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A novel neurotrophic drug for cognitive enhancement and Alzheimer's disease


Year of Publication:
Contact PI Name:
David Schubert
Contact PI Affiliation:
Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California, USA
Qi Chen, Marguerite Prior, Richard Dargusch, Amanda Roberts, Roland Riek, Cedric Eichmann, Chandramouli Chiruta, Tatsuhiro Akaishi, Kazuho Abe, Pamela Maher
Primary Reference (PubMED ID):
Funding Source:
Alzheimer's Association
Bruce Ford and Anne Smith Bundy Foundation
National Institute on Aging (NIA)
Fritz B. Burns Foundation
Study Goal and Principal Findings:

The overarching goal of this study was to improve the potency and pharmacokinetic properties of curcumin, and to test the improved analogs for efficacy in the APP/PS1 mouse model of AD. To this end, 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 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- J147.  J147  was found to be broadly neuroprotective  and  possess memory enhancing activity in normal animals, and the ability to prevent memory deficits in AD transgenic mice. The neurotrophic and memory-enhancing activities of J147 are associated with an increase in brain derived neurotrophic factor (BDNF) levels and the expression of BDNF responsive proteins, the 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. These pleiotrophic effects of a single molecule suggest that J147 has potential for the treatment of AD.

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
Model Type:
Strain/Genetic Background:
Not Applicable

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
Novel Object Recognition Test (NORT)
Barnes Maze
Y Maze
Morris Water Maze
beta Amyloid Load
Brain-beta Amyloid Peptide 40
Brain-beta Amyloid Peptide 42
Oxidative Stress Markers
Proinflammatory Markers
Synaptic Proteins
Brain-Derived Neurotrophic Factor (BDNF)
Long Term Potentiation (LTP)
Cell Biology
Neuroprotection-Trophic Withdrawal
Neuroprotection-Amyloid Neurotoxicity
Neuroprotection-Oxidative Stress
Body Weight