Báo cáo khoa học: Lysophosphatidylcholine modulates fibril formation of amyloid beta peptide doc

Lysophosphatidylcholine modulates fibril formation of

amyloid beta peptide

Abdullah Md. Sheikh and Atsushi Nagai

Department of Laboratory Medicine, Shimane University School of Medicine, Izumo, Japan

Introduction

Alzheimer’s disease (AD) is a neurodegenerative

disorder that is manifested clinically as progressive

dementia. Histopathologically, it is characterized by

degenerative changes in the neurons, together with

intra-neuronal deposition of hyperphosphorylated Tau

and extracellular accumulation of peptides comprising

39–43 amino acids, called amyloid beta (Ab) peptides,

which are generated by secretase-mediated cleavage of

transmembrane amyloid precursor protein [1]. Bio￾chemical analysis of the Ab peptides isolated from AD

Keywords

Alzheimer’s disease; amyloid beta peptide;

fibril formation; lysophosphatidylcholine;

phospholipid–Ab interaction

Correspondence

A. Nagai, Department of Laboratory

Medicine, Shimane University Faculty of

Medicine, 89-1 Enya-cho, Izumo 693-8501,

Japan

Tel ⁄ Fax: +81 853 20 2312

E-mail: [email protected]

(Received 14 July 2010, revised 29 Novem￾ber 2010, accepted 6 December 2010)

doi:10.1111/j.1742-4658.2010.07984.x

Phospholipids are known to influence fibril formation of amyloid beta (Ab)

peptide. Here, we show that lysophosphatidylcholine (LPC), a polar phos￾pholipid, enhances Ab(1-42) fibril formation, by decreasing the lag time

and the critical peptide concentration required for fibril formation, and

increasing the fibril elongation rate. Conversely, LPC did not have an

enhancing effect on Ab(1-40) fibril formation, and appeared to be inhibi￾tory. Tyrosine fluorescence spectroscopy showed that LPC altered the

fluorescence spectra of Ab(1-40) and Ab(1-42) in opposite ways. Further,

8-anilino-1-naphthalene sulfonic acid fluorescence spectroscopy showed

that LPC significantly increased the hydrophobicity of Ab(1-42), but not of

Ab(1-40). Tris-tricine gradient SDS ⁄PAGE revealed that LPC increased the

formation of higher-molecular-weight species of Ab(1-42), including trimers

and tetramers. LPC had no such effect on Ab(1-40), and thus may specifi￾cally influence the oligomerization and nucleation processes of Ab(1-42) in

a manner dependent on its native structure. Dot-blot assays confirmed that

LPC induced Ab(1-42) oligomer formation at an early time point. Thus

our results indicate that LPC specifically enhances the formation of Ab(1-

42) fibrils, the main component of senile plaques in Alzheimer’s disease

patients, and may be involved in Alzheimer’s disease pathology.

Structured digital abstract

l MINT-8077403: A beta (1-42) (uniprotkb:P05067) and A beta (1-42) (uniprotkb:P05067)

bind (MI:0407) by electron microscopy (MI:0040)

l MINT-8077463: A beta (1-42) (uniprotkb:P05067) and A beta (1-42) (uniprotkb:P05067)

bind (MI:0407) by filter binding (MI:0049)

l MINT-8077369, MINT-8077387: A beta (1-42) (uniprotkb:P05067) and A beta (1-42) (uni￾protkb:P05067) bind (MI:0407) by fluorescence technology (MI:0051)

l MINT-8077417, MINT-8077428, MINT-8077436, MINT-8077448: A beta (1-40) (uni￾protkb:P05067) and A beta (1-40) (uniprotkb:P05067) bind (MI:0407) by comigration in sds

page (MI:0808)

Abbreviations

Ab, amyloid beta peptide; AD, Alzheimer’s disease; LPC, lysophosphatidylcholine; ThT, thioflavin T.

634 FEBS Journal 278 (2011) 634–642 ª 2011 The Authors Journal compilation ª 2011 FEBS