asp1 site both in male and female transgenic mice in vivo and in cell lines and primary neuronal culture derived from timed pregnant rats in vitro, resulting in a much higher C99 level and C99/C89 ratio. All other mutations at this site, including the protective Icelandic A673T mutation, reduced C99 generation, and decreased the C99/C89 ratio. Furthermore, A673V mutation caused stronger dimerization between mutant and wild-type APP, enhanced the lysosomal degradation of the mutant APP, and inhibited ?-secretase cleavage of the mutant C99 to generate A?, leading to recessively inherited AD. The results demonstrate that APP673 regulates APP processing and the BACE1 cleavage site selection is critical for amyloidogenesis in AD pathogenesis, and implicate a pharmaceutical potential for targeting the APP673 site for AD drug development.SIGNIFICANCE STATEMENT ?-site APP cleaving enzyme 1 (BACE1) is essential for amyloid ? protein production. We discovered that A673V mutation shifted the BACE1 cleavage site from the Glu11 to the Asp1 site, resulting in much higher C99 level and C99/C89 ratio. All other mutations at this site of amyloid ? precursor protein (APP) reduced C99 generation and decreased the C99/C89 ratio. Furthermore, A673V mutation resulted in stronger dimerization between mutant and wild-type APP, enhanced the lysosomal degradation of the mutant APP, and inhibited ?-secretase cleavage of the mutant C99 to generate amyloid ? protein, leading to recessively inherited Alzheimer's disease (AD). The results demonstrate that APP673 regulates APP processing, and the BACE1 cleavage site selection is critical for amyloidogenesis in AD pathogenesis, and implicate a pharmaceutical potential for targeting the APP673 site for AD drug development.

Project description: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 (A?). Using immunoblotting and immunostaining analyses, we measured the production of full-length amyloid precursor protein (APP), soluble APP?, C-terminal fragments CTF99 and CTF83, monomeric and oligomeric A?, A? deposits and beta site amyloid precursor protein cleaving enzyme 1 (BACE1), in different stages of disease progression in MCAT/A?PP and A?PP 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, A?PP, MCAT/A?PP 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, A?PP, MCAT/A?PP and WT mice. We found that the A?PP transgenic mice that carried the human MCAT gene lived 5 months longer than did the A?PP mice. We also found that the overexpression of MCAT in the brain sections from the MCAT/A?PP transgenic mice significantly correlated with a reduction in the levels of full-length APP, CTF99, BACE1, A? levels (40 and 42), A? deposits and oxidative DNA damage relative to the brain sections from the A?PP mice. Interestingly, we found significantly increased levels of soluble APP? and CTF83 in the MCAT/A?PP mice, relative to the A?PP mice. These data provide direct evidence that oxidative stress plays a primary role in AD etiopathology and that in MCAT mice express A?, MCAT prevents abnormal APP processing, reduces A? levels and enhances A?-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.

Dataset Information

Swedish mutant APP-based BACE1 binding site peptide reduces APP ?-cleavage and cerebral A? levels in Alzheimer's mice.

Publications

Swedish mutant APP-based BACE1 binding site peptide reduces APP β-cleavage and cerebral Aβ levels in Alzheimer's mice.

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