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

Authors: 
Belfort, G., Rensselaer Polytechnic Institute
Murray, B., Rensselaer Polytechnic Institute
Sharma, B., Rensselaer Polytechnic Institute
Ranganathan, S. V., The RNA Institute, University at Albany, State University of New York
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 function2-3. From a review of our own published work and the recent literature including aggregation kinetics4 and structural morphology4, Aβ clearance1, 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

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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.