Modification of Amyloid-β_1-42 Fibril Structure by Methionine-35 Oxidation

Article type: Research Article

Authors: Hou, Liming^{a; 1} | Lee, Hyoung-gon^{b; 1} | Han, Fang^c | Tedesco, Johnathan M.^d | Perry, George^{b; e} | Smith, Mark A.^{b; 2} | Zagorski, Michael G.^{c; *}

Affiliations: [a] Abbott Vascular Inc., Menlo Park, CA, USA | [b] Department of Pathology, Case Western Reserve University, Cleveland, OH, USA | [c] Department of Chemistry, Case Western Reserve University, Cleveland, OH, USA | [d] Department of Chemistry, Lake Erie College, Painesville, OH, USA | [e] College of Sciences, University of Texas at San Antonio, San Antonio, TX, USA

Correspondence: [*] Correspondence to: Michael G. Zagorski, Ph.D., Department of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106-7078, USA. Tel.: +1 216 368 3706; Fax: +1 216 368 3006; E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

Note: [2] Deceased.

Abstract: Oxidative stress and amyloid-β (Aβ) formation are important processes that occur in Alzheimer's disease (AD). Amyloid formation is associated with the aggregation and precipitation of the Aβ peptide, while oxidative stress results from an imbalance in pro-oxidant/antioxidant homeostasis that produces harmful reactive oxygen species. The methionine-35 (Met35) residue of the Aβ peptide plays an important role in AD oxidative stress events and the associated neurotoxicity. We and other research groups previously demonstrated that in vitro oxidation of the Met35 side-chain to the sulfoxide (Met35red → Met35ox) impedes assembly and aggregation of monomeric Aβ peptide into protofibrils, the latter being the immediate precursors of amyloid plaques. Here, we report that Met35 oxidation state affects the stability of preexisting amyloid fibrils and plaques, where the Met35red → Met35ox process leads to changes in the morphology of filaments, protofibrils, mature fibrils, and loss of Congo red birefringence in senile plaques isolated from the brains of AD patients. The most notable differences were in fibril flexibility, as evidenced by changes from straight fibrils to irregularly shaped, rope-like fibrils. These findings suggest that the Met35 oxidation state and amyloid plaque formation may be intimately linked.

Keywords: Alzheimer's disease, amyloid-β, atomic force microscopy, fibrillization, oxidative stress

DOI: 10.3233/JAD-122389

Journal: Journal of Alzheimer's Disease, vol. 37, no. 1, pp. 9-18, 2013