388 - Chronic Hyperglycemia Promotes Hippocampal REST Epigenetic Gene Inactivation with Cognitive Impairment and Neurotoxicity

Abstract

Here we showed that persistent hyperglycemia, a hallmark of some chronic metabolic diseases promotes epigenetic changes in the CNS that convey in higher susceptibility to neurodegeneration, compromising learning and memory. In order to investigate of impact of chronic hyperglycemia (10 or 60 days) on these neurochemical and behavioral parameters, Wistar rats received a single intraperitoneal injection of 55 mg/kg streptozotocin (STZ). Some rats also receive also insulin to control glycaemia (INS; 1.5 IU; human insulin NPH; Novolin®N twice a day). Hyperglycemia treatment compromised short- and long-term memory, as well as spatial memory, effect that was accompanied by significant CSF and plasma oxidative stress. Insulin expression was markedly reduced in the hippocampus, but with normal canonical insulin/insulin-like signaling. Oxygen consumption experiments showed uncoupled mitochondria with increased expression of complex I (NDUFA6), probably as a compensatory response to the mitochondrial stress elicited by the excess of nutrients. Furthermore, the hyperglycemic state induced a subcellular redistribution of hippocampal α-synuclein, even when the total content of the protein remained unchanged. Hippocampus was also depicted by marked reduction of IL-10 expression, increased GFAP expression, reduced content of BDNF and increased caspase-3 activation. This neurotoxic environment occurred in parallel with a specific and significant global DNA hypermethylation and hypomethylation of LINE-1 region (genome instability) in STZ rats. DNA hypermethylation affected the expression of REST, a neurocognitive transcription factor in the adult brain, which was significantly decreased in the hippocampus of STZ rats. In agreement, REST promoter was also hypermethylated. In contrast, the gene expression of the truncate toxic splice variant REST4 was significantly up-regulated. INS administration efficiently prevented all these epigenetic alterations and the cognitive impairments. It could be concluded that controlling glucose homeostasis, mainly in the elderly, could reduce the risk of the development of cognitive impairment and neurodegenerative diseases.