(318a) Anti-Amyloid Failures Increase As Aducanumab for Alzheimer’s Disease Flops: A Chemical Engineer’s Perspective

Belfort, G., Rensselaer Polytechnic Institute
Although the amyloid (abeta peptide, AÎ²) hypothesis is 25 years old, is the dominant model of Alzheimerâ€™s Disease (AD) pathogenesis, and currently guides the development of potential treatments, it is still controversial. One possible reason is a lack of a clear mechanistic path from the cleavage products of the amyloid precursor protein (APP) such as soluble AÎ² monomer and a series of recently discovered soluble molecular fragmentsto the deleterious effects on synaptic form and function1, 2. Another reason is the successive failure of antibodies against AÎ² and secretase inhibitors, highlighted by the recent decision by Biogen and Eisai to terminate two phase III trials of their anti-AÎ² antibody, aducanumab3. Both biophysical properties of these molecular entities and the balance between production and clearance are considered critical for AD pathogenesis. From a review of the recent literature including aggregation kinetics4 and structural morphology4, AÎ² clearance4, molecular simulations5, long term potentiation measurements with inhibition binding, and the binding of a commercial monoclonal antibody, aducanumab, we hypothesize that the N-terminal domains of neurotoxic AÎ² oligomers are implicated in causing the disease. We call this the â€œN-Terminal Hypothesis for ADâ€6. Recently reported experimental structures also show a flexible/exposed N-terminal region (AÎ²1-14) in the disease relevant AÎ²1-42 fibril7. Additionally, since monomers are not neurotoxic while dimers, trimers etc. are, this suggests that at least two N-termini are necessary for LTP deficit induction. It then follows that the mechanism of toxicity could be due to multivalent interactions between the N-termini (â‰¥2) of AÎ² oligomers with glutamate N-methyl D-aspartate receptors. MD simulations demonstrate increased flexibility of the protective versus the causative variants for N-termini in dimers8. Taken together, these collective findings strongly suggest that the N-terminus of AÎ² oligomers could be causative for AD. Many of the failed antibodies bind to the N-terminus but may not bind multivalently. Since about one in a 1000 antibody molecules pass the blood brain barrier is it possible that too few pass through to exert a long-term affect. Finally, it maybe that AD, which is thought to take ~20 years to mature, is being treated too late and has progressed to far to be reversed. This suggests that early detection is critical9.

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