IGF-1 gene transfer protects against A oligomer-induced neuronal damage and memory impairment in mice

SELLÉS, MARIA CLARA; ZAPPA VILLAR, MARIA FLORENCIA; REGGIANI, PAULA CECILIA; FERREIRA, SERGIO T

Washington

Congreso; 47th Annual Meeting, Society for Neuroscience; 2017

Society for Neuroscience

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 (AOs), 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 AOs 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 may not be 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 AO-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 AO-induced damage. We first found that exposure to AOs 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 over-expression of IGF-1 in hippocampal cultures for two weeks prior to exposure to AOs (500 nM). Cultures were then evaluated for neuronal binding of AOs, synaptic integrity, and neuronal oxidative stress. Interestingly, despite only a slight decrease in AO binding to neurons, viral-mediated expression of IGF-1 prevented AO-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 AOs, a model we have implemented to study the in vivo impact of AOs. Interestingly, brain over expression of IGF-1 protected against memory impairment induced by AOs, 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 AOs.