title: Transducible P11-CNTF rescues the learning and memory impairments induced by amyloid-beta peptide in mice.
abstract: 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 (Abeta) 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 Abeta25-35-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 Abeta were substantially rescued by supplement with the P11-CNTF. Furthermore, mRNAs of enzymes involved in the Abeta 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.
authors.affiliation: Department of Biochemistry and Pharmacology, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Tai Ping Road, 27, Beijing 100850, China.
authors.forename: Heng Yan
authors.initials: HY
authors.lastname: Qu
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.forename: Xu Ling
authors.initials: XL
authors.lastname: Li
authors.forename: Jian Ping
authors.initials: JP
authors.lastname: Zhou
authors.forename: Bao Quan
authors.initials: BQ
authors.lastname: Zhao
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.forename: Man Ji
authors.initials: MJ
authors.lastname: Sun
mesh_terms: D016229:Amyloid beta-Peptides; D000818:Animals; D015153:Blotting, Western; D002795:Choline O-Acetyltransferase / Q000096:biosynthesis; D020934:Ciliary Neurotrophic Factor / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D003001:Cloning, Molecular; D017931:DNA Primers; D003704:Dementia / Q000139:chemically induced / Q000517:prevention & control; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D007381:Intermediate Filament Proteins / Q000096:biosynthesis; D007859:Learning Disabilities / Q000139:chemically induced* / Q000188:drug therapy* / Q000523:psychology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced* / Q000188:drug therapy* / Q000523:psychology; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D064231:Nestin; D016874:Neurofibrillary Tangles / Q000473:pathology; D010750:Phosphoproteins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011993:Recombinant Fusion Proteins / Q000138:chemical synthesis / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D016229:Amyloid beta-Peptides; D020934:Ciliary Neurotrophic Factor; D017931:DNA Primers; D007381:Intermediate Filament Proteins; C577484:NES protein, human; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; C111405:P11 (CBL); D010750:Phosphoproteins; D011993:Recombinant Fusion Proteins; D002795:Choline O-Acetyltransferase