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The neurotrophic compound J147 reverses cognitive impairment in aged Alzheimer’s disease mice


Year of Publication:
Contact PI Name:
David Schubert
Contact PI Affiliation:
The Salk Institute for Biological Studies, Cellular Neurobiology Laboratory, La Jolla, California, USA
Richard Dargusch, Jennifer L Ehren, Chandramouli Chiruta, Marguerite Prior
Primary Reference (PubMED ID):
Funding Source:
Bruce Ford and Anne Smith Bundy Foundation
Alzheimer's Association
National Institute of Neurological Disorders and Stroke (NINDS)
Fritz B. Burns Foundation
Alzheimer's Drug Discovery Foundation (ADDF)
Study Goal and Principal Findings:

Curcumin is a curry spice with multiple biological activities that is also effective in transgenic AD mouse models. To improve the potency and pharmacokinetic properties of curcumin, the authors synthesized a series of hybrid molecules between curcumin and cyclohexyl-bisphenol A (CBA), a compound that has neurotrophic activity which curcumin lacks. The best compound from this initial synthesis was CNB-001, a molecule that has improved stability over curcumin and that is neuroprotective in multiple neurotoxicity assays in which curcumin is inactive. Next, the authors generated a large number of derivatives of CNB-001 and selected the best compound on the basis of activity in our multiple toxicity assays. The result was a much more potent molecule called J147. Further experimentation found that J147 was broadly neuroprotective compound with memory enhancing activity in aged rodents as well as AD transgenic mice. The neurotrophic and memory-enhancing activities of J147 were found to be  associated with an increase in brain derived neurotrophic factor (BDNF) levels and the expression of BDNF responsive proteins, enhancement of LTP, synaptic protein preservation, the reduction of markers for oxidative stress and inflammation, the reduction of amyloid plaques, and lower levels of soluble Aβ1–42 and Aβ1–40. Therefore, the range of biological activities of J147 relevant to human AD is also much more extensive than any of the compounds that have failed in clinical trials. In addition, J147 is very potent, has good medicinal chemical properties for a CNS drug, is apparently safe, and is orally active. Thus,  J147 is an exciting new compound with the potential to be an AD therapeutic by slowing disease progression through neuroprotection as well as providing immediate cognition benefits.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
Therapeutic Target:
ATP Synthase F1 Subunit alpha (ATP5F1A)

Animal Model

Model Information:
Model Type:
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
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
Radial Arm Water Maze
Elevated Plus Maze
Contextual Fear Conditioning
Y Maze
beta Amyloid Deposits
Brain-Buffer Insoluble beta Amyloid Peptide 40
Brain-Buffer Insoluble beta Amyloid Peptide 42
Brain-Buffer Soluble beta Amyloid Peptide 40
Brain-Buffer Soluble beta Amyloid Peptide 42
beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1)
Amyloid Precursor Protein (APP)
Nerve Growth Factor (NGF)
Synaptic Proteins
Brain-Derived Neurotrophic Factor (BDNF)
Blood Brain Barrier Penetration
Plasma t1/2
Brain t1/2
Oral Bioavailability (F%)
Drug Concentration-Brain
Drug Concentration-Plasma
Target Screen
hERG Assay
Ames Test
Body Weight
Food Intake
CYP450 Inhibition
Micro Array Expression Analysis