A researcher at the Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases at UT Health San Antonio has received a $402,500 grant from the Cure Alzheimer's Fund. The two-year grant will support research into how microglia, which are immune cells in the brain, may play a role in spreading toxic tau proteins associated with Alzheimer’s disease.
Sarah C. Hopp, PhD, an associate professor of pharmacology at the Biggs Institute and the South Texas Alzheimer's Disease Research Center, is leading the study. Her laboratory has previously contributed to understanding how microglia behave in the brain. The research will investigate whether microglial uptake of tau is a primary mechanism that drives its spread throughout the brain and whether certain molecular pathways determine if this process protects or harms neurons.
The Cure Alzheimer's Fund is a nonprofit organization that supports research "with the highest probability of preventing, slowing or reversing Alzheimer's disease."
According to a paper on the CureAlz website describing Hopp's upcoming study, "While tau aggregates are a defining feature of Alzheimer's disease and closely track with brain cell loss, memory problems and cognitive decline, much still isn't known about how it spreads or what role the brain's immune system plays in the process."
There is evidence that toxic forms of tau can cause healthy tau proteins to misfold as well. "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," according to the paper. "Microglia … 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."
Hopp’s team has identified cellular mechanisms that allow microglia to internalize tau and mapped points controlling whether microglia destroy it or release it back into the brain. Only about one-quarter of microglia take up misfolded tau. This subpopulation shows unique gene expression related to endocytosis (engulfing tau), stress within lysosomes (cell recycling centers), and migration.
These changes indicate that when microglia ingest too much tau, their ability to digest it declines. As a result, they may release inflammatory signals and possibly spread tau rather than clear it.
Further experiments showed that while microglia initially reduced tau buildup, ongoing stress caused them to release “seeds” of tau capable of spreading pathology further.
The team also found that LRP1 (low-density lipoprotein receptor-related protein 1) is crucial for taking up tau; removing LRP1 sharply decreased how much tau was internalized by microglia.
The findings suggest that although microglia help protect against Alzheimer’s early on by clearing toxic proteins like tau, continued stress or genetic factors could turn this protective function into one that worsens disease progression.
Hopp's group plans three complementary aims in their new study.
"Together, these studies will clarify whether microglia act as barriers or accelerators in the cascade of Alzheimer's disease," according to the paper. "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."
