A novel specific Aβ42 oligomer antibody ameliorates the neurotoxicity of patient-derived brain extracts

Anders Sandberg, Rosa Crespo Rodriguez, Ernesto Berenjeno Correa, Tjado Morrema, Jeroen J. Hoozemans, Wiep Scheper

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Background: In Alzheimer’s disease (AD), the neurotoxicity of amyloid-β 1-42 (Aβ42) stems mostly from soluble oligomeric aggregates of this peptide. However, the study of these aggregates has been hampered by their unstable and elusive nature, thus questioning the very definition of them as distinct targets for drug development. Here, we assess the toxicity of physiologically-derived Aβ using extracts from deceased patients and controls in primary neuron cultures. By using a monoclonal antibody with a unique binding profile, ALZ-201, we demonstrate that all of the Aβ toxicity observed in human-derived brain extracts stem from soluble Aβ42 aggregates. Method: Brain tissue samples from 10 individuals were confirmed as AD (n=7) and non-AD (n=3) cases using IHC staining for Aβ and p-Tau aggregates. Extracts were prepared as described in Hong et al. 2018 (doi:10.1007/s00401-018-1846-7) and immunodepleted with either the antibody 4G8 (removes all Aβ), ALZ-201 (100% specific for non-fibrillar soluble Aβ42 aggregates) or an isotype control to ALZ-201 (does not bind any Aβ). Fractions were biochemically characterized, and toxicity assays were performed in primary mouse neuronal cultures using an automated cell imaging platform. Result: The total Aβ content was higher in AD cases, as expected. The toxicity of the patient extracts exceeded those obtained from non-AD cases with respect to neuronal loss and morphological determinants such as synapse density and measures of neurite complexity. Immunodepletion using 4G8 dramatically reduced Aβ in the AD patient samples and the control samples. This is in contrast to immunodepletion using ALZ-201 or the isotype control, for which there was no detectable difference. Despite this remarkable difference in Aβ content, the therapeutic effect of depletion with 4G8 and ALZ-201 was comparable, whereas there was no effect after depletion using the isotype control. Conclusion: The results demonstrate that very small amounts of soluble aggregated Aβ42 likely account for a large part of the toxicity in AD patients. The unique antibody, ALZ-201, is capable of depleting these without targeting other forms of Aβ. Since this natural toxic form of Aβ is extremely low in abundance, this feature may be a critical attribute for achieving a true therapeutic effect in actual patients.

Original languageEnglish
Article numbere053659
Number of pages1
JournalAlzheimer's and Dementia
Issue numberS9
Early online date31 Dec 2021
Publication statusPublished - Dec 2021

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