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Dec 19, 2011
Alzheimer's J147 drug heals memory and brain damage by going beyond amyloid plaque research
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The horrors of Alzheimer’s disease are well known, and the specter of this disease will fall over most of us in one way or another.  Enormous quantities of resources are currently being spent on seeking cures or ameliorative treatments, with very little success or progress.


A common thread of reasoning supports most research on treatment of Alzheimer’s Disease.  Alzheimer’s is associated with the formation of amyloid plaques in brain tissue.  A primary role for amyloid plaques in Alzheimer’s is suggested by certain genetic correlations, and by the ability of such plaques to trigger a variety of immune responses which may contribute to the disease.  Oddly, however, removal of the amyloid plaques does not seem to alter the progression of Alzheimer’s.  A wide range of variations have been put forward to patch up holes in the amyloid hypothesis.  Unfortunately, no effective drug treatments have come out of this extensive R&D effort.


An old adage says ‘If at first you don’t succeed, try, try again.’  Another, not quite so old, states that ‘Insanity is repeating the same actions and expecting different results.’ 


A team of researchers at the Salk Institute decided to try something completely different.  Reasoning that the strongest correlation with Alzheimer’s is the age of the victim, the Salk researchers decided to test potential drugs against a range of age-associated pathologies. 


Using cultures of neurons as the initial test ‘subjects’, they carried out an iterative drug discovery process based on efficacy of drug candidates in preventing or relieving a variety of age-associated pathologies.  These included lowered ability to absorb metabolic energy, oxidative stress, decreased presence of molecules that support development and maintenance of synaptic structures, and amyloid toxicity. 


Beginning with curcumin, a compound extracted from the spice turmeric (associated with aiding the healing process), they found that a heterocyclic derivative of curcumin showed significant neuroprotective abilities in the various neuron cultures.  A large number of derivatives were formed in a single reaction having multiple end points.  These products were then separated and tested individually.  J147 was the most promising candidate product of this process.


If you sat down to design an Alzheimer’s drug candidate, you couldn’t get much better than J147.  It is reasonably small (molecular weight of 351), penetrates the blood-brain barrier, is orally active, and appears to have no obvious side effects.  It is strongly neuroprotective, with broad activity at levels many times greater than the compounds from which it was developed.  It has brain-derived neurotrophic factor-like effects without requiring the presence of the BDNF receptor. 


In tests with healthy rats and mice, J147 is found to enhance both short- and long-term memory following a short period of treatment.  In Alzheimer’s rats and mice, learning was enhanced, and short-term memory deficits were reversed with short-term treatment.  J147 reduces oxidative stress and the associated damage from immune reaction and free-radicals.


J147 also increases the expression of BDNF without requiring BDNF receptors, apparently by activating downstream targets of BDNF.  This activity supports long-term memory and the survival of existing neurons, as well as the growth and differentiation of new neurons and synaptic structures.  BDNF receptors are primarily located in the hippocampus, cortex and basal forebrain, but the BDNF-like activity of J147 may be felt in other parts of the brain, offering possible treatments for depression and similar disorders. 


In short, J147 appears to offer strong protection against all the ills of mankind – or at least those associated with an aging brain.  Perhaps one of the more interesting results is the ability to assist normal brains with memory and increased stability against mood/thought disorders.  Will this be the new fluoride in our future water systems?  That is, a drug which is administered to all members of society? 


While that future seems a bit unlikely, the option would not exist save for an innovative choice in research plan at Salk.  Since their efforts met with encouraging success, how long will it take the FDA to approve human testing?  Hopefully J147 will be put on the fast track. At this point, failure would be as informative as success!


Following the crowd, while perhaps effective early on, may not be the best approach toward solving a problem.  The quest for fusion power is a good example of the poor effectiveness of lemming research, but that is a topic for another column.

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