INIBIOLP   05426
INSTITUTO DE INVESTIGACIONES BIOQUIMICAS DE LA PLATA "PROF. DR. RODOLFO R. BRENNER"
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
IGF-1 gene transfer protects against Abeta oligomer-induced neuronal damage and memory impairment in mice.
Autor/es:
SELLÉS MC; FERREIRA ST; ZAPPA VILLAR MF; REGGIANI PC
Lugar:
Washington
Reunión:
Congreso; 47th Annual Meeting, Society for Neuroscience; 2017
Institución organizadora:
Society for Neuroscience
Resumen:
Alzheimer´s disease (AD) is the main cause of dementia worldwide. Although the prevalence of AD is increasing, there is no effective therapy to treat this neurodegenerative disease. Considerable evidence indicates that soluble oligomers of the amyloid-beta peptide (ABOs), which accumulate in AD brains, are implicated in early synaptic dysfunction and memory impairment in AD. Previously, we have reported that exposure of primary hippocampal neurons to ABOs induces internalization of dendritic insulin receptors (IR) and inhibition of insulin receptor substrate-1 (IRS-1), inducing neuronal insulin resistance. Insulin plays important roles in neuronal survival, learning and memory, and its possible beneficial effects have been tested in clinical trials for AD. Although insulin appears to improve cognition in control individuals and in early stages of AD, protective effects were not readily observed in late stages of the disease. Possible explanations for this include the removal of IRs from the neural surface instigated by oligomers, and blockade of IR-mediated signaling by ABO-induced IRS-1 inhibition. We have now investigated whether insulin-like growth factor 1 (IGF-1) could be utilized to circumvent IR signaling blockade and to promote alternative activation of insulin-related pathways, thus protecting neurons from ABO-induced damage. We first found that exposure to ABOs did not affect surface levels of IGF-1 receptor in hippocampal neuronal cultures. To test our hypothesis, we employed a recombinant adenoviral vector (RAd-IGF-1) to induce overexpression of IGF-1 in hippocampal cultures for two weeks prior to exposure to ABOs (500 nM). Cultures were then evaluated for neuronal binding of ABOs, synaptic integrity, and neuronal oxidative stress (production of reactive oxygen species, ROS). Interestingly, despite only a slight decrease in ABO binding to neurons, viral-mediated expression of IGF-1 prevented ABO-induced dendritic spine loss and excessive ROS production. Next, we performed intracerebroventricular (i.c.v.) injection of RAd-IGF-1 in Swiss mice two weeks prior to i.c.v. infusion of ABOs, a model we have implemented to study the in vivo impact of ABOs. Interestingly, brain expression of IGF-1 protected against memory impairment induced by ABOs, as assessed using the novel object recognition test. Results suggest that RAd-IGF-1 gene therapy could be a promising strategy to protect neuronal damage and memory impairment induced by ABOs.