Adenovirus-mediated expression of IGF-1 protects against neuronal damage and memory impairment in a mouse model of Alzheimer?s disease

ZAPPA VILLAR MF; REGGIANI PC; FORTUNA JTS; DE SOUZA AS; SELLES MC; PEREIRA Y; FERREIRA ST

Lisboa

Congreso; 14th International Conference on Alzheimer's and Parkinson's Diseases; 2019

mmObjectives:Alzheimer?s disease (AD) is the main cause of dementia worldwide. Activationof brain insulin signaling preserves memory in AD models and appearsbeneficial in patients. In contrast, the role of insulin-like growth factor 1 (IGF1)remains controversial. Converging evidence implicates soluble oligomers of theamyloid- â peptide (A â Os) in early synapse dysfunction and memoryimpairment in AD. Our aim was to determine the possible protective actions ofIGF1 against A â O toxicity in AD models.MethodsWe investigated the protective actions of IGF1 in vitro using an adenoviralvector (AdIGF1) to drive expression of IGF1 in hippocampal cultures exposed toA â Os. In vivo, memory impairment was induced by intracerebroventricularinfusion of A â Os in female mice that had been previously treated (or not) withAdIGF1 or AG1024 (IGF1 receptor tyrosine kinase activity inhibitor). Memorywas evaluated in the novel object recognition task.ResultsHippocampal cultures infected with AdIGF1 showed decreased binding ofA â Os to neurons and marked protection against A â O-induced neuronaloxidative stress and loss of dendritic spines. Mice infected with AdIGF1 wereprotected against A â O-induced memory deficits. Conversely, previoustreatment with AG1024 exacerbated memory impairment induced by a subtoxicdose of A â Os.ConclusionsResults indicate a protective role of IGF1 in AD, as IGF1 overexpressionprotected against neuronal damage and memory deficits induced by A â Os,whereas inhibiting IGF1R signaling potentiated memory impairment induced bya sub-toxic dose of A â Os. This suggests that reduced brain IGF1 signalingmight facilitate the development of AD, and that activating IGF1 signaling couldbe therapeutic.