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Identification of insulin signalling factors that delay age-related memory impairment

Periodic Reporting for period 1 - AGE-MEMORY (Identification of insulin signalling factors that delay age-related memory impairment)

Reporting period: 2016-06-01 to 2018-05-31

Human's life expectancy is continuously increasing and and with an ever-increasing proportion of elderly people, novel treatments of age-related diseases are necessary. One of the first systems that deteriorate with ageing is cognitive function, causing learning, memory, concentrating and decision making disabilities. It affects 18.5% of individuals over -50's and it can start during the mid-twenties. Age-related memory impairment is a major symptom of Alzheimer's disease and so far it is not curable. Identification of evolutionarily conserved pathways that enhance ageing in animals can be pharmacological targets for relative treatments in future.
Model organisms share common mechanisms that boost or delay ageing, such as the insulin signalling (IIS)and the TOR signalling, which is regulated by IIS signalling. Reduction of IIS and TOR extend lifespan in animals and can improve health, even in humans. Also, increasing evidence suggests that IIS might affect brain ageing. thus IIS manipulation might delay age-related memory impairment.
The overall objectives of this project was to study the effect of lowered IIS on learning and memory through ageing, the identification of IIS components that govern learning and memory decline and the characterisation of the mechanisms/factors through which IIS affects memory decline.
In this project we studied the effect of IIS on learning and memory in C. elegans and Drosophila melanogaster. IIS mutants had improved learning capacity, through FOXO factor, but declined LTAM, through reduced TOR activity. We found that acute TOR inhibition reduced LTAM through S6Kinase de-activation and serotonergic cells-specific autophagy induction through atg1 upregulation. Interestingly, autophagy induction affected both memory and mood, making them less afraid, with higher exploratory activated and more motivated to move towards the light. This effect was abrogated by autophagy inhibition specifically in the ellipsoid bodies, a brain area that has been associated with LTAM formation. To elucidate the neuronal network through which autophagy exerts its effects on behaviour and cognition, we performed biochemical and genetic analysis that revealed serotonin 5HT7 receptor as the mediator of autophagy-triggered mood and cognitive alterations. Downregulation of 5ht7 in nmda-specific cells, which reside mainly in ellipsoid bodies, caused a depression-like phenotype, but unaltered memory performance. Rapamycin treated flies exhibited decreased glutamatergic activity, possibly through increased endocytosis of NMDA2 receptor, which is mainly expressed in ellipsoid bodies and has been largely implicated in LTAM formation. We believe that 5HT7 might regulate levels of NMDA2 endocytosis and, through this, affects mood and memory. Moreover, upregulation of 5ht7 in nmda expressing cells caused in flies a phenotype similar to upregulated serotonergic autophagy and rapamycin treatment. In support, developmental defects triggered by paneuronal autophagy upregulation were recapitulated by dopaminergic specific upregulation of 5ht7. Hence, we believe that we have found a novel mechanism through which autophagy coordinates mood and cognition via 5HT7 receptor and NMDA2 receptor. Interestingly, this mechanism seems to be evolutionarily conserved in worms, where mutants for ser-2, a highly homologous to 5ht7 receptor serotonin receptor gene, have increased autophagy and they are resistant to rapamycin treatment mediated memory decline and lifespan enhancement. Finally, we find that mitophagy inducer Urolithin A inhibits learning decline through aging. However we did not manage to detect any neuronal morphological alteration in aged Urolithin A treated worms, compared to the controls.

The above results were presented (oral presentation) at the international EMBO Workshop on Molecular Neurobiology, 8-12 May 2018, Fodele, Crete, Greece.
The novel mechanism we have identified is a major contribution to the state of the art in the field and it will help elucidate the route through which neuronal metabolism regulates cognition, mood and memory formation. Furthermore, we have found that a chemical that is formed after the consumption of pomegranates can ameliorate learning disabilities. We expect that until the end of this project we will have elucidated the relative mechanism. This will have a major impact in the research field and will suggest novel biomedical treatments for age-related memory impairment. Hence, it might contribute to the improvement of daily life of elderly people, with the appropriate socio-economic impact for future societies.