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

BIBLIOGRAPHIC THERAPEUTIC AGENT ANIMAL MODEL EXPERIMENTAL DESIGN OUTCOMES

Bibliographic

Year of Publication:
2013
Contact PI Name:
Sam Gandy
Contact PI Affiliation:
Department of Psychiatry and The Mount Sinai Alzheimer’s Disease Research Center, Mount Sinai School of Medicine, New York, New York, USA
Co-Authors:
John W. Steele, M. Lenard Lachenmayer, Shulin Ju, Aryeh Stock, Jessica Liken, Soong Ho Kim, Luz M. Delgado, Iván E Alfaro, Sebastian Bernales, Giuseppe Verdile, et al.,
Primary Reference (PubMED ID):
22850627
Funding Source:
United States Department of Veterans Affairs (VA)
Fidelity Biosciences Research
Canadian Institutes of Health Research (CIHR)
National Institute on Aging (NIA)
Alzheimer Society of Ontario
Baxter Healthcare
National Institute of Neurological Disorders and Stroke (NINDS)
Alzheimer Society of Canada
National Health and Medical Research Council of Australia
Study Goal and Principal Findings:

The goal of this study was to test the efficacy of latrepirdine on behavioral deficits and AD-related neuropathology in the TgCRnD8 mouse model. Latrepirdine treatment of male TgCRND8 transgenic mice found found to be associated with  the modulation of  Atg5-dependent autophagic activity via the mTOR-signaling pathway; potentiation of APP metabolite degradation in cell culture and in mouse brain; improvement in the memory behavior and reduction in the accumulation of insoluble Aβ42, and α-synuclein. The data suggest that, despite mixed results in clinical trials, latrepirdine may be useful as a lead scaffold for developing clinically safe, BBB-penetrating, pro-autophagic, pro-neurogenic drugs for treatment and/or prevention of cerebral proteinopathies, including α-synucleinopathies and Alzheimer’s cerebral amyloidosis.

Bibliographic Notes:
Full Author List: John W. Steele, M. Lenard Lachenmayer, Shulin Ju, Aryeh Stock, Jessica Liken, Soong Ho Kim, Luz M. Delgado, Iván E Alfaro, Sebastian Bernales, Giuseppe Verdile, Prashant Bharadwaj, Veer Gupta, Renae Barr, Amy Friss, Georgia Dolios, Rong Wang, Dagmar Ringe, Paul Fraser, David Westaway, Peter H. St George-Hyslop, Paul Szabo, Norman R. Relkin, Joseph D. Buxbaum, Charles G. Glabe, Andrew A. Protter, Ralph N. Martins, Michelle E. Ehrlich, Gregory A. Petsko, Zhenyu Yue, Sam Gandy.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
Dimebon
PubMed
PubChem
DrugBank
ClinicalTrials
Patents
Therapeutic Target:
Multi Target

Animal Model

Model Information:
Species:
Mouse
Model Type:
APP
Model Name:
TgCRND8
ALZFORUM
Strain/Genetic Background:
Not Reported

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Biomarkers
Dose
Formulation
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest

Outcomes

Outcome Measured
Outcome Parameters
Behavioral
Fear Conditioning Response
Histopathology
beta Amyloid Load
Biochemical
Amyloid Precursor Protein (APP) Metabolites
alpha Synuclein
Brain-beta Amyloid Peptide 40
Brain-beta Amyloid Peptide 42
Brain-beta Amyloid Oligomers
Cell Biology
Autophagic Markers
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