title: Latrepirdine improves cognition and arrests progression of neuropathology in an Alzheimer's mouse model.
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.
authors: Department of Neurology, Mount Sinai School of Medicine, New York, NY, USA.
authors: J W
authors: JW
authors: Steele
authors: M L
authors: ML
authors: Lachenmayer
authors: S
authors: S
authors: Ju
authors: A
authors: A
authors: Stock
authors: J
authors: J
authors: Liken
authors: S H
authors: SH
authors: Kim
authors: L M
authors: LM
authors: Delgado
authors: I E
authors: IE
authors: Alfaro
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authors: S
authors: Bernales
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authors: Verdile
authors: P
authors: P
authors: Bharadwaj
authors: V
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authors: Gupta
authors: R
authors: R
authors: Barr
authors: A
authors: A
authors: Friss
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authors: G
authors: Dolios
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authors: R
authors: Wang
authors: D
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authors: Ringe
authors: P
authors: P
authors: Fraser
authors: D
authors: D
authors: Westaway
authors: P H
authors: PH
authors: St George-Hyslop
authors: P
authors: P
authors: Szabo
authors: N R
authors: NR
authors: Relkin
authors: J D
authors: JD
authors: Buxbaum
authors: C G
authors: CG
authors: Glabe
authors: A A
authors: AA
authors: Protter
authors: R N
authors: RN
authors: Martins
authors: M E
authors: ME
authors: Ehrlich
authors: G A
authors: GA
authors: Petsko
authors: Z
authors: Z
authors: Yue
authors: S
authors: S
authors: Gandy
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D000071187:Autophagy-Related Protein 5; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D003071:Cognition / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D010446:Peptide Fragments / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D007211:Indoles; D008869:Microtubule-Associated Proteins; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D051844:alpha-Synuclein; C075222:amyloid beta-protein (1-42); C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; C010119:latrepirdine