Heparan Sulfate Proteoglycans (HSPGs) Serve as the Mediator Between Monomeric Tau...

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Heparan Sulfate Proteoglycans (HSPGs) Serve as the Mediator Between Monomeric Tau and Its Subsequent Intracellular ERK1/2 Pathway Activation

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FROM: https://medicalxpress.com/news/2022-...er-longer.html A cure for Alzheimer's is taking longer than expected; here's why by Carnegie Mellon University, Department of Chemical Engineering (2022-01-21) In her latest research paper, published in the Journal of Molecular Neuroscience, Anne Robinson, Head of Carnegie Mellon's Department of Chemical Engineering, explains why understanding the progression of neurodegeneration in Alzheimer's disease, and its eventual treatment, is much more complex than researchers have previously thought. One in ten Americans over the age of 65 suffer from Alzheimer's, rising to one in three in those over 80. It is the sixth-leading cause of death in the United States, and more than five million people currently live with the disease. Worldwide, that number jumps to nearly 50 million. Age is the most significant factor in whether a person shows symptoms of Alzheimer's, and although diagnostic information to confirm the disease is improving, there are still no cures or treatments to slow down or stop the progression of the disease. In all neurodegenerative diseases, degeneration begins in one part of the brain and is transmitted to other areas, causing widespread damage and loss of brain tissue. In Alzheimer's, several things, such as the presence of A-beta peptide or an injury, can cause tau—a protein in neurons responsible for stabilizing those neurons—to begin shaping itself in dysfunctional ways; the first in a cascade of events. Scientists, however, are still unsure of how this pathogenic tau is transferred from cell to cell, thus spreading across the brain and wreaking havoc. Understanding how to contain the disease to a small area of the brain could help slow its progression and halt the cognitive degeneration associated with Alzheimer's. "There have been a number of Alzheimer's models that try to explain how malformed tau gets transmitted from one part of the brain to the other," says Robinson. "Many of these models approach the problem from an all-or-nothing standpoint—normal tau protein only goes this way; malformed tau protein only goes that way, or malformed tau enters the cell this way; normal tau another way. However, operating under these models has historically produced seemingly conflicting data; data that researchers who study Alzheimer's have been hard-pressed to reconcile." (SNIP)

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Original Paper:

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FROM: https://link.springer.com/article/10...31-021-01943-2 Heparan Sulfate Proteoglycans (HSPGs) Serve as the Mediator Between Monomeric Tau and Its Subsequent Intracellular ERK1/2 Pathway Activation Liqing Song, Daniel E. Oseid, Evan A. Wells, Troy Coaston & Anne S. Robinson Journal of Molecular Neuroscience (2022-01-18) Abstract The conversion of soluble tau protein to insoluble, hyperphosphorylated neurofibrillary tangles (NFTs) is a major hallmark leading to neuronal death observed in neurodegenerative tauopathies. Unlike NFTs, the involvement of monomeric tau in the progression of tau pathology has been less investigated. Using live-cell confocal microscopy and flow cytometry, we demonstrate that soluble 0N4R monomers were rapidly endocytosed by SH-SY5Y and C6 glioma cells via actin-dependent macropinocytosis. Further, cellular endocytosis of monomeric tau has been demonstrated to be HSPG-dependent, as shown in C6 glial cells with genetic knockouts of xylosyltransferase-1—a key enzyme in HSPG synthesis—with a reduced level of tau uptake. Tau internalization subsequently triggers ERK1/2 activation and therefore, the upregulation of IL-6 and IL-1β. The role of ERK1/2 in regulating the levels of pro-inflammatory gene transcripts was confirmed by inhibiting the MEK-ERK1/2 signaling pathway, which led to the attenuated IL-6 and IL-1β expressions but not that of TNF-α. Moreover, as a key regulator of tau internalization, LRP1 (low-density lipoprotein receptor-related protein 1) levels were downregulated in response to monomeric tau added to C6 cells, while it was upregulated in HSPG-deficient cells, suggesting that the involvement of LRP1 in tau uptake depends on the presence of HSPGs on the cell surface. The subsequent LRP1 knockdown experiment we performed shows that LRP1 deficiency leads to an attenuated propensity for tau uptake and further elevated IL-6 gene expression. Collectively, our data suggest that tau has multiple extracellular binding partners that mediate its internalization through distinct mechanisms. Additionally, this study demonstrates the important role of both HSPGs and LRP1 in regulating cellular immune responses to tau protein monomers, providing a novel target for alleviating the neuroinflammatory environment before the formation of neurofibrillary tangles. (SNIP)

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