Objective: The aim of this work was to elucidate the effect of SIRT6 overexpression on cognition.

Background: Recent evidence show that astrocytes are important for higher brain function, and may be pivotal for learning and memory. Astroglial release of neurotrophic factors and cytokines alters the survival and function of neurons. Astrocytes also affect neuronal metabolism, a process essential for long-term memory formation. The sirtuins, NAD+ dependent deacetylases, regulate longevity and metabolism. There is a growing body of evidence that SIRT6 affects longevity and metabolic profile.

Methods: Age-dependent effects of SIRT6 were examined using a battery of behavioral tests. Brains of aged mice were dyed using immunohistochemistry. The effect of SIRT6 overexpression in neurons or astrocytes on the susceptibility to neurotoxicity, was assessed by viability assays and the effect of conditioned media from wild-type and SIRT6 overexpressing astrocytes were examined.

Results: Aged SIRT6 overexpressing mice exhibit enhanced long–term spatial memory in comparison to their age-matched wild-type littermates. SIRT6 expression levels significantly increased in the hippocampus and frontal cortex. Staining these brain sections with neuronal marker NeuN or microglial marker Iba-1, found no significant difference between WT and mice overexpressing SIRT6. Staining with glial fibrillary acidic protein (GFAP), a marker for astrocytes, showed a significant increase in GFAP in mice overexpressing SIRT6. A significant increase in newly generated neurons, stained with doublecortin (DCX) was found in the hippocampus of SIRT6 overexpressing mice. In vitro, conditioned media of SIRT6 astrocytes protected neurons against 6-hydroxydopamine (6-OHDA) neurotoxic insults.

Conclusions: Aged SIRT6 overexpressing mice show enhanced cognitive capabilities, and an increased GFAP staining, a marker for astrocytes, in the hippocampus. These findings suggest that SIRT6 may not only enhance life span but also preserve life quality as it may delay age-related memory and cognitive decline. The effects of SIRT6 may be partially conveyed by astrocytes function.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/cognitive-effects-of-sirt6-overexpression-emerging-role-of-astrocytes/