title: Swedish mutant APP-based BACE1 binding site peptide reduces APP β-cleavage and cerebral Aβ levels in Alzheimer's mice.
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.affiliation: 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.
authors.forename: Song
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Psychiatry and Behavioral Neurosciences, Morsani College of Medicine, University of South Florida, Tampa, FL 33613.
authors.forename: Huayan
authors.initials: H
authors.lastname: Hou
authors.affiliation: Departments of Biomedical Sciences and Pathology, Saitama Medical Center and Saitama Medical University, Kawagoe, Saitama 350-8550, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Mori
authors.affiliation: Department of Psychiatry and Behavioral Neurosciences, Morsani College of Medicine, University of South Florida, Tampa, FL 33613.
authors.forename: Darrell
authors.initials: D
authors.lastname: Sawmiller
authors.affiliation: Department of Neurosurgery and Brain Repair, Center Of Excellence for Aging &Brain Repair, Morsani College of Medicine, University of South Florida, Tampa, FL 33613.
authors.forename: Adam
authors.initials: A
authors.lastname: Smith
authors.affiliation: Department of Psychiatry and Behavioral Neurosciences, Morsani College of Medicine, University of South Florida, Tampa, FL 33613.
authors.forename: Jun
authors.initials: J
authors.lastname: Tian
authors.affiliation: Department of Neurology, Daping Hospital, the Third Military Medical University, Chongqing 400042, China.
authors.forename: Yanjiang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Neuroimmunology Laboratory, Department of Psychiatry and Behavioral Neurosciences, Morsani College of Medicine, University of South Florida, Tampa, FL 33613.
authors.forename: Brian
authors.initials: B
authors.lastname: Giunta
authors.affiliation: Department of Neurosurgery and Brain Repair, Center Of Excellence for Aging &Brain Repair, Morsani College of Medicine, University of South Florida, Tampa, FL 33613.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Sanberg
authors.affiliation: 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.
authors.forename: Sheqing
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Psychiatry and Behavioral Neurosciences, Morsani College of Medicine, University of South Florida, Tampa, FL 33613.
authors.forename: Jun
authors.initials: J
authors.lastname: Tan
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001522:Behavior, Animal; D001665:Binding Sites / Q000235:genetics; D001812:Blood-Brain Barrier / Q000378:metabolism; D016466:CHO Cells; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D003412:Cricetulus; D004195:Disease Models, Animal; D015870:Gene Expression; D006624:Hippocampus / Q000378:metabolism; D008568:Memory; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D059748:Proteolysis; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010455:Peptides; D011993:Recombinant Fusion Proteins; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse