The role of HSPGs in tau uptake in cell and mouse models - Project Summary Alzheimer’s disease (AD) is the most common type of dementia and causes progressive memory loss. AD is a major challenge for our society since increasing numbers of individuals are affected. Currently, there are no treatments that can stop or reverse the disease. AD leads to buildup of toxic clumps of two proteins in the brain: Amyloid-beta (Aβ), which forms plaques, and tau, which forms tangles. Prior research shows that tau tangles are more directly responsible for worsening symptoms and disease progression than Aβ. Tau spreads by being released from one cell and taken up (“tau uptake”) by a neighboring cell. Blocking tau uptake could potentially stop the disease from progressing. One key player of tau uptake is a group of molecules on the surface of cells called heparan sulfate proteoglycans (HSPGs). HSPGs consist of core proteins and side chains of sugars called heparan sulfate (HS). Our prior research showed that a specific HS length and pattern of sulfate groups (“size and sulfation code”) is required for binding to tau. However, there are still major gaps in our understanding of how HSPGs drive tau uptake: 1.) We do not know if the HS size and sulfation code applies to neurons and microglia, two cell types in the brain that are mainly affected in AD. 2.) We do not know which specific HSPG core proteins are involved in tau uptake. 3.) We have not tested the role of HSPGs in mouse models. Our work also showed that an enzyme called NDST1, which is involved in making HSPGs, plays a crucial role in tau uptake. Reducing the activity of NDST1 in cells changes the sulfation pattern of HSPGs and substantially lowers tau uptake. Studies in mice show that reducing NDST1 activity is non-toxic. This makes NDST1 a potential target for new treatments to block tau spread. In this study, we propose two main goals: Goal 1: Identify the specific HS size and sulfation code and the HSPG core proteins involved in tau uptake in human neurons and microglia. We will use advanced tools (pharmacological tools, CRISPR interference, sugar photocrosslinking, mass spectrometry) to determine which components of HSPGs are key for tau binding and how they differ between neurons and microglia. Goal 2: Test how HSPGs contribute to tau uptake and spread in a mouse model. We will use genetically modified mice to reduce NDST1 activity specifically in neurons or microglia and measure how this affects tau buildup and disease progression. This research will enhance our understanding how HSPGs control cellular tau uptake and spread in the brain. The results could lead to new treatments that block tau spread, thereby slowing or stopping the progression of AD and related conditions.
