An intranasally delivered peptide drug ameliorates cognitive decline in Alzheimer transgenic mice

• Published in: EMBO molecular medicine Vol. 9; no. 5; pp. 703 - 715
• Main Authors: Cheng, Yu‐Sung, Chen, Zih‐ten, Liao, Tai‐Yan, Lin, Chen, Shen, Howard C‐H, Wang, Ya‐Han, Chang, Chi‐Wei, Liu, Ren‐Shyan, Chen, Rita P‐Y, Tu, Pang‐hsien
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2017; EMBO Press; John Wiley and Sons Inc; Springer Nature
• Subjects: Administration, Intranasal; Alzheimer disease; Alzheimer Disease - complications; Alzheimer Disease - drug therapy; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid - antagonists & inhibitors; Amyloid - ultrastructure; Amyloid beta-Peptides - administration & dosage; Amyloid beta-Peptides - antagonists & inhibitors; Amyloid beta-Peptides - chemistry; Amyloid beta-Peptides - therapeutic use; Amyloid beta-Peptides - ultrastructure; Amyloid precursor protein; Animals; Brain - drug effects; Brain - pathology; Cell Line; Cognition - drug effects; Cognitive ability; Cognitive Dysfunction - complications; Cognitive Dysfunction - drug therapy; Cognitive Dysfunction - pathology; Design; Disease Models, Animal; EMBO27; EMBO28; Female; Intranasal administration; Memory; Memory Disorders - complications; Memory Disorders - drug therapy; Memory Disorders - pathology; Mice, Inbred C57BL; Neurodegenerative diseases; Peptide Fragments - administration & dosage; Peptide Fragments - antagonists & inhibitors; Peptide Fragments - chemistry; Peptide Fragments - therapeutic use; Peptide Fragments - ultrastructure; peptide therapy; Peptides; Peptides - administration & dosage; Peptides - chemistry; Peptides - therapeutic use; polyarginine; polyethylenimine; Presenilin 1; Research Article; Rodents; Transgenic animals; Transgenic mice; β-Amyloid; Aβ; peptide therapy; Alzheimer disease; polyarginine; polyethylenimine
• ISSN: 1757-4676; 1757-4684; 1757-4684
• DOI: 10.15252/emmm.201606666

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, R 8 ‐Aβ(25–35), on amyloid reduction and the improvement of cognitive functions were evaluated using APP/PS1 double transgenic mice. Daily intranasal administration of PEI‐conjugated R 8 ‐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. Synopsis Intranasal administration of an amyloid inhibitor peptide to Alzheimer transgenic mice reduces amyloid brain deposition in the brain and ameliorates cognitive decline. A peptide, R 8 ‐Aβ(25–35), combining polyarginines (polyR) (for charge repulsion) and a segment derived from the core region of Aβ amyloid (for sequence recognition) was designed. Daily intranasal administration of the PEI‐conjugated R 8 ‐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 could be easily extended to other proteinaceous aggregate‐associated diseases. Graphical Abstract Intranasal administration of an amyloid inhibitor peptide to Alzheimer transgenic mice reduces amyloid brain deposition in the brain and ameliorates cognitive decline.