Báo cáo khoa học: Amyloid oligomers: spectroscopic characterization of amyloidogenic protein states

MINIREVIEW

Amyloid oligomers: spectroscopic characterization of

amyloidogenic protein states

Mikael Lindgren1 and Per Hammarstro¨ m2

1 Department of Physics, Norwegian University of Science and Technology, Trondheim, Norway

2 IFM-Department of Chemistry, Linko¨ping University, Linko¨ping, Sweden

Introduction

Amyloidosis manifests itself through the extracellular

deposition of insoluble protein fibrils, leading to tissue

damage and disease. The fibrils form when normally

soluble proteins and peptides misfold and self-associate

in an abnormal manner [1]. The mechanisms behind

the self-assembly of naturally occurring proteins into

Keywords

amyloid proteins; fluorescence

spectroscopy; oligomeric amyloid state;

prefibrillar intermediate state; real-time

detection

Correspondence

M. Lindgren, Department of Physics,

Norwegian University of Science and

Technology, Trondheim, Norway

Fax: +47 73597710

Tel: +47 73593414

E-mail: [email protected]

(Received 4 September 2009, revised

14 December 2009, accepted 7 January

2010)

doi:10.1111/j.1742-4658.2010.07571.x

It is assumed that protein fibrils manifested in amyloidosis result from an

aggregation reaction involving small misfolded protein sequences being

in an ‘oligomeric’ or ‘prefibrillar’ state. This review covers recent optical

spectroscopic studies of amyloid protein misfolding, oligomerization and

amyloid fibril growth. Although amyloid fibrils have been studied using

established protein-characterization techniques throughout the years, their

oligomeric precursor states require sensitive detection in real-time. Here,

fluorescent staining is commonly performed using thioflavin T and other

small fluorescent molecules such as 4-(dicyanovinyl)- julolidine and

1-amino-8-naphtalene sulphonate that have high affinity to hydrophobic

patches. Thus, populated oligomeric intermediates and related ‘prefibrillar

structures’ have been reported for several human amyloidogenic systems,

including amyloid-beta protein, prion protein, transthyretin, a-synuclein,

apolipoprotein C-II and insulin. To obtain information on the progression

of the intermediate states, these were monitored in terms of fluorescence

parameters, such as anisotropy, and quantum efficiency changes upon

protein binding. Recently, new antibody stains have allowed precise moni￾toring of the oligomer size and distributions using multicolor labelling and

single molecule detection. Moreover, a pentameric thiophene derivative

(p-FTAA) was reported to indicate early precursors during A-beta1-40

fibrillation, and was also demonstrated in real-time visualization of cerebral

protein aggregates in transgenic AD mouse models by multiphoton micros￾copy. Conclusively, molecular probes and optical spectroscopy are now

entering a phase enabling the in vivo interrogation of the role of oligomers

in amyloidosis. Such techniques used in parallel with in vitro experiments,

of increasing detail, will probably couple structure to pathogenesis in the

near future.

Abbreviations

AD, Alzheimer’s disease; ANS, 1-amino-8-naphthalene sulfonate; DCVJ, (4-(dicyanovinyl)-julolidine); LCO, oligomeric LCPs; LCP,

luminescent-conjugated polymers; p-FTAA, pentameric thiophene derivative; ThT, thioflavin T; TTR, transthyretin.

1380 FEBS Journal 277 (2010) 1380–1388 ª 2010 The Authors Journal compilation ª 2010 FEBS