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Eliminating membrane depolarization caused by the Alzheimer peptide A(1-42, aggr.) Approximately 15 percent of people who live to the age of 65 will develop some form of dementia; by age 85, that proportion increases to at least 35 percent. The most common of all the dementias is Alzheimer's disease. Four million Americans currently suffer from the condition, and experts estimate that 22 million people around the world will be so afflicted by 2025. Aß42 is invariably elevated with all mutations that cause the less common familial Alzheimer's disease and is also generally considered to be of key importance to the development of late onset disease. This form of ß-amyloid forms toxic fibrils much faster than Aß40, its shorter homologue. Neurotoxicity is thought to be due to ß-amyloid-induced membrane depolarization as well as subsequent calcium influx. A number of mechanisms have been proposed to explain this depolarization. In an earlier edition of TherapeuticAdvances we highlighted data suggesting ß-amyloid itself is able to form calcium channels in neurites; other suggested mechanisms involve the activation of AMPA/kainate and NMDA ionotropic receptor channels and mGluR1/G-protein. MIT researchers have developed a high-throughput screen that is able to identify molecules able to prevent Aß42 evoked membrane depolarization. This group found 10 potentially useful compounds, some of which reduce the Aß-induced membrane depolarization by up to 96%. Interestingly, the active compounds include specific tyrosine kinase inhibitors and inhibitors of certain chloride channels which are presumed to mediate the effects of mGluR1 receptor activation. In addition, dopaminergic and serotonergic agonists were identified due to their ability to compensate for the Aß-induced membrane depolarization by themselves causing a hyperpolarization. The hit compounds, show promise for the restoration of cognitive function in the treatment of early and mid-stage Alzheimer's disease. Link to journal abstract:
Adapted from Blanchard et al, Biochemical and Biophysical Research Communications, Vol. 293, No. 4, May 17, 2002 Interested in collaborating with this group? Contact leaddiscovery@bioportfolio.co.uk LeadDiscovery and BioPortfolio aims to provide reliable, insightful analysis on the biotechnology industry. However, this information is provided "as is" and no representations or warranties either express or implied of completeness, accuracy, or of any other nature are made with respect to this information. This information is neither an offer to sell nor a solicitation to buy the securities of any company. This information contains forward-looking statements, which involve risks and uncertainties which may not be listed. The biotechnology industry is an emerging industry and the securities of the companies mentioned in this report have a very high degree of risk and volatility. For this reason, this information is supplied on the condition that the reader will make his or her own determination as to its suitability for any purpose prior to any use of this information. The employees and officers of LeadDiscovery and BioPortfolio may hold positions in some or all of the stocks discussed in this report. This abstract has been produced by LeadDiscovery Ltd. Founded by life scientists for life scientists we aim to help industry identify cutting edge drug discovery options and academic/biotech institutions maximize the potential of their research. Abstracts strictly reflect the opinion of LeadDiscovery's editorial panel. While all reasonable efforts are made to ensure the accuracy of information provided LeadDiscovery and the publisher BioPortfolio, takes no responsibility for incorrect or misleading information. LeadDiscovery is designed for educational and drug development purposes only and is not intended or designed to offer medical advice or advice of any sort, and must not be used for such purpose. The information provided through LeadDiscovery and BioPortfolio should not be used for diagnosing or treating a health problem or a disease and no reliance should be placed on any information contained in this abstract or elsewhere on LeadDiscovery's and BioPortfolio's website. It is not intended to be a substitute for professional care. If you have or suspect you may have a health problem, you should consult your physician or other health care provider. |
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