Journal
METABOLITES
Volume 11, Issue 7, Pages -Publisher
MDPI
DOI: 10.3390/metabo11070421
Keywords
Alzheimer; amyloid accumulation; autophagy; bafilomycin A1; cultured cerebellar granule neuron; SH-SY5Y; trehalose
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Funding
- Spanish Ministry of Science, Innovation and University [RTI 2018-096303-B-C1]
- Comunidad de Madrid [B2017/BMD-3700]
- Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) [PI2016/01]
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Trehalose has been shown to induce autophagy in neurons and protect against amyloid protein aggregation, reducing Aβ levels and modulating the interaction between APP and BACE1 to prevent amyloidogenic processing.
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 (A beta) 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 A beta levels in a manner unrelated to its intracellular accumulation or its elimination through endocytosis or enzymatic degradation. Moreover, the levels of A beta 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.
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