A researcher with the Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases at UT Health San Antonio has received a two-year, $402,500 grant award from the Cure Alzheimer’s Fund to study how microglia, the brain’s resident immune cells, paradoxically might contribute to the spread of toxic forms of tau protein in the disease.<\/p>\n
Sarah C. Hopp, PhD, associate professor of pharmacology with the Biggs Institute and the South Texas Alzheimer’s Disease Research Center, along with her lab have been instrumental in uncovering the behavior of microglia. UT Health San Antonio is the academic health center of The University of Texas at San Antonio.<\/p>\n
Starting this month, Hopp’s lab will test the hypothesis that microglial uptake of tau is a key mechanism driving its spread through the brain, and that specific molecular pathways\u00a0determine\u00a0whether this process protects or harms neurons. The Cure Alzheimer’s Fund, also known as CureAlz, is a nonprofit organization that funds research “with the highest probability of preventing, slowing or reversing Alzheimer’s disease.”<\/p>\n
A paper describing Hopp’s upcoming study published on the CureAlz website, titled, “How Do Microglia Contribute to the Spread of Tau Pathology in Alzheimer’s Disease?”, says that 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.<\/p>\n
There is evidence, it says, that toxic forms of tau, which have become “misfolded” or dysfunctional, act like a “bad influence.”<\/p>\n
“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 \u2026 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.”<\/p>\n
Stressed microglia can release toxins<\/p>\n
The paper notes that Hopp’s team already has identified the cellular machinery that allows microglia to internalize tau and mapped the control points that\u00a0determine\u00a0whether microglia successfully\u00a0destroy it or\u00a0release\u00a0it back into the brain \u2013 finding that only about one-quarter of microglia take up misfolded tau.<\/p>\n
The team also has 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.<\/p>\n
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\u00a0possibly spread\u00a0tau instead of clearing it, the paper says.<\/p>\n
Additional\u00a0experiments 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.<\/p>\n
The team also has discovered that the receptor LRP1 (for low-density lipoprotein receptor-related protein 1) is essential\u00a0for tau\u00a0uptake, because removing LRP1 sharply reduced the amount of tau internalized by microglia.<\/p>\n
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, the paper says.<\/p>\n
The Hopp team’s new mission<\/p>\n
Hopp’s team will pursue three complementary\u00a0aims:<\/p>\n
\n\tIdentify\u00a0what makes certain microglia more likely to engulf tau than others \u2013 Using advanced gene-expression mapping, human stem-cell-derived microglia and postmortem Alzheimer’s disease 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.
\n\tStudy how microglia shift from being tau cleaners to tau spreaders \u2013 The team will focus on two processes: microglial migration and the lysosomal or recycling 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.
\n\tTest whether tau\u00a0uptake through receptor LRP1 is essential for disease progression \u2013 Using mice engineered to have microglia that lack LRP1, they will\u00a0determine\u00a0whether blocking this pathway slows or prevents the spread of tau across connected brain regions.\u00a0
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“Together, these studies will clarify whether microglia act as barriers or accelerators in the cascade of Alzheimer’s disease,” the paper concludes. “By\u00a0identifying\u00a0the 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 \u2013 clearing toxic proteins rather than helping them spread.<\/p>\n
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