Latrepirdine improves cognition and arrests progression of neuropathology in an Alzheimer's mouse model
Open Access
- 31 July 2012
- journal article
- research article
- Published by Springer Nature in Molecular Psychiatry
- Vol. 18 (8) , 889-897
- https://doi.org/10.1038/mp.2012.106
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.Keywords
This publication has 35 references indexed in Scilit:
- Autophagy failure in Alzheimer's disease—locating the primary defectNeurobiology of Disease, 2011
- Naturally Secreted Amyloid-β Increases Mammalian Target of Rapamycin (mTOR) Activity via a PRAS40-mediated MechanismJournal of Biological Chemistry, 2011
- A small‐molecule enhancer of autophagy decreases levels of Aβ and APP‐CTF via Atg5‐dependent autophagy pathway The FASEB Journal, 2011
- Reversal of autophagy dysfunction in the TgCRND8 mouse model of Alzheimer's disease ameliorates amyloid pathologies and memory deficitsBrain, 2010
- Discovery of a Proneurogenic, Neuroprotective ChemicalCell, 2010
- Molecular Interplay between Mammalian Target of Rapamycin (mTOR), Amyloid-β, and TauJournal of Biological Chemistry, 2010
- Mammalian autophagy: core molecular machinery and signaling regulationPublished by Elsevier ,2009
- The cellular pathways of neuronal autophagy and their implication in neurodegenerative diseasesBiochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2009
- Evaluation of Dimebon in cellular model of Huntington's diseaseMolecular Neurodegeneration, 2008
- Small molecules enhance autophagy and reduce toxicity in Huntington's disease modelsNature Chemical Biology, 2007