Salk Researchers Take a Stab at New Approach to Alzheimer's Tx
At present, there are few drugs that improve the memory deficits associated with normal aging and none that prevent cognitive decline in chronic neurodegenerative conditions such as Alzheimer's disease (AD). Except for the rare cases of familial AD, the cause of AD is not known, but the disease is highly correlated with aging, a process involving a wide variety of physiological changes. Therefore, it is likely that the cells in the aging brain are compromised not from a single cause but from the convergence of multiple insults. However, the currently most widely used approach to drug discovery is to identify a single molecular target and then make a drug that alters this target . Unfortunately, drugs for AD that were developed through this approach have all failed in clinical trials, perhaps because one target is not sufficient or because the targets are also critical for normal brain function so that their inactivation results in toxicity. Therefore, a different approach to drug discovery for AD is needed , . _PLoS
Currently, the major drug discovery paradigm for neurodegenerative diseases is based upon high affinity ligands for single disease-specific targets. For Alzheimer's disease (AD), the focus is the amyloid beta peptide (Aß) that mediates familial Alzheimer's disease pathology. However, given that age is the greatest risk factor for AD, we explored an alternative drug discovery scheme that is based upon efficacy in multiple cell culture models of age-associated pathologies rather than exclusively amyloid metabolism. Using this approach, we identified an exceptionally potent, orally active, neurotrophic molecule that facilitates memory in normal rodents, and prevents the loss of synaptic proteins and cognitive decline in a transgenic AD mouse model. _PLoSThe "amyloid hypothesis" has not been a productive research pathway for finding cures for Alzheimer's -- at least not yet. Salk researchers chose to develop a new series of pharmacological agents based upon the neuroprotective action of the herb curcumin. Curcumin does not enter the brain in high enough concentrations to reverse the symptoms of Alzheimer's Disease, once the disease has progressed to the symptomatic stage. But the new Salk molecules, based upon curcumin's effect, are able to reverse some of the signs of neurodegeneration in aging animal brains.
If the new drug -- J147 -- proves to be effective, and is as safe as curcumin itself, it is likely to become the prototype for a new approach to treating neurodegeneration of aging in general, and Alzheimer's in particular.