ApoE Isoforms Inhibit Amyloid Aggregation of Proinflammatory Protein S100A9

Author:

Ghosh Shamasree1,Tamilselvi Shanmugam1ORCID,Williams Chloe2,Jayaweera Sanduni W.3,Iashchishyn Igor A.1,Šulskis Darius4ORCID,Gilthorpe Jonathan D.2ORCID,Olofsson Anders3ORCID,Smirnovas Vytautas4ORCID,Svedružić Željko M.5,Morozova-Roche Ludmilla A.1ORCID

Affiliation:

1. Department of Medical Biochemistry and Biophysics, Umeå University, SE-90187 Umeå, Sweden

2. Department of Medical and Translational Biology, Umeå University, SE-90187 Umeå, Sweden

3. Department of Clinical Microbiology, Umeå University, SE-90187 Umeå, Sweden

4. Institute of Biotechnology, Life Sciences Center, Vilnius University, LT-10257 Vilnius, Lithuania

5. Department of Biotechnology, University of Rijeka, HR-51000 Rijeka, Croatia

Abstract

Increasing evidence suggests that the calcium-binding and proinflammatory protein S100A9 is an important player in neuroinflammation-mediated Alzheimer’s disease (AD). The amyloid co-aggregation of S100A9 with amyloid-β (Aβ) is an important hallmark of this pathology. Apolipoprotein E (ApoE) is also known to be one of the important genetic risk factors of AD. ApoE primarily exists in three isoforms, ApoE2 (Cys112/Cys158), ApoE3 (Cys112/Arg158), and ApoE4 (Arg112/Arg158). Even though the difference lies in just two amino acid residues, ApoE isoforms produce differential effects on the neuroinflammation and activation of the microglial state in AD. Here, we aim to understand the effect of the ApoE isoforms on the amyloid aggregation of S100A9. We found that both ApoE3 and ApoE4 suppress the aggregation of S100A9 in a concentration-dependent manner, even at sub-stoichiometric ratios compared to S100A9. These interactions lead to a reduction in the quantity and length of S100A9 fibrils. The inhibitory effect is more pronounced if ApoE isoforms are added in the lipid-free state versus lipidated ApoE. We found that, upon prolonged incubation, S100A9 and ApoE form low molecular weight complexes with stochiometric ratios of 1:1 and 2:1, which remain stable under SDS-gel conditions. These complexes self-assemble also under the native conditions; however, their interactions are transient, as revealed by glutaraldehyde cross-linking experiments and molecular dynamics (MD) simulation. MD simulation demonstrated that the lipid-binding C-terminal domain of ApoE and the second EF-hand calcium-binding motif of S100A9 are involved in these interactions. We found that amyloids of S100A9 are cytotoxic to neuroblastoma cells, and the presence of either ApoE isoforms does not change the level of their cytotoxicity. A significant inhibitory effect produced by both ApoE isoforms on S100A9 amyloid aggregation can modulate the amyloid-neuroinflammatory cascade in AD.

Funder

Swedish Medical Research Council

Faculty of Medicine, Umeå University

Insamlingsstiftelsen

Research Council of Lithuania

Kempe foundation

Åhlensfonden

Alzheimerfonden

Norrländska hjärtfonden

Söderbergs stiftelse

Hjärt-lungfonden

FAMY

European Fund for Regional Development

Ministry of Science and Education of the Republic of Croatia

Publisher

MDPI AG

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