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Can problems in the waste-clearing system lead to the accumulation of dementia-related tau protein in the brain?
Joanna Cooper, Ph.D.
University of Maryland, Baltimore
Baltimore, MD - United States
Background
Tau protein helps maintain the structure of brain cells. In Alzheimer’s and other brain diseases (such as frontotemporal dementia), the shape of tau becomes modified, or “misfolded”, a change that may contribute to the formation of tau tangles (a hallmark of these diseases) and subsequent nerve cell damage. Recent studies have found that misfolded tau may “escape” the brain cell’s natural waste-clearing process leading to build-up in the brain. During the natural waste-clearing process, unwanted proteins are normally sorted within multiple levels of cellular compartments to eventually be removed. In Alzheimer’s, however, abnormal tau appears to escape this process, leading to tau being able to accumulate and promote downstream changes, including damage to the cell.
In initial studies using brain cells grown in a laboratory dish, Dr. Joanna Cooper and colleagues found that the sorting of abnormal tau through these cellular compartments may not function correctly in Alzheimer’s. The researchers found that one such receptor, called sortilin-related receptor (or SORLA), plays a key role in this sorting; SORLA binds to tau. They also found, when SORLA activity was reduced, the amount of abnormal tau sent for disposal increased. These results suggest that SORLA may help prevent the removal of abnormal tau in Alzheimer’s and might lead to increased tau build-up.
Research Plan
Dr. Cooper and team will conduct a larger study to clarify how SORLA may prevent the disposal of abnormal tau. First, they will use brain cells grown in a laboratory dish to verify that SORLA binds to tau and that SORLA impacts how that tau is transported through cellular components. Next, they will genetically manipulate the brain cells to contain a genetic variation of SORLA, one that has already been linked to Alzheimer’s in previous studies. The researchers will determine whether this SORLA variation prevents tau removal and leads to increased tau accumulation. They will also use cutting-edge microscope techniques to identify how tau is sorted and transported in these cells.
Impact
The results of this project could shed new light on the mechanisms underlying tau changes related to Alzheimer’s and other brain diseases. They could also identify SORLA as a novel target for future dementia therapies.
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