Trehalose Reduces the Secreted Beta-Amyloid Levels in Primary Neurons Independently of Autophagy Induction.

Irene Benito-Cuesta,Francisco Wandosell,Lara Ordoñez-Gutierrez

doi:10.3390/metabo11070421

Abstract

The disaccharide trehalose was described as possessing relevant neuroprotective properties as an mTORC1-independent inducer of autophagy, with the ability to protect cellular membranes and denaturation, resulting from desiccation, and preventing the cellular accumulation of protein aggregates. These properties make trehalose an interesting therapeutic candidate against proteinopathies such as Alzheimer’s disease (AD), which is characterized by deposits of aggregated amyloid-beta (Aβ) and hyperphosphorylated tau. In this study, we observed that trehalose was able to induce autophagy in neurons only in the short-term, whereas long-term treatment with trehalose provoked a relevant anti-amyloidogenic effect in neurons from an AD mouse model that was not mediated by autophagy. Trehalose treatment reduced secreted Aβ levels in a manner unrelated to its intracellular accumulation or its elimination through endocytosis or enzymatic degradation. Moreover, the levels of Aβ precursor protein (APP) and beta-secretase (BACE1) remained unaltered, as well as the proper acidic condition of the endo-lysosome system. Instead, our results support that the neuroprotective effect of trehalose was mediated by a reduced colocalization of APP and BACE1 in the cell, and, therefore, a lower amyloidogenic processing of APP. This observation illustrates that the determination of the mechanism, or mechanisms, that associate APP and BACE is a relevant therapeutic target to investigate.

Highlights

Some of the properties described for trehalose make this sugar an interesting therapeutic candidate against abnormal protein aggregation observed in age-related neurodegenerative diseases, including Alzheimer’s disease (AD)
This effect differs from that observed with the autophagy inducer rapamycin (Figure S1B, and previously reported in [21]), but resembles, to a lesser extent, that observed with the v-ATPase inhibitor BafA1, which blocks lysosomal degradation and provokes the accumulation of non-degraded autophagosomes, shown as the increase of autophagic markers LC3-II, NBR1, and SQSTM1 (Figure S1B)
Trehalose decreased the phosphorylation levels of ribosomal protein S6 (RPS6) within the first hour of treatment, which gradually recovered to control levels over the hours, contrary to the progressive decrease observed with BafA1 or the sustained inhibition of rapamycin (Figure S1A,B)

Summary

Introduction

Some of the properties described for trehalose make this sugar an interesting therapeutic candidate against abnormal protein aggregation observed in age-related neurodegenerative diseases, including Alzheimer’s disease (AD). There is no general consensus regarding the mechanism of the induction of autophagy [6,7,8,9,10,11,12] This disaccharide is considered to protect cellular membranes, preventing protein denaturation by direct unions, protecting the cell against environmental stresses [1,13]. These properties make trehalose an interesting therapeutic approach against neurodegenerative proteinopathies such as Alzheimer’s disease (AD) [10].

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Results

Discussion

Conclusion