CRF receptor-1 antagonism mitigates Aβ pathology and cognitive and synaptic deficits in a mouse model of Alzheimer's disease

Bibliographic

Year of Publication:

2016

Contact PI Name:

Robert A. Rissman

Contact PI Affiliation:

Department of Neurosciences, University of California San Diego, La Jolla, California, USA

Co-Authors:

Cheng Zhang, Ching-Chang Kuo, Setareh H. Moghadam, Louise Monte, Shannon N. Campbell, Kenner C. Rice, Paul E. Sawchenko, Eliezer Masliah

Primary Reference (PubMED ID):

26555315

Funding Source:

National Institute on Aging (NIA)

Alzheimer's Association

Alzheimer's Art Quilt Initiative

Clayton Medical Research Foundation

The Leona M. and Harry B. Helmsley Charitable Trust

Study Goal and Principal Findings:

Introduction: Stress and corticotropin-releasing factor (CRF) have been implicated as mechanistically involved in Alzheimer's disease (AD), but agents that impact CRF signaling have not been carefully tested for therapeutic efficacy or long-term safety in animal models.

Methods: To test whether antagonism of the type-1 corticotropin-releasing factor receptor (CRFR1) could be used as a disease-modifying treatment for AD, we used a preclinical prevention paradigm and treated 30-day-old AD transgenic mice with the small-molecule, CRFR1-selective antagonist, R121919, for 5 months, and examined AD pathologic and behavioral end points.

Results: R121919 significantly prevented the onset of cognitive impairment in female mice and reduced cellular and synaptic deficits and beta amyloid and C-terminal fragment-β levels in both genders. We observed no tolerability or toxicity issues in mice treated with R121919.

Discussion: CRFR1 antagonism presents a viable disease-modifying therapy for AD, recommending its advancement to early-phase human safety trials.

Therapeutic Agent

Therapeutic Information:

Therapy Type:

Small Molecule

Therapeutic Agent:

R121919

PubMed

PubChem

Patents

Therapeutic Target:

Corticotropin-Releasing Factor Receptor 1 (CRFR1)

Open Targets

Pharos

Agora

Therapeutic Notes:

Corticotropin-Releasing Factor Receptor 1 (CRFR1) has been nominated as a potential target for AD. Nominated targets are obtained from several sources, including the National Institute on Aging's Accelerating Medicines Partnership in Alzheimer's Disease (AMP-AD) consortium. Targets have been identified using computational analyses of high-dimensional genomic, proteomic and/or metabolomic data derived from human samples. See Agora link for more information.

Animal Model

Model Information:

Species:

Mouse

Model Type:

APPxPS1

Model Name:

APPswe/PSEN1dE9 (line 85)

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

Morris Water Maze

Histopathology

beta Amyloid Load

Biochemical

APP-CTF83 (CTF alpha)

APP-CTF99 (CTF beta)

beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Activity

Brain-Buffer Soluble beta Amyloid Peptide 40

Brain-Buffer Soluble beta Amyloid Peptide 42

Brain-Buffer Soluble beta Amyloid Peptide 38

Brain-Detergent Soluble beta Amyloid Peptide 40

Brain-Detergent Soluble beta Amyloid Peptide 42

Brain-Detergent Soluble beta Amyloid Peptide 38

Immunochemistry

Synaptophysin

Microtubule-Associated Protein 2 (MAP2)

Pharmacodynamics

Target Engagement (Binding to Corticotropin-Releasing Factor Receptors)

Toxicology

Liver Enzymes

Liver Morphology

Body Weight

Grooming Behavior

Glucocorticoids