Oligomeric Intermediates in Amyloid Formation: Structure Determination and Mechanisms of Toxicity

Marcus Fändrich

doi:10.1016/j.jmb.2012.01.006

R

EVIEW

Oligomeric Intermediates in Amyloid Formation:

Structure Determination and Mechanisms of Toxicity

Marcus Fändrich

Max-Planck Research Unit for Enzymology of Protein Folding and Martin Luther University Halle-Wittenberg,

Weinbergweg 22, 01620 Halle (Saale), Germany

Received 28 November 2011;

received in revised form

3 January 2012;

accepted 5 January 2012

Available online

12 January 2012

Edited by S. Radford

Keywords:

amyloid;

protein folding disease;

oligomer;

intermediate;

structure

Oligomeric intermediates are non-fibrillar polypeptide assemblies that

occur during amyloid fibril formation and that are thought to underlie the

aetiology of amyloid diseases, such as Alzheimer's disease, Parkinson's

disease and Huntington's disease. Focusing primarily on the oligomeric

states formed from Alzheimer's disease β-amyloid (Aβ) peptide, this review

will make references to other polypeptide systems, highlighting common

principles or sequence-specific differences. The covered topics include the

structural properties and polymorphism of oligomers, the biophysical

mechanism of peptide self-assembly and its role for pathogenicity in

amyloid disease. Oligomer-dependent toxicity mechanisms will be

explained along with recently emerging possibilities of interference.

Intermediates in Amyloid Fibril Formation

The formation of amyloid fibrils is a molecular

self-assembly reaction that involves the transient

stabilization of a range of differently structured

intermediates.

1

Interest in these states was strongly

fuelled by data demonstrating their role as patho-

genic agents in several neurodegenerative dis-

orders.

2

Different classes of amyloid intermediates

have been identified, including oligomers, proto-

fibrils and annular aggregates.

2–4

Each class prob-

ably represents a group of states and comprises

multiple subspecies. A plethora of additional terms

have been coined to account for this diversity. For

instance, Aβ peptide forms structures including

paranuclei, globulomers, Aβ⁎56 and Aβ-derived

diffusible ligands.

5

This peptide also represents one

of the most intensively examined amyloidogenic

systems. Therefore, a significant proportion of this

overview will be dedicated to this peptide and its

structural intermediates, but comparisons will be

made with other polypeptide systems to highlight

important analogies or differences. Initially, this

review will outline the structural specifics of the

different classes of intermediates and mature fibrils,

before closing up with their biological properties

and currently pursued strategies of interference.

Structure of Mature Amyloid Fibrils

Mature amyloid fibrils are the terminal stage of

the fibrillogenic pathway.

1,4

They possess a long,

E-mail address: fandrich@enzyme-halle.mpg.de.

Abbreviations used: AD, Alzheimer's disease; PD,

Parkinson's disease; CR, Congo red; ThT, thioflavin T; EM,

electron microscopy; FCS, fluorescence correlation

spectroscopy; ANS, 1-anilino-8-naphthalene sulfonate;

MD, molecular dynamics; ROS, reactive oxygen species;

MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-

diphenyltetrazolium bromide; LTP, long-term

potentiation; NMDA, N-methyl

D-

aspartate.

doi:10.1016/j.jmb.2012.01.006 J. Mol. Biol. (2012) 421, 427–440

Contents lists available at www.sciencedirect.com

Journal of Molecular Biology

journal homepage: http://ees.elsevier.com.jmb

Oligomeric Intermediates in Amyloid Formation: Structure Determination and Mechanisms of Toxicity

Fändrich, Marcus

Follow Journal of Molecular Biology , Volume 421 (4) Elsevier – Aug 24, 2012