| January 18, 2012 |
Researchers Spice up Alzheimer's Drug Discovery
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A new ray of hope may be on the horizon for Alzheimer disease (AD) patients and their families. A research team led by David Schubert and Marguerite Prior of the Salk Institute for Biological Studies, La Jolla, California, USA, designed a drug that mitigates multiple age-related pathologies. Dubbed "J147," the new drug improves cognitive functions in normal rodents and in a mouse model of AD (Chen et al. 2011). It may signal a new approach for developing AD- and other neurodegenerative disease-fighting drugs.
A new AD drug discovery paradigm
The causes of AD are not well understood. Less than 5% of all instances of AD are caused by gene mutations that regulate the metabolism of the amyloid beta (Aβ) peptide. Yet, most of the drugs for treating AD are designed to reduce Aβ accumulation. The Salk Institute team felt that a better approach is to target not just a single molecule but a battery of age-associated physiological factors, including oxidative stress, the loss of trophic factors, reduced energy metabolism, and inflammation. They designed six cell culture assays that evaluate a drug's ability to mitigate these and related factors as a group. They then synthesized molecular hybrids between curcumin, a major component of the Indian spice curry, and cyclohexyl-bisphenol A (CBA). They chose curcumin because it has multiple biological targets and has been reported to mitigate AD in transgenic AD mouse models. They chose CBA because it has neurotrophic activity, which curcumin lacks. The team's objective was to produce molecules that are more potent and have better pharmacokinetic properties than curcumin alone. They screened the hybrid molecules using the six cell culture-based assays and found that one, CNB-001, is more stable and neuroprotective than curcumin alone. They then generated a large number of CNB-001 derivatives and found one, J147, to be the most effective.
J147 makes rats and mice smarter
The Salk team administered J147 orally to mice and rats and evaluated its effects using a number of behavior tests. They found that it improves several aspects of memory in normal rats and wild-type C57BL/6J (000664) mice. Additionally, it improves cognitive functions and ameliorates AD in the B6.Cg-Tg(APPswe,PSEN1dE9)85Dbo/Mmjax (MMRRC 034832) mouse, a transgenic model of AD. Specifically, it prevents learning deficits, improves memory, and reduces the number of amyloid plaques and the levels of soluble Aβ1-42 and Aβ1-40 in this mouse. It reduces the levels of markers of oxidative stress and inflammation and of heat shock proteins (they are no longer needed to counteract the protein mis-folding caused by oxidative stress). It also increases synaptic protein expression and the levels of brain-derived neurotrophic factor (BDNF). BDNF regulates the expression of several genes involved in synaptic spine formation and in the phosphorylation of proteins involved in learning and memory.
The B6.Cg-Tg(APPswe,PSEN1dE9)85Dbo/Mmjax (MMRRC 034832) mouse is available from The Jackson Laboratory Mutant Mouse Regional Resource Center. Its pathology and behavior are extensively characterized. It develops plaques and loses synaptic markers by nine months of age and exhibits clear deficits in the Morris water maze assay.
In summary, the Salk Institute team demonstrated the potential of a new drug discovery paradigm for AD and other neurodegenerative diseases. In this paradigm, a candidate drug is not one that targets a single molecule but rather an array of age-related markers of neurodegeneration. The Salk Institute team developed such a drug: J147. It enhances learning and memory in normal and AD transgenic rodents, maintains synaptic proteins, and reduces biochemical markers of oxidative stress and inflammation and reduces the levels of soluble Aβ in AD transgenic mice. It is powerful and apparently safe. If it works as well in humans as it does in rodents, it could ameliorate AD by slowing down neurodegeneration and increasing cognition.
The Jackson Laboratory's Alzheimer's Disease Mouse Model Resource
The Jackson Laboratory offers a variety of excellent mouse models of AD. Many are congenics with stable genetic inbred strain backgrounds, usually C57BL/6J (000664). Many carry alleles that are potential targets for AD therapies. Read details on JAX AD mouse models and supporting resources and services.
