Latrepirdine (dimebon) enhances autophagy and reduces intracellular GFP-Aβ42 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.
Centre of Excellence for Alzheimer's Disease Research and Care, School of Medical Sciences, Edith Cowan University, WA, Australia.
Prashant R
PR
Bharadwaj
Giuseppe
G
Verdile
Renae K
RK
Barr
Veer
V
Gupta
John W
JW
Steele
M Lenard
ML
Lachenmayer
Zhenyu
Z
Yue
Michelle E
ME
Ehrlich
Gregory
G
Petsko
Shulin
S
Ju
Dagmar
D
Ringe
Sonia E
SE
Sankovich
Joanne M
JM
Caine
Ian G
IG
Macreadie
Sam
S
Gandy
Ralph N
RN
Martins
D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D015536:Down-Regulation / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007424:Intracellular Fluid / Q000187:drug effects / Q000378:metabolism*; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
D016229:Amyloid beta-Peptides; D007211:Indoles; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D049452:Green Fluorescent Proteins; C010119:latrepirdine