RESUMO
BACKGROUND/OBJECTIVE: Alzheimer's disease (AD) is a progressive incurable neurodegenerative disorder. Glial cell line-derived neurotrophic factor (GDNF) is a prominent regulator of brain tissue and has an impressive potential for use in AD therapy. While its metabolism is still not fully understood, delivering neuropeptides such as GDNF via umbilical cord blood mononuclear cells (UCBMCs) to the sites of neurodegeneration is a promising approach in the development of innovative therapeutic avenues. METHODS: UCBMCs were transduced with adenoviral vectors expressing GDNF and injected into AD transgenic mice. Various parameters including homing and survival of transplanted cells, expression of GDNF and synaptic proteins, as well as spatial memory were evaluated. RESULTS: UCBMCs were observed in the hippocampus and cortex several weeks after transplantation, and their long-term presence was associated with improved spatial memory. Post-synaptic density protein 95 (PSD-95) and synaptophysin levels in the hippocampus were also effectively restored following the procedure in AD mice. CONCLUSIONS: Our data indicate that gene-cell therapy with GDNF-overexpressing UCBMCs may produce long-lasting neuroprotection and stimulation of synaptogenesis. Such adenoviral constructs could potentially possess a high therapeutic potential for the treatment of AD.
Assuntos
Doença de Alzheimer/metabolismo , Doença de Alzheimer/terapia , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Modelos Animais de Doenças , Fator Neurotrófico Derivado de Linhagem de Célula Glial/biossíntese , Hipocampo/metabolismo , Memória Espacial/fisiologia , Doença de Alzheimer/genética , Animais , Proteína 4 Homóloga a Disks-Large/biossíntese , Proteína 4 Homóloga a Disks-Large/genética , Feminino , Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Células HEK293 , Humanos , Camundongos , Camundongos Transgênicos , Gravidez , Sinaptofisina/biossíntese , Sinaptofisina/genéticaRESUMO
INTRODUCTION: Alzheimer's ß-amyloid peptide (ßAP) is known to possess a wide range of toxic effects on neurons in vitro and in vivo; however, there is little information available regarding its impact on other excitable tissues such as skeletal muscles, which, apart from brain cells, are thought to also be targets of ßAP. METHODS: Utilizing the combination of electrophysiology and myography, we investigated whether ßAP also impairs the functioning of myocytes in frogs and mice. RESULTS: Although application of ßAP in the range of 10(-6) to 10(-8) M induced depolarization of muscle fibers in both species, it impaired contractility in frogs but not in mice, by reducing endplate potential amplitude and increasing the threshold potential. CONCLUSIONS: Unchanged contractility in the mouse in the presence of ßAP is due to a higher safety factor of neuromuscular transmission in mammals compared with amphibians. Possible clinical implications are discussed.