Transducible P11-CNTF rescues the learning and memory impairments induced by amyloid-beta peptide in mice

• Published in: European journal of pharmacology Vol. 594; no. 1; pp. 93 - 100
• Main Authors: Qu, Heng Yan, Zhang, Ting, Li, Xu Ling, Zhou, Jian Ping, Zhao, Bao Quan, Li, Qian, Sun, Man Ji
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 10.10.2008; Elsevier
• Subjects: Adult and adolescent clinical studies; Alzheimer's disease; Amyloid beta-Peptides; Amyloid-beta peptide; Animals; Biological and medical sciences; Blood-brain barrier; Blotting, Western; Choline O-Acetyltransferase - biosynthesis; Ciliary neurotrophic factor; Ciliary Neurotrophic Factor - chemical synthesis; Ciliary Neurotrophic Factor - metabolism; Ciliary Neurotrophic Factor - pharmacology; Cloning, Molecular; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Dementia - chemically induced; Dementia - prevention & control; DNA Primers; Flow Cytometry; Fluorescent Antibody Technique; Intermediate Filament Proteins - biosynthesis; Learning and memory; Learning Disorders - chemically induced; Learning Disorders - drug therapy; Learning Disorders - psychology; Male; Maze Learning - drug effects; Medical sciences; Memory Disorders - chemically induced; Memory Disorders - drug therapy; Memory Disorders - psychology; Mice; Mice, Inbred C57BL; Microscopy, Electron, Transmission; Nerve Tissue Proteins - biosynthesis; Nestin; Neurofibrillary Tangles - pathology; Neurology; Organic mental disorders. Neuropsychology; Pharmacology. Drug treatments; Phosphoproteins - chemistry; Phosphoproteins - metabolism; Phosphoproteins - pharmacology; Protein transduction domain; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Recombinant Fusion Proteins - chemical synthesis; Recombinant Fusion Proteins - pharmacology; Reverse Transcriptase Polymerase Chain Reaction; Learning and memory; Protein transduction domain; Blood-brain barrier; Ciliary neurotrophic factor; Alzheimer's disease; Amyloid-beta peptide; Memory disorder; Cognitive disorder; Alzheimer disease; Memory; Central nervous system; Blood brain barrier; Encephalon; Learning; Acquisition process; Degenerative disease; Nervous system diseases; Rodentia; Cerebral disorder; Vertebrata; Mammalia; Mouse; Animal; Central nervous system disease; Pharmacokinetics
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2008.06.109

Alzheimer's disease is a progressive brain disorder with the loss of memory and other intellectual abilities. Amyloid species and neurofibrillary tangles are the prime suspects in damaging and killing nerve cells. Abnormal accumulation of Amyloid-beta peptide (Aβ) may cause synaptic dysfunction and degeneration of neurons. Drugs that can prevent its formation and accumulation or stimulate its clearance might ultimately be of therapeutic benefit. Ciliary neurotrophic factor (CNTF), a neurotrophic cytokine, promotes the survival of various neurons in brain. However, the blood-brain barrier hinders the systemic delivery of CNTF to brain. Recently the 11-amino acid of protein transduction domain TAT has successfully assisted the delivery of many macromolecules to treat preclinical models of human disease. The present study aimed to evaluate whether P11-CNTF fusion protein (P11-CNTF) is protective against the Aβ25-35-induced dementia in mice. Immunofluorescence experiments showed that P11 effectively carried CNTF to the SH-SY5Y cells in vitro, and to the brains of mice in vivo. The learning and memory impairments of mice induced by Aβ were substantially rescued by supplement with the P11-CNTF. Furthermore, mRNAs of enzymes involved in the Aβ metabolism, e.g. neprilysin (NEP), endothelin-converting enzyme 1 (ECE-1) and insulin degrading enzyme (IDE), increased in the P11-CNTF treated dementia mice, accompanied by the proliferation of nestin- and choline acetyltransferase (ChAT)-positive cells in hippocampus. It implies that the delivery of P11-CNTF may be a novel treatment for Alzheimer's disease.