Chemical Engineering Seminar

The histopathological hallmark of Alzheimer's disease (AD) is the accumulation of monomeric Aβ into misfolded oligomers and fibrils. In an attempt to reduce or remove Aβ deposits from the brain and provide treatment for AD, one antibody drug, aducanumab (Biogen-Idec, currently in Phase III trials), is thought to bind to the N-terminus.  It reduced Aβ deposits in PET brain scans at high doses (10 mg), but failed to significantly slow the mental decline of 30 people at intermediate dosages (6 mg)¹. Unfortunately at high doses, aducanumab caused brain swelling and micro-hemorrhaging.  Nonetheless these results are encouraging, and together with the following three findings suggest that the N-terminus plays a molecular role in affecting long term potentiation (LTP) and depression (LTD) deficits through binding with the glutamate and N-methyl D-aspartate receptors. 

• The first finding is a recent seminal discovery of the first protective variant of Aβ_1-42 (A2T) for AD². It is relevant here because understanding the underlying folding, aggregation and binding behavior of the A2T variant provides possible clues to its protective mechanism. 
• The second finding involves a comparison of the conformational landscape of the Aβ monomer for wild type, A2T and a early-onset AD inducing mutant A2V³. Our simulations reveal that although all three variants remain generally as collapsed coils in solution, there exist significant subtle structural differences among them. A2T causes the extreme N-terminus to engage periodically in unusual electrostatic interactions with distant residues that flank the CHC, K16 and E22, resulting in a unique population comprising relatively strong N-terminal-CHC interactions³. This last finding suggests that the A2T protection maybe due to either a "capping" of the CHC preventing it from propagating toxic oligomers or aggregates, and/or stabilizing the primarily disordered N-terminus through binding to the flanking charged residues of the CHC (Q₁₅KLVFFAED₂₃). 
• The third finding, reported by the Selkoe group, states that "co-administering antibodies to the Aβ N-terminus prevented LTP and LTD deficits (of hippocampus cells), whereas antibodies to the CHC or C-terminus were less effective"⁴. They showed that soluble Aβ dimers from Alzheimer's disease patients' cortex induce their effects by perturbing glutamatergic synaptic transmission, and are the smallest synaptotoxic species that impair synaptic plasticity and memory. 

In this talk, we present recent results to support these finding and hypothesis.

1.  Underwood, E. Neuroscience: Alzheimer's amyloid theory gets modest boost. Science 2015, 349 (6247), 464.

2.  Jonsson, T.; Atwal, J. K.; Steinberg, S.; Snaedal, J.; Jonsson, P. V.; Bjornsson, S.; Stefansson, H.; Sulem, P.; Gudbjartsson, D.; Maloney, J.; Hoyte, K.; Gustafson, A.; Liu, Y.; Lu, Y.; Bhangale, T.; Graham, R. R.; Huttenlocher, J.; Bjornsdottir, G.; Andreassen, O. A.; Jonsson, E. G.; Palotie, A.; Behrens, T. W.; Magnusson, O. T.; Kong, A.; Thorsteinsdottir, U.; Watts, R. J.; Stefansson, K. A mutation in APP protects against Alzheimer's disease and age-related cognitive decline. Nature 2012, 488 (7409), 96-9.

3.  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. Biophysical journal 2015, 108 (3), 738-747.

4.  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.