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Latrepirdine Improves Cognition and Arrests Progression of Neuropathology in an Alzheimer’S Mouse Model

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Latrepirdine Improves Cognition and Arrests Progression of Neuropathology in an Alzheimer’S Mouse Model Molecular Psychiatry (2013) 18, 889 -- 897 & 2013 Macmillan Publishers Limited All rights reserved 1359-4184/13 www.nature.com/mp ORIGINAL ARTICLE Latrepirdine improves cognition and arrests progression of neuropathology in an Alzheimer’s mouse model JW Steele1,2,3,21, ML Lachenmayer1,4,21,SJu5, A Stock1, J Liken5, SH Kim1,2, LM Delgado6, IE Alfaro7, S Bernales7,8, G Verdile9, P Bharadwaj9, V Gupta9, R Barr9, A Friss10, G Dolios10, R Wang10, D Ringe5, P Fraser11, D Westaway12, PH St George-Hyslop12, P Szabo13, NR Relkin13, JD Buxbaum2,10,14, CG Glabe15, AA Protter8, RN Martins9,16,17, ME Ehrlich1,10,18, GA Petsko5,13,ZYue1,19 and S Gandy1,2,20 Latrepirdine (Dimebon) is a pro-neurogenic, antihistaminic compound that has yielded mixed results in clinical trials of mild to moderate Alzheimer’s disease, with a dramatically positive outcome in a Russian clinical trial that was unconfirmed in a replication trial in the United States. We sought to determine whether latrepirdine (LAT)-stimulated amyloid precursor protein (APP) catabolism is at least partially attributable to regulation of macroautophagy, a highly conserved protein catabolism pathway that is known to be impaired in brains of patients with Alzheimer’s disease (AD). We utilized several mammalian cellular models to determine whether LAT regulates mammalian target of rapamycin (mTOR) and Atg5-dependent autophagy. Male TgCRND8 mice were chronically administered LAT prior to behavior analysis in the cued and contextual fear conditioning paradigm, as well as immunohistological and biochemical analysis of AD-related neuropathology. Treatment of cultured mammalian cells with LAT led to enhanced mTOR- and Atg5-dependent autophagy. Latrepirdine treatment of TgCRND8 transgenic mice was associated with improved learning behavior and with a reduction in accumulation of Ab42 and a-synuclein. We conclude that LAT possesses pro-autophagic properties in addition to the previously reported pro-neurogenic properties, both of which are potentially relevant to the treatment and/or prevention of neurodegenerative diseases. We suggest that elucidation of the molecular mechanism(s) underlying LAT effects on neurogenesis, autophagy and behavior might warranty the further study of LAT as a potentially viable lead compound that might yield more consistent clinical benefit following the optimization of its pro-neurogenic, pro-autophagic and/or pro-cognitive activities. Molecular Psychiatry (2013) 18, 889--897; doi:10.1038/mp.2012.106; published online 31 July 2012 Keywords: Alzheimer’s disease; amyloid; autophagy; therapeutics INTRODUCTION function and calcium homeostasis;1 (3) modulation of Ab release from Latrepirdine (Dimebon; dimebolin) is a neuroactive compound cultured cells, isolated intact nerve terminals, and from hippocampal 10 with antagonist activity at histaminergic, a-adrenergic and neurons in living mouse brain; and (4) promotion of neurogenesis in 11 serotonergic receptors.1 Based on its effects on cognition in the murine hippocampus. We reported that latrepirdine (LAT) 10 rodents,2--6 taken in conjunction with its highly favorable safety stimulates APP catabolism and Ab secretion, an unexpected result profile, the compound has formed the basis for clinical trials for for a drug that was claimed to benefit AD. In pursuit of a parsi- both Alzheimer’s disease (AD)7 and Huntington’s disease (HD),8 monious subcellular mechanism underlying this unexpected result, despite a poor understanding of the molecular mechanisms we considered the possibility that LAT-stimulated Ab release might underlying its putative mnemoactive properties. occur via an unconventional secretory pathway associated with induc- Latrepirdine has been reported to possess several properties tion of macroautophagy (autophagy),12 a highly regulated process that are potentially relevant to the treatment of neurodegenera- that can be activated in response to various stressful conditions.13 tive diseases: (1) protection of cultured cells from the cytotoxicity Several laboratories have demonstrated that autophagy has a of amyloid-b (Ab) peptide;9 (2) stabilization of mitochondrial neuroprotective role in cell and animal models of neurodegene- 1Department of Neurology, Mount Sinai School of Medicine, New York, NY, USA; 2Department of Psychiatry and The Mount Sinai Alzheimer’s Disease Research Center, New York, NY, USA; 3Laboratory of Molecular and Cellular Neuroscience, Rockefeller University, New York, NY, USA; 4Department of Neurology, University of Bonn, Bonn, Germany; 5Departments of Biochemistry and Chemistry, Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, MA, USA; 6Facultad de Ciencias Biolo´ gicas, Universidad Andre´s Bello, Santiago, Chile; 7Fundacio´n Ciencia & Vida, Santiago, Chile; 8Medivation, Inc., San Francisco, CA, USA; 9Centre of Excellence for Alzheimer’s Disease Research & Care, School of Medical Sciences, Edith Cowan University, Perth, WA, Australia; 10Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY, USA; 11Tanz Centre for Research in Neurodegenerative Diseases and Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada; 12Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, AB, Canada; 13Department of Neurology and Neurosciences, Weill Medical College of Cornell University, New York, NY, USA; 14Department of Psychiatry, Seaver Autism Center for Research and Treatment, and The Friedman Brain Institute, Mount Sinai School of Medicine, New York, NY, USA; 15Department of Neurology, University of California Irvine School of Medicine, Irvine, CA, USA; 16School of Psychiatry and Clinical Neurosciences, University of Western Australia, Crawley, WA, Australia; 17Sir James McCusker Alzheimer’s Disease Research Unit, Hollywood Private Hospital, Nedlands, WA, Australia; 18Department of Pediatrics, Mount Sinai School of Medicine, New York, NY, USA; 19Department of Neuroscience, Mount Sinai School of Medicine, New York, NY, USA and 20James J Peters VA Medical Center, Bronx, NY, USA. Correspondence: Dr S Gandy, Departments of Neurology and Psychiatry, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1137, New York, NY 10029, USA. E-mail: [email protected] 21These authors contributed equally to this work. Received 24 April 2012; accepted 31 May 2012; published online 31 July 2012 Latrepirdine arrests amyloid-b neuropathology JW Steele et al 890 rative diseases, including AD, HD14 and Parkinson’s disease.15 test for homogeneity of variance were utilized for inclusion in parametric Converging data indicate that therapeutic manipulation of tests (P40.05 for Shapiro-Wilk and Levene’s tests). Independent samples autophagy with rapamycin can improve behavioral function and t-tests (parametric design) or Mann--Whitney U tests (nonparametric arrest neuropathology in at least two mouse models of AD.16--18 To design) were utilized to determine significant mean differences between this end, small molecule enhancers of rapamycin (SMERs; most two groups. One-way analysis of variance (parametric analysis) or Kruskal-- notably SMER-28) induced autophagy, improved cell viability Wallis test (nonparametric analysis) were used to compare three or more and promoted clearance of neurodegenerative disease- groups, depending on whether the data fit the assumptions of parametric related proteins including APP metabolites (among them Ab,19 analysis (see above). Two-way analyses of variance were used to analyze huntingtin20 and a-synuclein20) in cellular models. CHX time-course experiments with regard to effects of time and treatment, Herein, we report the following: (1) LAT modulates Atg5- and interactions. Bonferroni’s or Dunn’s correction for multiple compar- dependent autophagic activity in a dose-dependent manner and isons were utilized depending on whether data fit the assumptions of via the mTOR-signaling pathway; (2) LAT potentiates the parametric or nonparametric design, respectively. Significance for t-tests degradation of APP metabolites in cell culture and in mouse and analyses of variances are reported with a Pp0.05 using two-tailed brain; and (3) LAT improves the memory behavior of TgCRND8 tests with an a-level of 0.05. All statistical analyses were performed using mice while reducing the accumulation of insoluble Ab42. Given SPSS v18.0 and/or GraphPad Prism 5 (La Jolla, CA, USA). the pressing need for effective disease-modifying treatment for symptomatic AD and the current evidence that Ab-lowering 21 agents might only be effective for prophylaxis, we argue that RESULTS identification of the molecular basis of the pro-cognitive and anti- Acute latrepirdine treatment induced autophagy via the mTOR- neurodegeneration actions of LAT remains highly valuable. pathway in cultured cells We sought to determine whether LAT might regulate autophagy as one mechanism of its reported anti-neurodegeration activity. MATERIALS AND METHODS We treated HeLa cells stably expressing LC3 fused with EGFP Preparation and handling of latrepirdine 23 (eGFP-LC3) for 3 or 6 h in the absence or presence of 50 mM The synthesis and characterization of LAT was described previously.10 latrepirdine. Treatment with latrepirdine for 3 (data not shown) or Briefly, latrepirdine was purchased from SinoChemexper (Shanghai, China) 6 h (Figure 1a) markedly enhanced the number of eGFP-LC3 and purity of the compound was determined to be 499%, or provided punctae, indicating that LAT induced the formation of autophago- directly by Medivation
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