Tatiana Korolenko

Title: Effect of autophagy inducer trehalose in pharmacological model of alzheimer’s disease in mice

Abstract

Induction of autophagy is a prospective approach to the treatment of neurodegeneration (Pupushev et al., 2025). Disaccharide trehalose is every other day to drink for two weeks increased autophagy in liver and heart of mice with negligible adverse effects, which was approved later for use in humans according to FDA requirements. Earlier we have also shown positive effect of trehalose drinking in experimental db/db mice with model of diabetes with changes of brain cells and behavioral characteristics (Korolenko et al., 2020). Db/db mice (carrying a mutation in the gene encoding leptin receptor) showed autophagy suppression. The db/db model manifested some inflammation symptoms: overexpression of TNF-α in the spleen and under expression of IL-10 in the liver and spleen (cytokine imbalance).

Trehalose treatment significantly reduced blood glucose concentration and glycated hemoglobin in experiment with db/db mice. Treatment of db/db mice by trehalose was followed also by increased autophagy induction in the heart and liver (increased autolysosomes volume density studied by morphometric electron-microscopic method). Trehalose exerted beneficial cardiac effects possibly via increased lipophagy (uptake of lipid droplets).

The aim of our next work was to study of different variants of trehalose treatment, predominantly of 2-4% trehalose solution drunk for several (2-4) weeks in a murine model of Alzheimer Disease (AD), induced by the different regimens of dietary trehalose treatment in an Amyloid-beta 25-35-induced murine model of Alzheimer Disease (AD). Amyloid-beta-treated mice received 2% trehalose solution daily, or 4% trehalose solution daily (continuous mode), in intermittent mode – every other day to drink for 2 weeks. We revealed the dose-dependent effects on autophagy activation in the frontal cortex and hippocampus, and restoration of behavioral disturbances. A continuous intake of 4 % trehalose solution caused the greatest effect.

Activation of autophagy was shown in organs studied 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 response test, and neuronal density in the frontal cortex and hippocampus. Trehalose successfully restored these parameters to the level of the control group. Thus, high doses of trehalose had increased efficacy towards cognitive impairment in a model of early AD-like pathology in mice. These findings possibly could be taken into account for translational studies and the development of new clinical approaches for AD therapy.

We can suggest that trehalose drinking can reduce the accumulation of neurotoxic aberrant/misfolded proteins; partially trehalose revealed also an anti-inflammatory effect, inhibiting detrimental oxidative stress owing to the enhancement of endogenous antioxidant defense represented by the Nrf2 lysosome and autophagosome biogenesis pathways through the protein factors TFEB and FOXO1 (which this disaccharide can activate). So, in general, the autophagy activation by trehalose had several positive effects on the heart, liver and brain of AD mice.  Lipophagy activation seems to be one of a promising mechanism for study and future therapy.

Audience take away from presentation:

Activation of autophagy was shown in brain cells of mice with experimental neurodegeneration; and the significant recovery of behavioral tests that corresponds to associative long-term memory and learning. This regimen of trehalose also produced an anxiolytic effect in the open response test, and neuronal density in the frontal cortex and hippocampus. Trehalose successfully restored these parameters to the level of the control group. Thus, high doses of trehalose had increased efficacy towards cognitive impairment in a model of early AD-like pathology in mice. These findings possibly could be taken into account for translational studies and the development of new clinical approaches for AD therapy.