Targeted RGS14414 gene delivery into brain induces recovery of memory loss in ageing and Alzhemer´s disease

I Navarro-Lobato1,2, MF Lopez-Aranda3, M Masmudi-Martin1,2, JF Lopez-Tellez1,2, SJ Posadas1,2, G Delgado1,2, N Comino-Gonzalez1,2, E Blanco Calvo4, JM Luque1, ZU Khan1,2. 1University of Malaga, Dept. Medicine, Faculty of Medicine, Spain, 2University of Malaga, Lab. Neurobiology, CIMES, Spain, 3University of California Los Angeles, Neuroscience, USA, 4University of Malaga, Dept. Psychobiology, Faculty of Psychology, Spain

Deficits in memory function are not only comorbid with many psychiatric and neurological disorders but also accompany normal ageing. Intact memory function is critical to carry out daily life activities and therefore, cognitive enhancement pharmacological agents are viewed as a strategy to treat memory deficits. However, available stimulants and drugs have failed to produce therapeutic efficacy in humans. More effective and precise therapeutic strategies are needed. In this respect, recently, we observed that that the gene delivery of a regulator of G-protein signaling 14 of 414 amino acids (RGS14414) into layer 6 neurons of area V2 of secondary visual cortex enhanced visual memory to such extent that it led to the conversion of short-term memory of 45 minutes into long lasting long-term memory. Here, we have tested of whether this RGS14414 protein can prevent and/or reverse a episodic memory loss in two most representative models, normal ageing and Alzheimer\'s disease, where memory deficit has consistently been observed. Wistar Han rats of 3-24 months old and transgenic hAPPSwInd mice model of Alzheimer’s disease of 2-12 months old were included in this study. Animal performance on ORM task, a test known as hallmark of episodic memory, was used to evaluate the visual memory status. In this test, animals were exposed to two identical objects for a time period in an open field and then they were analyzed for the length of time object information is retained in the memory. Statistical analysis was performed using a one way ANOVA followed by Tukey-Kramer post hoc tests. In our experiments, we found that expression of RGS14414 protein into the layer 6 neurons of area V2 not only reversed the episodic memory deficit in ageing rats and transgenic mice model of Alzheimer’s disease but also prevented its onset in both models. These findings indicate that RGS14414 protein-mediated activation of area V2 neurons is adequate to amend the memory loss seen in both ageing and Alzheimer’s disease, and the combination of RGS14414 protein and its targeted expression into area V2 could serve as a potential strategy for the treatment of episodic memory deficits in patients.

This work was supported by the projects from Ministerio de Ciencia e Innovación (BFU2010-16500) y Junta de Andalucía (CTS-586).