The document discusses several unanswered questions about amyloid beta (Aβ) oligomers, which are assemblies of Aβ peptides implicated in Alzheimer's disease. Some key unanswered questions mentioned include what the relationship is between different oligomeric forms, if all dimers and trimers are the same, and if the size or structure of oligomers correlates with their toxicity. The document also lists several unquestioned answers, such as that naturally occurring oligomers derived from cells or brain tissue may not be fully natural, and that stabilizing oligomers with certain inhibitors can still protect against toxicity. Overall, the document examines open issues and challenges in characterizing different Aβ oligomer species and understanding their role in Alzheimer's disease pathogenesis.

1. Un
answered
questions
Aβ Oligomers &
Hilal A. Lashuel
Un
Swiss Federal Institute of Technology-Lausanne
Brain Mind Institute
Laboratory of Molecular and Chemical Biology of Neurodegeneration questioned
answers
http://lashuel-lab.epfl.ch/

2. Unanswered Questions
• What is the relationship between the different oligomeric forms of Aβ, which
are on- and off-pathway and does it matter?
• Are all dimers, trimers, dodecamers the same?
• Does the size of the oligomer matter if we can’t measure it accurately?
• Can we correlate size and structure to toxicity if the structure and aggregation
states of the oligomers are dynamic and changing during the time of the
experiment?
• Could the difference in activity between synthetic and cell-derived oligomers
be simply due to the kinetic stability of the oligomers formed in these
preparations, SDS-Dimer are more stable?
– Can we compare synthetic, secreted or brain-derived oligomers if these samples are characterized
by different level of complexity and molecular environments.
H. Lashuel, http://lashuel-lab.epfl.ch/

3. Unquestioned answers
• Natural Oligomers: How natural are natural oligomers?
Cell-derived, Brain-derived Oligomers.
• SDS-Stable oligomers: Why are these oligomers so stable?
Are these species “covalently linked oligomers”?
To what extent do covalent oligomers (e.g. disulfide-linked) oligomers mimic “natural oligomers”?
• SDS-Stable Oligomers are the building block of amyloid fibrils in vivo and are
the early mediators of neuronal dysfunction.
• Quaternary structure and Conformational antibodies: Is it possible to develop
conformational and species (dimer or trimer) specific antibodies using heterogeneous
and unstable mixtures of oligomers as antigens?
e.g. ADDLS are dodecamers???
• Some oligomer species are more relevant to AD pathogenesis than others…
What is the evidence that one oligomeric species is more toxic or correlate with
disease progression than other? LACK of comparative studies. WHY?
– Synthetic vs. Natural
– Dimers vs. Trimers, Aβ*56, ADDLS or Protofibrils
• Several inhibitors of Aβ fibrillization act by stabilizing oligomeric forms of Aβ,
yet these molecules protect against Aβ toxicity.
H. Lashuel, http://lashuel-lab.epfl.ch/

4. What about the Process of fibrillization?
Wogulis M. et al
J Neurosci, 2005
Jan A. et al
J. Biol. Chem, 2010
Jan A. et al
J. Biol. Chem, 2008
Kuperstein I. et al
EMBO Journ, 2010
H. Lashuel, http://lashuel-lab.epfl.ch/

5. What can we improve?
• It is not always about Aβ
• Self-criticism
• Honest and open discussion and debate about data
(communicate and negative results)
• More Comparative studies
• Sharing and exchange of reagents
• Consensus on expreimental standards and terminology
• More collaborations (interdisciplinary), especially to tackle very difficult and
technically challenging questions.
• Develop better Tools: Proactive recruitment and collaboration of experts from other
fields
• Private Foundations and Funding Agencies could play a more active role to
foster and facilitate these interactions.
H. Lashuel, http://lashuel-lab.epfl.ch/