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

Prashant R Bharadwaj, Giuseppe Verdile, Renae K. Barr, Veer Gupta, John W Steele, M Lenard Lachenmayer, Zhenyu Yue, Michelle E. Ehrlich, Gregory Petsko, Shulin Ju, Dagmar Ringe, Sonia E Sankovich, Joanne M Caine, Ian G. Macreadie, Sam Gandy, Ralph Martins

Research output: Contribution to journalArticle

51 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)949-67
Number of pages19
JournalJournal of Alzheimer's Disease
Volume32
Issue number4
DOIs
Publication statusPublished - 2012
Externally publishedYes

Keywords

  • Amyloid beta-Peptides
  • Autophagy
  • Down-Regulation
  • Green Fluorescent Proteins
  • Humans
  • Indoles
  • Intracellular Fluid
  • Peptide Fragments
  • Saccharomyces cerevisiae
  • Up-Regulation
  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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