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Small molecule p75NTR ligands reduce pathological phosphorylation and misfolding of tau, inflammatory changes, cholinergic degeneration, and cognitive deficits in AβPPL/S transgenic mice


Year of Publication:
Contact PI Name:
Frank M. Longo
Contact PI Affiliation:
Department of Neurology and Neurological Sciences, Stanford, California, USA
Thuy-Vi V. Nguyen, Lin Shen, Lilith Vander Griend, Lisa N. Quach, Nadia P. Belichenko, Nay Saw, Tao Yang, Mehrdad Shamloo, Tony Wyss-Coray, Stephen M. Massa
Primary Reference (PubMED ID):
Funding Source:
National Institute on Aging (NIA)
Jean Perkins Foundation
Horngren Family Alzheimer’s Research Fund
Study Goal and Principal Findings:

This investigation aimed at testing the anti-degenerative activities of two p75NTR ligands LM11A-31 and LM11A-24 in the AβPPL/S mouse model of AD. The authors investigated the effects of the compounds on a range of AD-related phenotypic traits including ability to mitigate tau pathology, neuroinflammation, neuritic degeneration and behavioral deficits. Following oral administration, both ligands reached brain concentrations known to provide neuroprotection in vitro. Compound induction of p75NTR cleavage provided evidence for CNS target engagement. LM11A-31 and LM11A-24 reduced excessive phosphorylation of tau, and LM11A-31 also inhibited its aberrant folding. Both ligands decreased activation of microglia, while LM11A-31 attenuated reactive astrocytes. Along with decreased inflammatory responses, both ligands reduced cholinergic neurite degeneration. In addition to the amelioration of neuropathology in AD model mice, LM11A-31, but not LM11A-24, prevented impairments in water maze performance. Noth ligands prevented deficits in fear conditioning. These findings support a role for p75NTR ligands in preventing fundamental tau-related pathologic mechanisms in AD, and further validate the development of these small molecules as a new class of therapeutic compounds.

Therapeutic Agent

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

Animal Model

Model Information:
Model Type:
Strain/Genetic Background:

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
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


Outcome Measured
Outcome Parameters
Morris Water Maze
Contextual Fear Conditioning
Activated Microglia
Activated Astrocytes
Degenerating Neurites
Dystrophic Neurites
p75 Neurotrophin Receptor (p75NTR)
p75 Neurotrophin Receptor (p75NTR)
Drug Concentration-Plasma
Drug Concentration-Brain
Target Engagement (Activation p75 Neurotrophin Receptor)
Cerep Profile