Elucidation of Apoe-induced glial cell Tau pathology in PSP

Pathway Grant

Principal Investigator: Dr. Seiji Kaji, Kyoto University

Progressive supranuclear palsy (PSP) is a debilitating neurodegenerative disease, which impairs the movement and cognitive functions of affected individuals. Studies from autopsy cases revealed that PSP patients’ brains contain inclusions of aggregated proteins inside particular types of cells. One of the main components of these inclusions is the protein, Tau, which has adopted a pathological structure and function. A unique feature of PSP brains is that the inclusions of Tau are seen in glial cells, the cell types which support the function of neurons. To uncover the cause of neurodegenerative diseases, large genetic studies have been carried out, which revealed that apolipoprotein E (ApoE) is associated with some neurodegenerative diseases including Alzheimer’s disease (AD) and PSP. These neurodegenerative diseases have pathological similarities since both diseases cause accumulation of Tau in brains. Through our previous research, we discovered that ApoE accumulates and becomes a part of protein aggregates in the brains of AD and PSP cases. Moreover, we found that ApoE proteins, when they are in aggregated forms, enhance the formation of defective Tau protein aggregates. Therefore, defective ApoE function and aggregation can be a root cause of disease onset in PSP.

In our project, we aim to clarify how ApoE aggregates contribute to the development of PSP. This knowledge is particularly important since we recently reported that some forms of ApoE are resistant to become aggregated, suggesting that modulation of the ApoE status will prevent the disease progression in PSP. Additionally, through the project, we will address the question of which genetic variants (known as isoforms) of ApoE have protective or adverse effects on PSP pathology with a primary focus on the inclusion formation in glial cells. Our novel approach, that is based on the analysis of ApoE dynamics, will provide us a critical perspective on how to design novel therapeutic strategies for PSP.