Latrepirdine (dimebon) enhances autophagy and reduces intracellular GFP-A?42 levels in yeast.

ABSTRACT: Latrepirdine (Dimebon), an anti-histamine, has shown some benefits in trials of neurodegenerative diseases characterized by accumulation of aggregated or misfolded protein such as Alzheimer's disease (AD) and has been shown to promote the removal of ?-synuclein protein aggregates in vivo. An important pathway for removal of aggregated or misfolded proteins is the autophagy-lysosomal pathway, which has been implicated in AD pathogenesis, and enhancing this pathway has been shown to have therapeutic potential in AD and other proteinopathies. Here we use a yeast model, Saccharomyces cerevisiae, to investigate whether latrepirdine can enhance autophagy and reduce levels of amyloid-? (A?)42 aggregates. Latrepirdine was shown to upregulate yeast vacuolar (lysosomal) activity and promote transport of the autophagic marker (Atg8) to the vacuole. Using an in vitro green fluorescent protein (GFP) tagged A? yeast expression system, we investigated whether latrepirdine-enhanced autophagy was associated with a reduction in levels of intracellular GFP-A?42. GFP-A?42 was localized into punctate patterns compared to the diffuse cytosolic pattern of GFP and the GFP-A?42 (19:34), which does not aggregate. In the autophagy deficient mutant (Atg8?), GFP-A?42 showed a more diffuse cytosolic localization, reflecting the inability of this mutant to sequester GFP-A?42. Similar to rapamycin, we observed that latrepirdine significantly reduced GFP-A?42 in wild-type compared to the Atg8? mutant. Further, latrepirdine treatment attenuated A?42-induced toxicity in wild-type cells but not in the Atg8? mutant. Together, our findings provide evidence for a novel mechanism of action for latrepirdine in inducing autophagy and reducing intracellular levels of GFP-A?42.

SUBMITTER: Bharadwaj PR 

PROVIDER: S-EPMC3529125 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature