Is diabetes mellitus a road to neurodegeneration?

SARAVIA, F:

Rio de Janeiro

Congreso; First Ibero-American Congress on Neuromodulation; 2005

The influence of diabetes mellitus on brain pathology is increasingly recognized in humans and experimental models: the disease is associated with cognitive deficits, increased risk of stroke, dementia and depression. The hippocampus –brain structure, part of the limbic system involved in learning and memory process- seems to be a sensitive target for this pathology. Working with an spontaneous animal model (NOD mice) of T1D and with a pharmacological model, streptozotocin-treated mice, we found more reactive astrocytes in the hippocampus of both models compared with controls. These astrocytes are also positive for Apolipoprotein E, linked to degeneration. These facts suggest probably a neuronal dysfunction. The expression of early genes like c-Fos and Jun is also enhanced in the hippocampus of diabetic mice, suggestive of abnormal activation. In the adult, the hippocampal dentate gyrus is one of the few brain regions able to produce new neurons. This plastic event named neurogenesis is modulated by several factors and allows the incorporation of new granule cells into the brain circuitry. In both mentioned models we found a strong decrease in the dentate gyrus proliferation, using bromodeoxiuridine (BrdU) incorporation and posterior immunodetection. Elevated levels of circulating glucocorticoids are linked to defective neurogenesis and they could play a negative regulation in T1D: corticosterone is very high in STZ-treated mice and NOD mice. In the literature, reduction of dentate gyrus neurogenesis is associated to some types of depression and interestingly, antidepressants needs hippocampal neurogenesis to display their behavioral effects. In order to investigate if the ability for hippocampal proliferation could be restored in diabetic animals we treated them with the antidepressant fluoxetine, a serotonin reuptake inhibitor during 10 days. We found that fluoxetine administration was able to recover proliferation in dentate gyrus. The phenotype of differentiated cells was studied using specific neuronal (â-III tubulin for immature neurons, Neu-N for mature neurons) and glial  (GFAP) markers in combination with BrdU detection and analyzed with confocal microscopy. In the STZ model, the antidepressant treatment influenced significantly the phenotype of DG proliferating cells increasing the neuronal phenotype proportion in detriment of glial cells. Our data show clearly the diabetic brain sharing some hippocampal alterations with the aged brain: marked astrogliosis, irregular neuronal activation, deficient neurogenesis. Conversely, the link between depression and diabetes is well established in humans. Our work can contribute to better understand the complexity of these interactions.