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

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

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