Tau aggregates are a defining feature of Alzheimer’s disease (AD) and closely track with brain cell loss, memory problems, and cognitive decline. Yet, scientists still do not fully understand how tau spreads through the brain or what role the brain’s immune system plays in the process. There is evidence that toxic forms of tau, which are misfolded, act like a “bad influence.” When they encounter nearby healthy tau proteins, they cause them to misfold as well, triggering a chain reaction that spreads from one brain region to another. Microglia, the brain’s resident immune cells, are among the first to encounter these toxic tau “seeds.” Normally, microglia protect the brain by clearing debris and helping repair damage. But growing evidence suggests that microglia may also contribute to tau’s spread by engulfing misfolded tau and inadvertently releasing it, thereby amplifying its harmful effects.
Dr. Hopp’s lab has been instrumental in uncovering how and why this happens. Her team has identified the cellular machinery that allows microglia to internalize tau and mapped the control points that determine whether microglia successfully destroy it or release it back into the brain. These discoveries have reshaped our understanding of AD and revealed that microglia are key players in disease progression. In preliminary work, Dr. Hopp’s team found that only about one-quarter of microglia take up misfolded tau, suggesting that a distinct subpopulation carries out this function. They also discovered that this subpopulation expresses a unique set of genes linked to endocytosis (the process by which microglia engulf tau), stress in the cell’s recycling centers (lysosomes), and migration. These changes suggest that when microglia ingest too much tau, their ability to properly digest it breaks down, leading them to release inflammatory signals and possibly spread tau instead of clearing it. Additional experiments confirmed this pattern: early on, microglia reduced tau buildup, but over time, stress in their lysosomes caused them to release tau “seeds” that could spread pathology further. The team also discovered that the receptor LRP1 is essential for tau uptake—removing LRP1 sharply reduced the amount of tau internalized by microglia. Taken together, these findings suggest that while microglia initially help protect the brain by clearing tau, prolonged stress or genetic vulnerabilities can flip that protective process into one that worsens the disease. Dr. Hopp will test the hypothesis that microglial uptake of tau is a key mechanism driving its spread through the brain, and that specific molecular pathways determine whether this process protects or harms neurons.
To investigate this, the team will pursue three complementary aims. In the first aim, they will identify what makes certain microglia more likely to engulf tau than others. Using advanced gene-expression mapping, human stem-cell-derived microglia, and postmortem AD brain tissue, they will define the distinct “fingerprint” of these tau-engulfing cells. This will help reveal which cellular features or environmental cues push microglia toward this specialized role. In the second aim, they will study how microglia shift from being tau cleaners to tau spreaders. The team will focus on two processes: microglial migration and the lysosomal system to pinpoint when and how the protective roles of microglia break down. Understanding this transition could uncover new intervention points to preserve healthy microglial function. In the third aim, they will test whether tau uptake through LRP1 is essential for disease progression. Using mice engineered to have microglia that lack LRP1, they will determine whether blocking this pathway slows or prevents the spread of tau across connected brain regions.
Together, these studies will clarify whether microglia act as barriers or accelerators in the cascade of AD. By identifying the molecular switches that control this process, Dr. Hopp’s work could open the door to new treatments aimed at keeping microglia in their protective mode—clearing toxic proteins rather than helping them spread.
