Up regulated hippocampal insulin pathway and oxidative stress are related to opposite changes in olfaction and episodic memory in a compensatory metabolic syndrome model in rats.

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Insulin resistance, a major component of metabolic syndrome (MetS), is involved in phosphorylated tau and beta amyloid buildup, linking MetS to neurodegenerative processes, e.g., Alzheimer's disease. One of the initial signs of neurodegeneration, in diseases such as Parkinson's and Alzheimer's, is olfactory dysfunction. Accordingly, in previous reports we found that high carbohydrate diet based on 30% sucrose in drinking water, increased visceral fat and insulin resistance, leading to an augment of oxidative stress and reduced brain energy metabolism, upregulating amyloidogenic genes (APP and BACE1) in hypothalamus and hippocampus. Thus, herein we comparatively evaluated the effect of sucrose induced MetS on episodic memory, olfaction, protein expression in amyloidogenic and insulin pathways, lipoperoxidation, antioxidant and BACE1 enzymatic activity between the hippocampus and olfactory bulb in male Wistar rats. Also, cellular structure of the olfactory bulb was analyzed. After 24 weeks of 30% sucrose consumption, we found preserved performance in a memory test; decreased hippocampal expression of APP and hyperactivation of the insulin pathway, low levels of lipoperoxidation, and high activity of antioxidant and BACE1 enzymes. Olfactory dysfunction was present in MetS rats, accompanied by morphological alterations in the olfactory bulb along with BACE1 increased activity. Thus, chronic high-sucrose consumption may prime the brain for neurodegenerative processes by modulating insulin signaling, oxidative stress homeostasis and amyloidogenic pathways in a region-dependent manner, with the olfactory system emerging as an early and sensitive target of metabolic dysfunction.

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