title: An intranasally delivered peptide drug ameliorates cognitive decline in Alzheimer transgenic mice.
abstract: Alzheimer's disease (AD) is the most common neurodegenerative disease. Imbalance between the production and clearance of amyloid β (Aβ) peptides is considered to be the primary mechanism of AD pathogenesis. This amyloid hypothesis is supported by the recent success of the human anti-amyloid antibody aducanumab, in clearing plaque and slowing clinical impairment in prodromal or mild patients in a phase Ib trial. Here, a peptide combining polyarginines (polyR) (for charge repulsion) and a segment derived from the core region of Aβ amyloid (for sequence recognition) was designed. The efficacy of the designed peptide, R8-Aβ(25-35), on amyloid reduction and the improvement of cognitive functions were evaluated usingAPP/PS1double transgenic mice. Daily intranasal administration of PEI-conjugated R8-Aβ(25-35) peptide significantly reduced Aβ amyloid accumulation and ameliorated the memory deficits of the transgenic mice. Intranasal administration is a feasible route for peptide delivery. The modular design combining polyR and aggregate-forming segments produced a desirable therapeutic effect and could be easily adopted to design therapeutic peptides for other proteinaceous aggregate-associated diseases.
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Yu-Sung
authors.initials: YS
authors.lastname: Cheng
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.
authors.forename: Zih-Ten
authors.initials: ZT
authors.lastname: Chen
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.
authors.forename: Tai-Yan
authors.initials: TY
authors.lastname: Liao
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.
authors.forename: Chen
authors.identifier: 0000-0003-1497-5899
authors.initials: C
authors.lastname: Lin
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.
authors.forename: Howard C-H
authors.initials: HC
authors.lastname: Shen
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.|Institute of Biochemical Sciences, National Taiwan University, Taipei, Taiwan.
authors.forename: Ya-Han
authors.initials: YH
authors.lastname: Wang
authors.affiliation: Biomedical Imaging Research Center, Department of Nuclear Medicine, National Yang-Ming University and Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Chi-Wei
authors.initials: CW
authors.lastname: Chang
authors.affiliation: Biomedical Imaging Research Center, Department of Nuclear Medicine, National Yang-Ming University and Taipei Veterans General Hospital, Taipei, Taiwan.|Molecular and Genetic Imaging Core, Taiwan Mouse Clinic, Academia Sinica, Taipei, Taiwan.
authors.forename: Ren-Shyan
authors.initials: RS
authors.lastname: Liu
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan pyc@gate.sinica.edu.tw benrosetu@yahoo.com.|Institute of Biochemical Sciences, National Taiwan University, Taipei, Taiwan.
authors.forename: Rita P-Y
authors.identifier: 0000-0003-3987-033X
authors.initials: RP
authors.lastname: Chen
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan pyc@gate.sinica.edu.tw benrosetu@yahoo.com.
authors.forename: Pang-Hsien
authors.identifier: 0000-0003-2821-7335
authors.initials: PH
authors.lastname: Tu
mesh_terms: D000281:Administration, Intranasal; D000544:Alzheimer Disease / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D000682:Amyloid / Q000037:antagonists & inhibitors / Q000648:ultrastructure; D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000627:therapeutic use* / Q000648:ultrastructure; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D002460:Cell Line; D003071:Cognition / Q000187:drug effects; D060825:Cognitive Dysfunction / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D008569:Memory Disorders / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000627:therapeutic use* / Q000648:ultrastructure; D010455:Peptides / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D010455:Peptides; C078592:amyloid beta-protein (1-40); C074636:amyloid beta-protein (25-35); C015462:polyarginine
keywords: Alzheimer disease; Aβ; peptide therapy; polyarginine; polyethylenimine