Latrepirdine (Dimebon(TM)) enhances autophagy and reduces intracellular GFP-A beta (42) levels in yeast

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 α-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-β (Aβ)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 Aβ yeast expression system, we investigated whether latrepirdine-enhanced autophagy was associated with a reduction in levels of intracellular GFP-Aβ₄₂. GFP-Aβ₄₂ was localized into punctate patterns compared to the diffuse cytosolic pattern of GFP and the GFP-Aβ₄₂ (19:34), which does not aggregate. In the autophagy deficient mutant (Atg8Δ), GFP-Aβ₄₂ showed a more diffuse cytosolic localization, reflecting the inability of this mutant to sequester GFP-Aβ₄₂. Similar to rapamycin, we observed that latrepirdine significantly reduced GFP-Aβ₄₂ in wild-type compared to the Atg8Δ mutant. Further, latrepirdine treatment attenuated Aβ₄₂-induced toxicity in wild-type cells but not in the Atg8Δ mutant. Together, our findings provide evidence for a novel mechanism of action for latrepirdine in inducing autophagy and reducing intracellular levels of GFP-Aβ₄₂.