Abstract
The disaccharide trehalose is commonly considered to stimulate autophagy. Cell treatment with trehalose could decrease cytosolic aggregates of potentially pathogenic proteins, including mutant huntingtin, α-synuclein, and phosphorylated tau that are associated with neurodegenerative diseases. Here, we demonstrate that trehalose also alters the metabolism of the Alzheimer disease-related amyloid precursor protein (APP). Cell treatment with trehalose decreased the degradation of full-length APP and its C-terminal fragments. Trehalose also reduced the secretion of the amyloid-β peptide. Biochemical and cell biological experiments revealed that trehalose alters the subcellular distribution and decreases the degradation of APP C-terminal fragments in endolysosomal compartments. Trehalose also led to strong accumulation of the autophagic marker proteins LC3-II and p62, and decreased the proteolytic activation of the lysosomal hydrolase cathepsin D. The combined data indicate that trehalose decreases the lysosomal metabolism of APP by altering its endocytic vesicular transport.
Highlights
By biochemical and cell biological approaches, we demonstrate that trehalose interferes with endocytic vesicular trafficking as indicated by decreased processing of cathepsin D (Cat D), redistribution of lysosome-associated protein (LAMP)2, and accumulation of the autophagy-related proteins microtubule-associated protein 1
To assess the effect of trehalose on amyloid precursor protein (APP) metabolism, human neuroglioma H4 cells that endogenously express APP were incubated with trehalose for different time periods, and APP levels were analyzed by Western immunoblotting
Trehalose significantly increased the secretion of soluble APP derived from ␣-secretory processing into conditioned media (Fig. 1, E and F), suggesting that the increased levels of cellular APP-full length (FL) were not caused by inhibition of APP secretion
Summary
Trehalose induced accumulation of APP-FL and of APP-CTFs in all tested cell lines (Fig. 1G), very similar to the effects observed in human H4 cells. Levels of APP-CTFs were stabilized and even increased after 1 and 2 h of cycloheximide treatment in the presence of trehalose (Fig. 1H). Purified membranes of H4 cells were incubated in the presence or absence of trehalose, and ␥-secretase activity was monitored by the detection of the APP intracellular domain (AICD) released into the supernatant.
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