TY - JOUR
T1 - Tau Fibrillation Induced by Heparin or a Lysophospholipid Show Different Initial Oligomer Formation
AU - Rasmussen, Helena Østergaard
AU - Nielsen, Janni
AU - de Poli, Angela
AU - Otzen, Daniel E.
AU - Pedersen, Jan Skov
N1 - Publisher Copyright:
© 2023 The Author(s)
PY - 2023/9
Y1 - 2023/9
N2 - The protein tau is involved in several neurogenerative diseases such as Alzheimer's Disease, where tau content and fibrillation have been linked to disease progression. Tau colocalizes with phospholipids and glycosaminoglycans in vivo. We investigated if and how tau fibrillation can be induced by two lysophospholipids, namely the zwitterionic 1-myristoyl-2-hydroxy-sn-glycero-3-phosphocholine (LPC) and the anionic 1-myristoyl-2-hydroxy-sn-glycero-3-phospho-(1′-rac-glycerol) (LPG) as well as the glycosaminoglycan heparin. We used a range of biophysical techniques including small-angle X-ray scattering, Thioflavin T fluorescence, and SDS-PAGE, collecting data at various time points to obtain structural information on each phase of the fibrillation. We find that LPC does not induce fibrillation or interact with tau. Low concentrations of LPG induce fibrillation by formation of small hydrophobic clusters with monomeric tau. At higher LPG concentrations, a core–shell complex is formed where tau wraps around LPG micelles with regions extending away from the micelles. For heparin, loosely associated oligomers are formed rapidly with around ten tau molecules. Fibrils formed with either LPG or heparin show similar final cross-section dimensions. Furthermore, SDS-resistant oligomers are observed for both LPG and heparin. Our study demonstrates that tau fibrillation can be induced by two different biologically relevant cofactors leading to structurally different initial states but similar cross-sectional dimensions for the fibrils. Structural information about initial states prior to fibril formation is important both to gain a better understanding of the onset of fibrillation in vivo, and for the development of targeted drugs that can reduce or abolish tau fibrillation.
AB - The protein tau is involved in several neurogenerative diseases such as Alzheimer's Disease, where tau content and fibrillation have been linked to disease progression. Tau colocalizes with phospholipids and glycosaminoglycans in vivo. We investigated if and how tau fibrillation can be induced by two lysophospholipids, namely the zwitterionic 1-myristoyl-2-hydroxy-sn-glycero-3-phosphocholine (LPC) and the anionic 1-myristoyl-2-hydroxy-sn-glycero-3-phospho-(1′-rac-glycerol) (LPG) as well as the glycosaminoglycan heparin. We used a range of biophysical techniques including small-angle X-ray scattering, Thioflavin T fluorescence, and SDS-PAGE, collecting data at various time points to obtain structural information on each phase of the fibrillation. We find that LPC does not induce fibrillation or interact with tau. Low concentrations of LPG induce fibrillation by formation of small hydrophobic clusters with monomeric tau. At higher LPG concentrations, a core–shell complex is formed where tau wraps around LPG micelles with regions extending away from the micelles. For heparin, loosely associated oligomers are formed rapidly with around ten tau molecules. Fibrils formed with either LPG or heparin show similar final cross-section dimensions. Furthermore, SDS-resistant oligomers are observed for both LPG and heparin. Our study demonstrates that tau fibrillation can be induced by two different biologically relevant cofactors leading to structurally different initial states but similar cross-sectional dimensions for the fibrils. Structural information about initial states prior to fibril formation is important both to gain a better understanding of the onset of fibrillation in vivo, and for the development of targeted drugs that can reduce or abolish tau fibrillation.
KW - amyloidogenesis
KW - core–shell structure
KW - fibrillation mechanism
KW - ITC
KW - SAXS
UR - http://www.scopus.com/inward/record.url?scp=85165059915&partnerID=8YFLogxK
U2 - 10.1016/j.jmb.2023.168194
DO - 10.1016/j.jmb.2023.168194
M3 - Journal article
C2 - 37437877
AN - SCOPUS:85165059915
SN - 0022-2836
VL - 435
JO - Journal of Molecular Biology
JF - Journal of Molecular Biology
IS - 17
M1 - 168194
ER -