Modulating effect of liposomal miR-101 on the processes of amyloidogenesis, smell, sleep and neuroinflammation in experimental Alzheimer's disease

Abstract

The current therapy for Alzheimer's disease does not give patients a chance of recovery. Therefore, it is relevant to study the novel factors of influence, in particular microRNA, on the pathogenic mechanisms of amyloidosis. The aim of this work was to determine the effect of miR-101 on early predictors of amyloidosis in experimental Alzheimer's disease in animals. The study was carried out on 25 male rats of 14 months of age. A model of Alzheimer's disease was created by intrahippocampal administration of Aβ40 aggregates to animals. Ten days later, a 10-day course of nasal administration of miR-101 in liposomes was launched. The level of endogenous Aβ42 and cytokines (TNFα, IL-6 and IL-10) was determined in the supernatants of the nerve tissues of the target brain structures (hippocampus, olfactory bulbs, and olfactory tubercles). A neuroethological method of presenting smells of isovaleric acid and peanut butter was used to assess the olfactory system functional state in the experimental rats. In the course of polygraphic registration of the sleep-wakefulness cycle, the representation of wakefulness and individual sleep phases, as well as proportion of incomplete and complete sleep cycles were determined. It was shown that injection of Aβ40 aggregates into the hippocampus simulates an amyloidogenic state in the rat’s hippocampus and olfactory tubercles, but not in the olfactory bulbs. Moreover, a pro-inflammatory state was registered in the hippocampus of the animal brain (an increase in the concentration of pro-inflammatory cytokines TNFα and IL-6), while the cytokine level in the olfactory bulbs and tubercles did not change. When studying the functional state of olfactory analyzers in the rats with Alzheimer's disease, we revealed negative changes in behavioral response to the smell of isovaleric acid and peanut butter. In terms of somnograms, the Aβ40 toxicity caused reduction in the deep slow-wave sleep stage combined with deficiency of the paradoxical sleep phase, and predominance of incomplete sleep cycles. Nasal therapy with miR-101 in liposomes normalized the level of Aβ42 in the hippocampus and olfactory tubercles and decreased the level of proinflammatory cytokines in the hippocampus. MiR-101 prevented olfactory disfunctions in assessing smells of isovaleric acid and peanut butter, increased the ratio of deep slow-wave sleep and paradoxical sleep in the cycle structure and restored proportion of complete sleep cycles in animals. Thus, liposomal miR-101 has an anti-amyloidogenic and anti-inflammatory effect in rats with a model of Alzheimer's disease. It helps to restore the functional state of olfactory analyzer and optimize structural organization of the sleep-wakefulness cycle in sick animals.