Does the recent concern over several papers about Aβ*56 call into question the association of Alzheimers Disease with any amyloyd beta oligomer forms?

Question

The news item by Charles Piller just published in Science BLOTS ON A FIELD? A neuroscience image sleuth finds signs of fabrication in scores of Alzheimer’s articles, threatening a reigning theory of the disease highlights the recent news and activity around a series of papers discussion Aβ*56, a specific, proposed type of toxic oligomer of amyloid beta or Aβ.

There are questions of image altering and of the veracity of Aβ*56 isolation and measurements, and expressions of concern have been recently added to online versions of a numnber of papers referring to it going back to the 2006 Nature paper A specific amyloid-β protein assembly in the brain impairs memory.

Several drugs developed for treatment of Alzheimers Disease have targeted Aβ.

I'm having difficulty understanding how far the implications of the recent concern reaches. Is it simply the correlation with the particular form Aβ*56 associating with Alzheimers, or is it the connection between any oligomer of Aβ? Does the recent concern over several papers about it call into question the association of Alzheimers Disease with any Amyloyd beta oligomer forms?

Answer 1

Does the recent concern over several papers about Aβ*56 call into question the association of Alzheimers Disease with any amyloyd beta oligomer forms?

From my understanding, no. alzforum.org has many great comments on it, e.g. from David Brody:

In my own group, we tried replicating the Aβ *56 western blots for about a year, without success. We then moved on to other things.

Our later work on soluble Aβ aggregates/oligomers from human brain tissue indicated that they are considerably larger than Aβ *56 (Esparza et al., 2013; Esparza et al., 2016).

I think these larger soluble Aβ aggregates/oligomers may still be important potential therapeutic targets, but not Aβ *56.

The strongest evidence comes from the labs of Dennis Selkoe and Dominic Walsh.

References:

• Esparza TJ, Zhao H, Cirrito JR, Cairns NJ, Bateman RJ, Holtzman DM, Brody DL. Amyloid-β oligomerization in Alzheimer dementia versus high-pathology controls. Ann Neurol. 2013 Jan;73(1):104-19. PubMed.
• Esparza TJ, Wildburger NC, Jiang H, Gangolli M, Cairns NJ, Bateman RJ, Brody DL. Soluble Amyloid-beta Aggregates from Human Alzheimer's Disease Brains. Sci Rep. 2016 Dec 5;6:38187. PubMed.

or from Thomas Bayer:

In my view, Aβ-amyloid oligomers are valuable and realistic drug targets. However, not all Aβ oligomers described in in vivo or in vitro model systems do exist in human brain. Besides full-length Aβ, N-truncated Aβ peptides, pyroglutamate Aβ 3-42 and Aβ 4-42 represent a dominant fraction in the brains of patients with Alzheimer’s disease. Both N-truncated peptides show a high aggregation propensity to form stable aggregates as observed by NMR spectroscopy, for example (Bouter et al., 2013).

References:

• Antonios G, Borgers H, Richard BC, Brauß A, Meißner J, Weggen S, Pena V, Pillot T, Davies SL, Bakrania P, Matthews D, Brownlees J, Bouter Y, Bayer TA. Alzheimer therapy with an antibody against N-terminal Abeta 4-X and pyroglutamate Abeta 3-X. Sci Rep. 2015 Dec 2;5:17338. PubMed.

• Antonios G, Saiepour N, Bouter Y, Richard BC, Paetau A, Verkkoniemi-Ahola A, Lannfelt L, Ingelsson M, Kovacs GG, Pillot T, Wirths O, Bayer TA. N-truncated Abeta starting with position four: early intraneuronal accumulation and rescue of toxicity using NT4X-167, a novel monoclonal antibody. Acta Neuropathol Commun. 2013 Sep 6;1(1):56. PubMed.

• Bakrania P, Hall G, Bouter Y, Bouter C, Beindorff N, Cowan R, Davies S, Price J, Mpamhanga C, Love E, Matthews D, Carr MD, Bayer TA. Discovery of a novel pseudo β-hairpin structure of N-truncated amyloid-β for use as a vaccine against Alzheimer's disease. Mol Psychiatry. 2022 Feb;27(2):840-848. Epub 2021 Nov 15 PubMed.

• Bayer TA. N-Truncated Aβ Starting at Position Four-Biochemical Features, Preclinical Models, and Potential as Drug Target in Alzheimer's Disease. Front Aging Neurosci. 2021;13:710579. Epub 2021 Aug 20 PubMed.

• Bayer TA. Pyroglutamate Aβ cascade as drug target in Alzheimer's disease. Mol Psychiatry. 2022 Apr;27(4):1880-1885. Epub 2021 Dec 8 PubMed.

• Bouter Y, Dietrich K, Wittnam JL, Rezaei-Ghaleh N, Pillot T, Papot-Couturier S, Lefebvre T, Sprenger F, Wirths O, Zweckstetter M, Bayer TA. N-truncated amyloid β (Aβ) 4-42 forms stable aggregates and induces acute and long-lasting behavioral deficits. Acta Neuropathol. 2013 Aug;126(2):189-205. PubMed.

• Bouter Y, Liekefeld H, Pichlo S, Westhoff AC, Fenn L, Bakrania P, Bayer TA. Donanemab detects a minor fraction of amyloid-β plaques in post-mortem brain tissue of patients with Alzheimer's disease and Down syndrome. Acta Neuropathol. 2022 May;143(5):601-603. Epub 2022 Apr 16 PubMed.