Tau, heparan sulfate, and cyclophilin a interactions in alzheimer's disease
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Authors
Murray, Anqesha
Issue Date
2024-08
Type
Electronic thesis
Thesis
Thesis
Language
en_US
Keywords
Biology
Alternative Title
Abstract
In Alzheimer’s disease (AD), tau aggregates form neurofibrillary tangles (NFT), a pathological hallmark of AD. Tau pathology is known to spread in a prion-like manner mediated by tau binding to the cell-surface glycan heparan sulfate (HS), expressed by multiple cell types, including microglia. Tau also interacts with the abundant immunophilin and proline isomerase protein Cyclophilin A (CypA). However, the molecular details of tau−CypA and tau-HS interaction are poorly understood, especially in the context of microglia. Using a multidisciplinary approach, we characterized the interaction between heparan sulfate and tau. We show that tau's proline-rich region 2 (PRR2) domain plays an important role in tau-HS interaction by NMR and SPR. In addition, we characterized various HS analogs for their ability to disrupt tau-HS interaction and inhibit tau uptake in HMC3 microglial cells. Among the analogs, MPS, PPS (semi-synthetic), RPI-27, RPI-28, and RS (marine sulfated polysaccharides) disrupt tau-heparin interaction and cellular uptake in microglia. We further studied the interaction between PRR2 and CypA. Using SPR and NMR, we showed that tau can bind to CypA with nM affinity, and the PPR2 region interacts with CypA with 10 M affinity. CypA can catalyze proline isomerization in PPR2, specifically recognizing regions near P247 and P249 in PRR2. We demonstrated for the first time that HMC3 naturally expresses CypA and produces intracellular reactive oxygen species in response to CypA inhibition and tau uptake. and Our results deepened our understanding of tau, HS, and CypA interaction, which may contribute to the development of novel AD therapeutics.
Description
August2024
School of Science
School of Science
Full Citation
Publisher
Rensselaer Polytechnic Institute, Troy, NY