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Swedish mutant APP-based BACE1 binding site peptide reduces APP β-cleavage and cerebral Aβ levels in Alzheimer's mice.
Sci Rep. 2015 Jun 19; 5:11322.SR

Abstract

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 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 β-cleavage site, strongly inhibits BACE1 activity and thereby reduces Aβ 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 Aβ and a significant increase of soluble APPα. Intraperitoneal administration of this peptide to 5XFAD mice markedly reduced β-amyloid deposits as well as improved hippocampal-dependent learning and memory.

Authors+Show Affiliations

1] Department of Psychiatry and Behavioral Neurosciences, Morsani College of Medicine, University of South Florida, Tampa, FL 33613 [2] Center for Translational Research of Neurology Diseases, First Affiliated Hospital, Dalian Medical University, Dalian 116011, China.Department of Psychiatry and Behavioral Neurosciences, Morsani College of Medicine, University of South Florida, Tampa, FL 33613.Departments of Biomedical Sciences and Pathology, Saitama Medical Center and Saitama Medical University, Kawagoe, Saitama 350-8550, Japan.Department of Psychiatry and Behavioral Neurosciences, Morsani College of Medicine, University of South Florida, Tampa, FL 33613.Department of Neurosurgery and Brain Repair, Center Of Excellence for Aging &Brain Repair, Morsani College of Medicine, University of South Florida, Tampa, FL 33613.Department of Psychiatry and Behavioral Neurosciences, Morsani College of Medicine, University of South Florida, Tampa, FL 33613.Department of Neurology, Daping Hospital, the Third Military Medical University, Chongqing 400042, China.Neuroimmunology Laboratory, Department of Psychiatry and Behavioral Neurosciences, Morsani College of Medicine, University of South Florida, Tampa, FL 33613.Department of Neurosurgery and Brain Repair, Center Of Excellence for Aging &Brain Repair, Morsani College of Medicine, University of South Florida, Tampa, FL 33613.1] Department of Psychiatry and Behavioral Neurosciences, Morsani College of Medicine, University of South Florida, Tampa, FL 33613 [2] Department of Neurology, Changhai hospital, Shanghai 200433, China.Department of Psychiatry and Behavioral Neurosciences, Morsani College of Medicine, University of South Florida, Tampa, FL 33613.

Pub Type(s)

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

Language

eng

PubMed ID

26091071

Citation

Li, Song, et al. "Swedish Mutant APP-based BACE1 Binding Site Peptide Reduces APP Β-cleavage and Cerebral Aβ Levels in Alzheimer's Mice." Scientific Reports, vol. 5, 2015, p. 11322.
Li S, Hou H, Mori T, et al. Swedish mutant APP-based BACE1 binding site peptide reduces APP β-cleavage and cerebral Aβ levels in Alzheimer's mice. Sci Rep. 2015;5:11322.
Li, S., Hou, H., Mori, T., Sawmiller, D., Smith, A., Tian, J., Wang, Y., Giunta, B., Sanberg, P. R., Zhang, S., & Tan, J. (2015). Swedish mutant APP-based BACE1 binding site peptide reduces APP β-cleavage and cerebral Aβ levels in Alzheimer's mice. Scientific Reports, 5, 11322. https://doi.org/10.1038/srep11322
Li S, et al. Swedish Mutant APP-based BACE1 Binding Site Peptide Reduces APP Β-cleavage and Cerebral Aβ Levels in Alzheimer's Mice. Sci Rep. 2015 Jun 19;5:11322. PubMed PMID: 26091071.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Swedish mutant APP-based BACE1 binding site peptide reduces APP β-cleavage and cerebral Aβ levels in Alzheimer's mice. AU - Li,Song, AU - Hou,Huayan, AU - Mori,Takashi, AU - Sawmiller,Darrell, AU - Smith,Adam, AU - Tian,Jun, AU - Wang,Yanjiang, AU - Giunta,Brian, AU - Sanberg,Paul R, AU - Zhang,Sheqing, AU - Tan,Jun, Y1 - 2015/06/19/ PY - 2015/01/27/received PY - 2015/05/14/accepted PY - 2015/6/20/entrez PY - 2015/6/20/pubmed PY - 2016/6/9/medline SP - 11322 EP - 11322 JF - Scientific reports JO - Sci Rep VL - 5 N2 - 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 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 β-cleavage site, strongly inhibits BACE1 activity and thereby reduces Aβ 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 Aβ and a significant increase of soluble APPα. Intraperitoneal administration of this peptide to 5XFAD mice markedly reduced β-amyloid deposits as well as improved hippocampal-dependent learning and memory. SN - 2045-2322 UR - https://www.unboundmedicine.com/medline/citation/26091071/Swedish_mutant_APP_based_BACE1_binding_site_peptide_reduces_APP_β_cleavage_and_cerebral_Aβ_levels_in_Alzheimer's_mice_ L2 - https://doi.org/10.1038/srep11322 DB - PRIME DP - Unbound Medicine ER -