Title : Effect of trehalose treatment in a pharmacological model of Alzheimer disease in mice
Abstract:
Induction of autophagy is a prospective approach to the treatment of neurodegeneration. In the recent decade, trehalose attracted special attention. It is an autophagy inducer with negligible adverse effects and is approved for use in humans according to FDA requirements. Trehalose is glucose disaccharide with a flexible α-1-1'-glycosidic bond which has unique properties: induction of mTOR-independent autophagy (with kinase AMPK as the main target) and a chaperone-like effect on proteins imparting them natural spatial structure.
In the treatment of experimental neurodegeneration with disaccharide trehalose, various regimens are used, predominantly a 2% solution, drunk for several (2-4) weeks. We studied the effects of different regimens of dietary trehalose treatment in an amyloid-β (Aβ) 25-35-induced murine model of Alzheimer's disease (AD). Aβ-treated mice received 2% trehalose solution daily, 4% trehalose solution daily (continuous mode) or every other day (intermittent mode), to drink for two weeks. We revealed the dose-dependent effects on autophagy activation in the frontal cortex and hippocampus, and the restoration of behavioural disturbances. A continuous intake of 4% trehalose solution caused the greatest activation of autophagy and the complete recovery of step-through latency in the passive avoidance test that corresponds to associative long-term memory and learning. This regimen also produced an anxiolytic effect in the open field. The effects of all the regimens studied were similar in Aβ load, neuroinflammatory response, and neuronal density in the frontal cortex and hippocampus. Trehalose successfully restored these parameters to the levels of the control group. Thus, high doses of trehalose had increased efficacy towards cognitive impairment in a model of early AD-like pathology. These findings possibly could be taken into account for translational studies and the development of clinical approaches for AD therapy using trehalose.
In general, trehalose can reduce the accumulation of neurotoxic aberrant/misfolded proteins. Trehalose has also an anti-inflammatory effect and inhibits detrimental oxidative stress partially owing to the enhancement of endogenous antioxidant defence represented by the Nrf2 protein. This disaccharide activates lysosome and autophagosome biogenesis pathways through the protein factors TFEB and FOXO1. Future study of trehalose effect on autophagy in different cells is necessary.
