When Alzheimer’s Tau Knocks, This Neuron Receptor Opens the Door
Brain cells have no difficulty accommodating normal tau protein. In fact, tau protein maintains structure and stability within neurons, and it helps the transport of nutrients from one part of the cell to another. But abnormal tau protein is an unwelcome guest. By dint of its aberrant folding, abnormal tau forms sticky clumps. Worse, it seems to exert a bad influence on normal tau, which joins in the clumping behavior, preventing neurons from functioning normally or even surviving. So, when abnormal tau comes knocking, why do neurons allow it to enter?
Part of the answer may have been discovered by scientists based at the University of California, Santa Barbara. These scientists, led by neuroscientists Kenneth S. Kosik, MD, have uncovered evidence that the low-density lipoprotein receptor-related protein 1 (LRP1) controls the endocytosis of tau and its subsequent spread.
They presented their findings April 1 in the journal Nature, in an article titled, "LRP1 is a master regulator of tau uptake and spread." From its location on the brain cell membrane, LRP1 participates in several biological processes, including the neuronal uptake of cholesterol, which is used as part of cellular structure. And as Kosik and colleagues discovered, a neuron's LRP1 can also take up tau from the extracellular space, that is, tau that has been released by neighboring cells.
LRP1 is just one of several low-density lipoprotein receptors. It was singled out by process of elimination: By systematically inhibiting the neuronal expression of each of the members of this family via CRISPR interference technology, and then exposing the neurons to tau, the researchers determined that genetic silencing of LRP1 effectively inhibited tau uptake.
"Knockdown of LRP1 significantly reduced tau uptake in H4 neuroglioma cells and in induced pluripotent stem cell-derived neurons," the article's authors wrote. "Furthermore, downregulation of LRP1 in an in vivo mouse model of tau spread was found to effectively reduce the propagation of tau between neurons."
These findings not only shed light on an extensively studied but poorly understood phenomenon—the propagation of tau in neurodegenerative disease—it also hints at a way to control the spread of pathological tau.
"The discovery of a mechanism by which tau transits from cell to cell provides a clue that will open up a deep structural approach to the design of molecules that can prevent tau spread," said Kosik. Digging deeper, Kosik and colleagues found that a stretch of the amino acid lysine residues on the tau protein effectively says to LRP1, "open sesame."
"Since our cellular work showed that tau can interact with the cell-surface receptor LRP1 and that this causes tau's endocytosis, our hypothesis was that if we reduce LRP1 expression in the mice we should reduce the ability for neighboring neurons to take up tau," noted the study's lead author, postdoctoral researcher Jennifer Rauch.
To back their in vitro studies, the researchers injected tau into mice, some of which had their LRP1 genes downregulated by an LRP1 suppressor RNA. The tau proteins were bound by a small string of amino acids to a green fluorescent protein to help the scientists observe tau after it was injected.
"As soon as this construct is in a cell, the amino acid connector gets cut, and the fluorescent protein and tau separate from each other," Kosik explained. What they found was that in the animals with normal LRP1, the tau had a tendency to spread; in the LRP1-suppressed mice, the protein stayed put, greatly reducing the likelihood that it would be taken up and replicated by other, normal neurons. "This is the first time we've seen the complete obliteration of tau spread," he said.
Kosik and colleagues noted that low-density lipoprotein receptors are known to work in conjunction with heparan sulfate proteoglycans (HSPGs) in the uptake of macromolecules. They also explored the potential for cooperation between LRP1 and HSPGs. "This work," the article's authors indicated, "highlights LRP1 as a critical determinant for tau propagation and suggests that interventions along a single pathway or at a single nidus—in which tau, ApoE, and HSPGs operate dynamically in conjunction with LRP1—may remediate both plaque and tangle pathologies."
"[LRP1] is interesting in its own right because it's a little bit like an extracellular trash can," Kosik said. "It doesn't just pick up tau; if there's other rubbish out there, it also picks it up."
"When we reduce LRP1 expression, we see reduced tau spread in the animals," said Rauch, who has previously worked on the role of HSPGs on tau uptake. She pointed out a recent study that included Kosik and graduate student Juliana Acost-Uribe that described a patient with a severe genetic form of early-onset Alzheimer's but was spared getting the disease due to a second mutation that appeared to prevent tau spread. The team is keen to learn how this patient's second mutation might prevent tau spread possibly by interacting with LRP1.
"Next," Rauch said, "we are focusing on trying to decipher the interface of the tau-LRP1 interaction and understand if this could be a druggable target."
Ubigene Biosciences is co-founded by biological academics and elites from China, the United States, and France. We are located in Guangzhou Science City, which serves as a global center for high technology and innovation. Ubigene Biosciences has 1000㎡ office areas and laboratories, involving genome editing, cell biology technology, and zebrafish research. We provide products and services for plasmids, viruses, cells, and zebrafish. We aim to provide customers with better gene-editing tools for cell or animal research.
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