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:Alzheimer's disease (AD) is characterized pathologically by amyloid β (Aβ)-containing plaques. Generation of Aβ from amyloid precursor protein (APP) by two enzymes, β- and γ-secretase, has therefore been in the AD research spotlight for decades. Despite this, how the physical interaction of APP with the secretases influences APP processing is not fully understood. Herein, we compared two genetically identical human iPSC-derived neuronal cell types: low Aβ-secreting neuroprogenitor cells (NPCs) and high Aβ-secreting mature neurons, as models of low versus high Aβ production. We investigated levels of substrate, enzymes and products of APP amyloidogenic processing and correlated them with the proximity of APP to β- and γ-secretase in endo-lysosomal organelles. In mature neurons, increased colocalization of full-length APP with the β-secretase BACE1 correlated with increased β-cleavage product sAPPβ. Increased flAPP/BACE1 colocalization was mainly found in early endosomes. In the same way, increased colocalization of APP-derived C-terminal fragment (CTF) with presenilin-1 (PSEN1), the catalytic subunit of γ-secretase, was seen in neurons as compared to NPCs. Furthermore, most of the interaction of APP with BACE1 in low Aβ-secreting NPCs seemed to derive from CTF, the remaining APP part after BACE1 cleavage, indicating a possible novel product-enzyme inhibition. In conclusion, our results suggest that interaction of APP and APP cleavage products with their secretases can regulate Aβ production both positively and negatively. β- and γ-Secretases are difficult targets for AD treatment due to their ubiquitous nature and wide range of substrates. Therefore, targeting APP-secretase interactions could be a novel treatment strategy for AD. Colocalization of APP species with BACE1 in a novel model of low- versus high-Aβ secretion-Two genetically identical human iPSC-derived neuronal cell types: low Aβ-secreting neuroprogenitor cells (NPCs) and high Aβ secreting mature neurons, were compared. Increased full-length APP (flAPP)/BACE1 colocalization in early endosomes was seen in neurons, while APP-CTF/BACE1 colocalization was much higher than flAPP/BACE1 colocalization in NPCs, although the cellular location was not determined.

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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