Aggresomes and Alzheimer's Disease

Aggresomes are insoluble intracellular protein aggregates formed when the production of a protein exceeds the cellular capacity to degrade it. They can be produced by protein overexpression and/or inhibition of the proteasome pathway. Aggresomes were first described for integral transmembrane ubiquitinated proteins including Presenilin 1, but soluble, non-ubiquitinated proteins can also be deposited in aggresomes. Aggresomes consist of the aggregated protein(s) (often ubiquitinated), the proteasome, Hsp70 and the chaperonin systems of chaperones, surrounded by a vimentin cage. Aggresomes accumulate in the perinuclear/ pericentriolar region near the microtubule organizing center of the cell, composed of y-tubulin and associated proteins. Aggresomes or aggresome-like changes are implicated in cystic fibrosis, Huntington's disease, and Alzheimer's disease. We hypothesize that tau is degraded by the proteasome, and that an impairment in tau catabolism results in tau accumulation in the cytoplasm, promoting its aggregation into aggresomes or aggresome-like structures. The specific questions addressed by this proposal are: 1. Does the proteasome system contribute to tau degradation? Does proteasome inhibition alter tau localization, conformation, or phosphorylation? Is tau associated with aggresomes? Normal and mutant human tau isoforms will be expressed in non:neural cells in which aggresome formation has been shown to occur (e.g. COS-7 cells) as well as in neurobloastoma cells (SHSY-5Y, PC12). Are aggresomes present in neurons in Alzheimer's disease? The ubiquitination of PHF-tau and the localization of PHF-tau in perinuclear regions is supportive evidence, but aggresomes have not been demonstrated directly in AD. Do insults implicatedin Alzheimer's disease lead to proteasome inhibition and aggresome formation? A variety of insults including oxidative stress cause increased protein degradation via the proteasome pathway. This aim will determine if oxidative stress can result in aggresome formation. Can aggresome formation be inhibited? Potential treatments include upregulation of the proteasome pathway. 2. 3. 4. 5.