Latrepirdine (Dimebon™) Enhances Autophagy and Reduces Intracellular GFP-Aβ₄₂ Levels in Yeast

Article type: Research Article

Authors: Bharadwaj, Prashant R.^{a; d; 1} | Verdile, Giuseppe^{a; b; c; 1} | Barr, Renae K.^a | Gupta, Veer^a | Steele, John W.^{e; g} | Lachenmayer, M. Lenard^{e; k} | Yue, Zhenyu^{e; f} | Ehrlich, Michelle E.^{e; h; i} | Petsko, Gregory^l | Ju, Shulin^l | Ringe, Dagmar^l | Sankovich, Sonia E.^d | Caine, Joanne M.^d | Macreadie, Ian G.^{d; m} | Gandy, Sam^{e; g; j} | Martins, Ralph N.^{a; b; c; *}

Affiliations: [a] Centre of Excellence for Alzheimer's Disease Research and Care, School of Medical Sciences, Edith Cowan University, WA, Australia | [b] School of Psychiatry and Clinical Neurosciences, University of Western Australia, Crawley, WA, Australia | [c] Sir James McCusker Alzheimer's Disease Research Unit, Hollywood Private Hospital, Nedlands, WA, Australia | [d] CSIRO Preventative Health Flagship, Material Science and Engineering, VIC, Australia | [e] Department of Neurology, Mount Sinai School of Medicine, New York, NY, USA | [f] Department of Neuroscience, Mount Sinai School of Medicine, New York, NY, USA | [g] Department of Psychiatry and Alzheimer's Disease Research Centre, Mount Sinai School of Medicine, New York, NY, USA | [h] Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY, USA | [i] Department of Paediatrics, Mount Sinai School of Medicine, New York, NY, USA | [j] James J Peters VA Medical Centre, Bronx, NY, USA | [k] Department of Neurology, University of Bonn, Bonn, Germany | [l] Department of Biochemistry and Chemistry, Rosenstiel Basic Medical Sciences Research Centre, Brandeis University, Waltham, MA, USA | [m] School of Applied Sciences, RMIT University, Bundoora West Campus, Bundoora, VIC, Australia

Correspondence: [*] Correspondence to: Ralph N. Martins, Suite 22, Hollywood Medical Centre, 85 Monash Avenue, Nedlands 6009, WA, Australia. Tel.: +61 8 9347 4200; Fax: +61 8 9347 4299; E-mail: r.martins@ecu.edu.au.

Note: [1] These authors contributed equally.

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.

Keywords: Alzheimer's disease, amyloid-β, autophagy, latrepirdine, yeast model

DOI: 10.3233/JAD-2012-120178

Journal: Journal of Alzheimer's Disease, vol. 32, no. 4, pp. 949-967, 2012