(193a) N-Terminal Hypothesis for Alzheimer’s Disease: Arguments for and Against

One possible reason why the amyloid hypothesis for Alzheimer’s Disease (AD) pathogenesis is still controversial¹ is a lack of a mechanistic path from the cleavage products of the amyloid precursor protein (APP) to the deleterious effects on synaptic form and function^2-3. From a review of our own published work and the recent literature including aggregation kinetics⁴ and structural morphology⁴, Aβ clearance^{1, 4}, molecular simulations⁵, long term potentiation measurements with inhibition binding⁶, and the binding of a commercial monoclonal antibody, aducanumab⁷, we hypothesize that the N-terminal domains of neurotoxic Aβ oligomers are implicated in causing the disease. We call this the “N-Terminal Hypothesis for AD”⁸. In this talk, we present arguments for and against the N-terminal hypothesis.

References

1. Selkoe, D. J.; Hardy, J., The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO Molecular Medicine 2016, e201606210.

2. Welzel, A. T.; Maggio, J. E.; Shankar, G. M.; Walker, D. E.; Ostaszewski, B. L.; Li, S.; Klyubin, I.; Rowan, M. J.; Seubert, P.; Walsh, D. M.; Selkoe, D., J., Secreted amyloid beta-proteins in a cell culture model include N-terminally extended peptides that impair synaptic plasticity. Biochemistry 2014, 53 (24), 3908-3921.

3. Willem, M.; Tahirovic, S.; Busche, M. A.; Ovsepian, S. V.; Chafai, M.; Kootar, S.; Hornburg, D.; Evans, L. D.; Moore, S.; Daria, A.; Hampel, H.; Muller, V.; Giudici, C.; Nuscher, B.; Wenninger-Weinzierl, A.; Kremmer, E.; Heneka, M. T.; Thal, D. R.; Giedraitis, V.; Lannfelt, L.; Muller, U.; Livesey, F. J.; Meissner, F.; Herms, J.; Konnerth, A.; Marie, H.; Haass, C., η-Secretase processing of APP inhibits neuronal activity in the hippocampus. Nature 2015, 526 (7573), 443-7.

4. Murray, B.; Sorci, M.; Rosenthal, J.; Lippens, J.; Isaacson, D.; Das, P.; Fabris, D.; Li, S.; Belfort, G., A2T and A2V Aβ Peptides Exhibit Different Aggregation Kinetics, Morphology, Structure and LTP Inhibition. Proteins 2016, 84 (4), 488-500.

5. Das, P.; Murray, B.; Belfort, G., Alzheimer’s Protective A2T Mutation Changes the Conformational Landscape of the Aβ 1–42 Monomer Differently Than Does the A2V Mutation. Biophys J 2015, 108 (3), 738-747.

6. Shankar, G. M.; Li, S.; Mehta, T. H.; Garcia-Munoz, A.; Shepardson, N. E.; Smith, I.; Brett, F. M.; Farrell, M. A.; Rowan, M. J.; Lemere, C. A.; Regan, C. M.; Walsh, D. M.; Sabatini, B. L.; Selkoe, D. J., Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nature medicine 2008, 14 (8), 837-42.

7. Bussiere, T.; Weinreb, P.; Engber, T.; Rhodes, K.; Arndt, J.; Qian, F.; Dunstan, R.; Patel, S.; Grimm, J.; Maier, M. A Method of Reducing Brain Amyloid Plaques Using Anti-Ab Antibodies. US 20150315267 A1, 2015 Nov 5.

8. Murray, B.; Sharma, B.; Belfort, G., N-Terminal Hypothesis for Alzheimer's Disease. ACS Chem Neurosci 2017, 8 (3), 432-434.