RESUMEN
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.
Asunto(s)
Péptidos beta-Amiloides , Factor Neurotrófico Ciliar/farmacología , Discapacidades para el Aprendizaje/inducido químicamente , Discapacidades para el Aprendizaje/tratamiento farmacológico , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/tratamiento farmacológico , Fosfoproteínas/farmacología , Animales , Western Blotting , Colina O-Acetiltransferasa/biosíntesis , Factor Neurotrófico Ciliar/síntesis química , Factor Neurotrófico Ciliar/metabolismo , Clonación Molecular , Cartilla de ADN , Demencia/inducido químicamente , Demencia/prevención & control , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Proteínas de Filamentos Intermediarios/biosíntesis , Discapacidades para el Aprendizaje/psicología , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Trastornos de la Memoria/psicología , Ratones , Ratones Endogámicos C57BL , Microscopía Electrónica de Transmisión , Proteínas del Tejido Nervioso/biosíntesis , Nestina , Ovillos Neurofibrilares/patología , Fosfoproteínas/química , Fosfoproteínas/metabolismo , Proteínas Recombinantes de Fusión/síntesis química , Proteínas Recombinantes de Fusión/farmacología , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Pharmacological enhancement of hippocampal neurogenesis is a therapeutic approach for improvement of cognition in learning and memory disorders such as Alzheimer's disease. Here we report the development of an 11-mer peptide that we designed based on a biologically active region of the ciliary neurotrophic factor. This peptide, Peptide 6, induced proliferation and increased survival and maturation of neural progenitor cells into neurons in the dentate gyrus of normal adult C57BL6 mice. Furthermore, Peptide 6 increased the MAP2 and synaptophysin immunoreactivity in the dentate gyrus. Thirty-day treatment of the mice with a slow release bolus of the peptide implanted subcutaneously improved reference memory of the mice in Morris water maze. Peptide 6 has a plasma half life of over 6 h, is blood-brain barrier permeable, and acts by competitively inhibiting the leukemia inhibitory factor signaling. The fact that Peptide 6 is both neurogenic and neurotrophic and that this peptide is effective when given peripherally, demonstrates its potential for prevention and treatment of learning and memory disorders.