Latrepirdine (Dimebon™) Enhances Autophagy and Reduces Intracellular GFP-Aβ42 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 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 Aβ42 aggregates. Latrepirdine was shown to up-regulate yeast vacuolar (lysosomal) activity and promote transport of the autophagic marker (Atg8) to the vacuole. Using an in vitro 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.

Dihydropyrimidine-Thiones and Clioquinol Synergize To Target β-Amyloid Cellular Pathologies through a Metal-Dependent Mechanism

“…Dimebon, for example, enhances autophagy and reduces intracellular levels of GFP-A β 42 in yeast. 28 And an A β oligomerization yeast model has identified small molecules that target toxic A β structures directly. 29 Thus, multiple different models have revealed a path to identifying cytoprotective compounds targeting key aspects of A β cellular pathology that provide starting points for lead compound discovery.…”

Novel Sites of Neuroprotective Action of Dimebon (Latrepirdine)

“…Taken together, the increased phosphorylation of ERK1/2 and p38 kinases as well as elevated levels of Atg12-Atg5-Atg16 m R N A m a y i m p l y t h a t D i m e b o n m e d i a t e s t h e autophagosomal response. Bharadwaj et al similarly found that Dimebon facilitated removal of Aβ42-GFP levels via the autophagy pathway in yeast [24]. Chronic administration of Dimebon reportedly induced autophagy and α-synuclein removal in mouse brain [26].…”

“…However, the role of glutamate receptors and cholinesterases in Dimebon's neuroprotective action has been questioned [12]. Recent studies involving various experimental systems ranging from cellular to transgenic animal models of dementia-type neurodegeneration demonstrate that Dimebon stabilizes mitochondrial functions by preventing mitochondrial permeability transition [13][14][15][16][17], reducing accumulation of pathological proteins [18][19][20][21][22][23], and simulating autophagy [24][25][26][27], thereby showing a multimodal mechanism of action ( Table 1). All together, these findings support the re-evaluation of Dimebon's therapeutic potential and newly designed analogs as promising disease-modifying agents for neurodegenerative disorders [6,28].…”

Chemical Modulators of Protein Misfolding, Neurodegeneration and Tau

“…Dimebon protects yeast cells at low mM concentrations from Ab 42 toxicity, being ≈10 times less potent than the autophagy inducer rapamycin (see also section 4.2, Figure 4.1) [115]. Dimebon elicits autophagy-related protective 1 antagonism (receptors, r) and inhibition (enzymes, e, and ion Channels, iC) of Molecular Targets by dimebon [109,110] …”

“…Dimebon stimulates autophagy in a yeast model in an autophagyrelated gene 8 (Atg8)-dependent manner (see also Chapter 4 of the biology-oriented companion book [1]), promotes the sequestration of green fluorescent protein (GFP)-labeled Ab 42 in degrading autophagic vacuoles, and prevents its intracellular accumulation [115]. Dimebon protects yeast cells at low mM concentrations from Ab 42 toxicity, being ≈10 times less potent than the autophagy inducer rapamycin (see also section 4.2, Figure 4.1) [115].…”