Chronic Administration of Dimebon does not Ameliorate Amyloid-β Pathology in 5xFAD Transgenic Mice

Article type: Research Article

Authors: Peters, Owen M.^{a; 1} | Shelkovnikova, Tatyana^{a; b} | Tarasova, Tatiana^{b; e} | Springe, Signe^a | Kukharsky, Michail S.^b | Smith, Gaynor A.^c | Brooks, Simon^a | Kozin, Sergey A.^d | Kotelevtsev, Yury^{e; f} | Bachurin, Sergey O.^b | Ninkina, Natalia^{a; b; d} | Buchman, Vladimir L.^{a; b; *}

Affiliations: [a] School of Biosciences, Cardiff University, Museum Avenue, Cardiff, United Kingdom | [b] Institute of Physiologically Active Compounds of RAS, Chernogolovka, Moscow Region, Russian Federation | [c] Mailman Research Center, McLean Hospital/Harvard Medical School, Belmont, MA, USA | [d] Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russian Federation | [e] Pushchino State Institute for Natural Sciences, Pushchino, Moscow region, Russian Federation | [f] Centre for Cardiovascular Science, Queens Medical Research Institute, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, United Kingdom

Correspondence: [*] Correspondence to: Vladimir L. Buchman, School of Biosciences, Cardiff University, Museum Avenue, Cardiff, CF10 3AX, United Kingdom. Tel.: +44 2920 879068; E-mail: [email protected].

Note: [1] Current address: Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.

Abstract: Dimebon has been tested as a potential modifier of Alzheimer's disease (AD), resulting in mixed clinical trial outcomes. Originally utilized as an antihistamine, Dimebon was later found to ameliorate AD symptoms in initial human trials. Although subsequent trials have reportedly failed to replicate these finding, there is a growing body of evidence that Dimebon might be neuroprotective in certain models of neurodegeneration. The precise mechanism by which Dimebon is thought to act in AD is unclear, though changes in receptor activity, mitochondria function, and autophagy activity have been proposed. It is thus necessary to test Dimebon in transgenic animal model systems to determine if and how the drug affects development and manifestation of pathology, and which pathogenic processes are altered. In the present study we treated mice harboring five familial mutations associated with hereditary AD (5xFAD line) with a chronic regime of Dimebon. The compound was not found to improve the general health or motor behavior of these mice, nor prevent accumulation of Aβ peptides in the brain. Modest changes in response to an anxiogenic task were, however, detected, suggesting Dimebon might improve behavioral abnormalities and cognition in disease in a mechanism independent of protecting against amyloidosis.

Keywords: Alzheimer's disease, dimebolin, latrepirdine, tauopathy, therapeutics, transgenic mice

DOI: 10.3233/JAD-130071

Journal: Journal of Alzheimer's Disease, vol. 36, no. 3, pp. 589-596, 2013