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Activation of the 26S Proteasome for the Treatment of Alzheimer’s Disease

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One fundamental feature of Alzheimer’s disease (and several related neurodegenerative diseases) is the build-up in neurons of abnormal protein aggregates composed of the protein tau. One of the primary mechanisms that cells employ to prevent the accumulation of such misfolded, potentially toxic proteins is rapid degradation by the 26S proteasome, a degradative particle present in thousands of copies in all our cells. Our lab long has been investigating proteasome functions and molecular mechanisms. We recently made the unexpected discovery that the capacity of cells, including brain neurons, to destroy misfolded proteins, such as tau, can be increased by drugs that raise the levels of the cell-signaling molecule cyclic AMP (cAMP). A rise in cAMP causes a chemical modification and activation of the proteasome. These findings are exciting because they strongly suggest a new rational approach for drug development against Alzheimer’s and other neurodegenerative diseases.

In order to determine which treatment might be most effective in promoting tau degradation, we plan to compare the capacity of different phosphodiesterase inhibitors, a class of drugs that raise cAMP to cause a similar modification and activation of brain 26S proteasomes. In addition, we shall investigate whether other signaling molecules also may activate the proteasome and enhance the degradation of misfolded disease-associated proteins. Finally, our recent collaborative studies showed that aggregated tau can be damaging to cells by impairing the function of proteasomes and thus disrupting cell regulation. We shall investigate further how these toxic proteins actually impair protein degradation by the proteasome and how neurons may compensate for such damage by increasing the production of new proteasomes or by inducing autophagy (a distinct cellular system for degrading aggregated proteins).