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

Steele, J. W.; Lachenmayer, Lenard; Ju, S.; Stock, A.; Liken, J.; Kim, S. H.; Delgado, L. M.; Alfaro, I. E.; Bernales, S.; Verdile, G.; Bharadwaj, P.; Gupta, V.; Barr, R.; Friss, A.; Dolios, G.; Wang, R.; Ringe, D.; Fraser, P.; Westaway, D.; St George-Hyslop, P. H.; ... (2013). Latrepirdine improves cognition and arrests progression of neuropathology in an Alzheimer's mouse model. Molecular psychiatry, 18(8), pp. 889-897. Nature Publishing Group 10.1038/mp.2012.106

[img] Text
steele2013_molpsyc2.pdf - Published Version
Restricted to registered users only
Available under License Publisher holds Copyright.

Download (2MB) | Request a copy

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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Head Organs and Neurology (DKNS) > Clinic of Neurology

UniBE Contributor:

Lachenmayer, Lenard

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1359-4184

Publisher:

Nature Publishing Group

Language:

English

Submitter:

Valentina Rossetti

Date Deposited:

30 Jun 2014 14:12

Last Modified:

29 Oct 2015 12:09

Publisher DOI:

10.1038/mp.2012.106

Additional Information:

Steele JW and Lachenmeyer L contributed equally to this work

Uncontrolled Keywords:

Alzheimer's disease, amyloid, autophagy, therapeutics

BORIS DOI:

10.7892/boris.54124

URI:

https://boris.unibe.ch/id/eprint/54124

Actions (login required)

Edit item Edit item
Provide Feedback