Intreactions between apolipoprotein e, tau protein, and 3-o-sulfated heparan sulfate: implications for alzheimer's disease pathogenesis
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Authors
Mah, Dylan, James
Issue Date
2024-01
Type
Electronic thesis
Thesis
Thesis
Language
en_US
Keywords
Biology
Alternative Title
Abstract
Alzheimer’s Disease (AD) is a neurodegenerative disease characterized by progressive and irreversible decline in memory and cognitive function. It is the leading cause of dementia and the 7th most prevalent cause of death in the United States. On a pathological basis, AD is characterized by the accumulation of proteinaceous inclusions within and surrounding the cells of the brain: plaques composed of amyloid β peptide, and neurofibrillary tangles (NFTs) within neurons composed of microtubule binding protein tau.Of these two hallmarks, the extent of tau NFT pathology is more predictive of AD progression and dementia symptoms compared to amyloid β. Tau pathology propagates in a prion like mechanism, whereby misfolded tau seeds propagate between cells and induce misfolding of endogenous tau protein. This process is mediated by an uptake pathway involving 3-O-sulfated (3-O-S) cell surface heparan sulfate proteoglycans (HSPGs) and the LRP1 receptor.
Intriguingly, HSPGs and LRP1 are also known to be utilized by Apolipoprotein E (ApoE), an important lipid transport protein whose gene (APOE) is the most significant risk factor for late onset Alzheimer’s Disease. In these studies, we present the results of investigations into the heparan sulfate (HS) binding behavior of ApoE and its competition with tau protein, underlying the important role of 3-O-S in Alzheimer’s Disease.
Utilizing a variety of biophysics and cell-based techniques, we demonstrated that ApoE binds preferentially to 3-O-S heparan sulfate, an interaction it shares with tau. Going further, we show via competition Surface Plasmon Resonance (SPR), Nuclear Magnetic Resonance (NMR) titrations, and Sedimentation Velocity Ultracentrifugation (SV-AUC) that ApoE and tau compete for binding to heparin and HS rather than forming a ternary complex.
Taken together with other recent developments in our understanding of tau pathology and its interplay with ApoE, this dissertation’s findings have significant implications for the role of ApoE in influencing AD pathogenesis and point to potentially novel avenues of AD drug and biomarker development.
Description
January2024
School of Science
School of Science
Full Citation
Publisher
Rensselaer Polytechnic Institute, Troy, NY