Propagation of Tauopathy and Ubiquitin Proteasome System Dysfunction: Impact and Rescue with a UPS Activator

The brain of a patient with Alzheimer’s disease shows two abnormalities: clumps of a protein called amyloid into what is known as amyloid plaques, and clumps of a protein called tau into what is known as neurofibrillary tangles. One of the features of Alzheimer’s disease is that the tangles start in one part of the brain (areas involved in memory and learning), but they infect new regions and spread through the brain, contributing to the worsening of the disease. This project will investigate the impact of tau propagation on the functioning of the ubiquitin-proteasome system (UPS), the process by which cells break down proteins in order to use and dispose of/clear their component parts, and whether it can be rescued by an already-approved drug either by acting on the tau pathology itself or on its impact on the UPS.

We have spent several years studying how the tangles spread through the brain and what effect tangles have on brain function. We recently have described a way to prevent tangles forming in the brain by enhancing a molecular method known as “clearance,” which is a natural way that brain cells remove (“clear”) toxic or abnormal proteins. We have identified several drugs that can boost clearance and improve the brain’s ability to clear abnormal tau, thereby removing tangles. While we have been able to clear tangles to some extent at various stages of disease in a mouse model, we have not yet shown whether these drugs can prevent the spread of the tangles within the brain. This could be very important if we want to prevent tangles from taking hold, or making the disease worse. We propose to test whether the spread of tangles through the brain is a result of abnormal tau overwhelming the cell’s ability to clear it from cells, and if we can boost the cell’s defenses against tangles using drugs. If our drugs do prevent the spread of tangles through the brain by enhancing clearance, they would be good candidates for clinical trial in AD patients, as well as in patients suffering with tangles that cause a different dementia, frontotemporal dementia (FTD).