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A small molecule p75NTR ligand, LM11A-31, reverses cholinergic neurite dystrophy in Alzheimer's disease mouse models with mid- to late-stage disease progression

Bibliographic

Year of Publication:
2014
Contact PI Name:
Frank M. Longo
Contact PI Affiliation:
Department of Neurology and Neurological Sciences, Stanford University, Stanford, California, USA
Co-Authors:
Danielle A. Simmons, Juliet K. Knowles, Nadia P. Belichenko, Gargi Banerjee, Carly Finkle, Stephen M. Massa
Primary Reference (PubMED ID):
Funding Source:
National Institute on Aging (NIA)
United States Department of Veterans Affairs (VA)
National Institute of Neurological Disorders and Stroke (NINDS)
Study Goal and Principal Findings:

The goal of this study was to determine if the p75 NTR ligand, LM11A-31, could arrest or reverse the degeneration of cholinergic neurites in two mouse models of AD. Treatment of the mice was initiated at mid-to late stages of the AD-like disease progression characterized by adundant beta amyloid deposits, cholinergic degeneration and memory deficits. In mid-stage (6–8 months of age) male APPL/S mice, LM11A-31 administered for 3 months prevented and/or reversed atrophyof basal forebrain cholinergic neurites and cortical dystrophic neurites. A 1 month treatment of LM11A-31 in late-stage( 12-13 months of age) male APPL/S mice reversed the degeneration of cholinergic neurites in basal forebrain, ameliorated cortical dystrophic neurites, and normalized increased basal forebrain levels of p75NTR. Similar results were seen in late stage female Tg2576 mice. These findings suggest that LM11A-31 can reduce and/or reverse fundamental AD pathologies in late-stage AD mice. Thus, targeting p75NTR is a promising approach to reducing AD-related degenerative processes that have progressed beyond early stages. 

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
LM11A-31
Therapeutic Target:
Neurotrophin Receptor p75 (p75NTR)

Animal Model

Model Information:
Species:
Mouse
Model Type:
APP
Strain/Genetic Background:
C57BL/6
Species:
Mouse
Model Type:
APP
Strain/Genetic Background:
C57BL/6
Species:
Mouse
Model Type:
Non-transgenic
Strain/Genetic Background:
C57BL/6

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
Experiment Notes

Pharmacokinetic data is reported in: Knowles JK, Simmons DA, Nguyen TV, Vander Griend L, Xie Y, et al. (2013) Small molecule p75NTR ligand prevents cognitive deficits and neurite degeneration in an Alzheimer’s mouse model. Neurobiol Aging 34: 2052–2063.

Outcomes

Outcome Measured
Outcome Parameters
Immunochemistry
p75 Neurotrophin Receptor (p75NTR)
Cholinergic Neuritic Dystrophy
Pharmacodynamics
Target Engagement (Activation p75 Neurotrophin Receptor)
Pharmacokinetics
Drug Concentration-Brain
Toxicology
Body Weight
Water Consumption