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Latrepirdine improves cognition and arrests progression of neuropathology in an Alzheimer's mouse model

Molecular Psychiatry volume 18, pages 889–897 (2013)Cite this article

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Abstract

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 Aβ42 and α-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.

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Acknowledgements

The work in this manuscript was used in a dissertation by JWS as partial requirement for the fulfillment of the PhD degree. JWS is a trainee in the Integrated Pharmacological Sciences Training Program supported by grant T32GM062754 from the National Institute of General Medical Sciences. MLL was supported by the Deutsche Forschungsgemeinschaft. SG and CGG are members of the Oligomer Research Consortium of the Cure Alzheimer's Fund. We acknowledge the generous support of the NH&MRC (APP1009295 to RNM, GV, SG), the McCusker Alzheimer's Research Foundation (RNM, GV), Conicyt (PFB-16 to SB), the Fidelity Biosciences Research Initiative (SJ, JL, DR, GAP), Cure Alzheimer's Fund (SG; CGG), the US Department of Veterans Affairs (SG), the NIH (P01AG10491 to SG; U01AG01483 to PS; NS045283 to CGG, R01NS060123; U54RR022220 to ZY; P30 NS061777 and S10 RR022415 to RW; and P50AG05138 to Mary Sano), the Canadian Institutes of Health Research and Alzheimer Society of Ontario (PF), and Baxter Healthcare (PS and NRR). We would also like to thank Rosilyn Kazanjian for the gift in memory of Powel Kazanjian that supported the purchase of the Luminex xMAP100/200 system. We would like to thank Loren E Khan and Justine Bonet for technical assistance in animal colony management and Dr Yun Zhong for technical support.

Author information

Author notes

  1. J W Steele and M L Lachenmayer: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, Mount Sinai School of Medicine, New York, NY, USA

    J W Steele, M L Lachenmayer, A Stock, S H Kim, M E Ehrlich, Z Yue & S Gandy

  2. Department of Psychiatry and The Mount Sinai Alzheimer's Disease Research Center, New York, NY, USA

    J W Steele, S H Kim, J D Buxbaum & S Gandy

  3. Laboratory of Molecular and Cellular Neuroscience, Rockefeller University, New York, NY, USA

    J W Steele

  4. Department of Neurology, University of Bonn, Bonn, Germany

    M L Lachenmayer

  5. Departments of Biochemistry and Chemistry, Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, MA, USA

    S Ju, J Liken, D Ringe & G A Petsko

  6. Facultad de Ciencias Biológicas, Universidad Andrés Bello, Santiago, Chile

    L M Delgado

  7. Fundación Ciencia & Vida, Santiago, Chile

    I E Alfaro & S Bernales

  8. Medivation, Inc., San Francisco, CA, USA

    S Bernales & A A Protter

  9. Centre of Excellence for Alzheimer's Disease Research & Care, School of Medical Sciences, Edith Cowan University, Perth, WA, Australia

    G Verdile, P Bharadwaj, V Gupta, R Barr & R N Martins

  10. Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY, USA

    A Friss, G Dolios, R Wang, J D Buxbaum & M E Ehrlich

  11. Tanz Centre for Research in Neurodegenerative Diseases and Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada

    P Fraser

  12. Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, AB, Canada

    D Westaway & P H St George-Hyslop

  13. Department of Neurology and Neurosciences, Weill Medical College of Cornell University, New York, NY, USA

    P Szabo, N R Relkin & G A Petsko

  14. Department of Psychiatry, Seaver Autism Center for Research and Treatment, and The Friedman Brain Institute, Mount Sinai School of Medicine, New York, NY, USA

    J D Buxbaum

  15. Department of Neurology, University of California Irvine School of Medicine, Irvine, CA, USA

    C G Glabe

  16. School of Psychiatry and Clinical Neurosciences, University of Western Australia, Crawley, WA, Australia

    R N Martins

  17. Sir James McCusker Alzheimer's Disease Research Unit, Hollywood Private Hospital, Nedlands, WA, Australia

    R N Martins

  18. Department of Pediatrics, Mount Sinai School of Medicine, New York, NY, USA

    M E Ehrlich

  19. Department of Neuroscience, Mount Sinai School of Medicine, New York, NY, USA

    Z Yue

  20. James J Peters VA Medical Center, Bronx, NY, USA

    S Gandy

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  1. J W Steele
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Corresponding author

Correspondence to S Gandy.

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Competing interests

AP is Vice President of Preclinical Development for Medivation. SG holds research grant support from Amicus Pharmaceuticals and is a consultant to the Pfizer-Janssen Alzheimer's Immunotherapy Alliance. PS and NR hold research grant support from Baxter Healthcare (both PS and NR) and Pfizer (NR). NR is a consultant for Bristol Meyer Squibb and Eisai Research. GAP is on the scientific advisory boards of Amicus Pharmaceuticals and Neurophage.

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Steele, J., Lachenmayer, M., Ju, S. et al. Latrepirdine improves cognition and arrests progression of neuropathology in an Alzheimer's mouse model. Mol Psychiatry 18, 889–897 (2013). https://doi.org/10.1038/mp.2012.106

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