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Center for Nonlinear Studies |
Although the amyloid (abeta peptide, Aβ) hypothesis is 25 years old, is the dominant model of Alzheimer’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 Aβ monomer and a series of recently discovered soluble molecular fragments to the deleterious effects on synaptic form and function1,2. 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 kinetics3 and structural morphology3, Aβ clearance3, molecular simulations4, 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 Aβ oligomers are implicated in causing the disease. We call this the “N-Terminal Hypothesis for AD”. The supporting evidence related to this hypothesis includes the discovery of the following: (i) The first protective mutation of APP (A673T) or Aβ (A2T) against AD reduces BACE1 cleavage at the β-secretase position (N-terminus of Aβ) resulting in a drop in Aβ concentration of about 40%5. (ii) A causative mutation at the same location (A673V) or Aβ (A2V) against AD results in an increase in Aβ concentration of about 100%. (iii) The A2T and A2V mutants of Aβ1-42 increase the aggregation lag time prior to the onset of fibril formation compared with wild type Aβ1-42 by a factor of ~1.5 and ~8, respectively3. (iv) Aggregate morphology of the N-terminal mutants (A2T and A2V) is altered compared with wild type Aβ1-423. (v) Molecular dynamic (MD) simulations show the importance of N-terminus on monomer folding and lowering of the formation of neurotoxic β-hairpin structures4. (vi) Long term potentiation (LTP) deficit, which correlates with memory and learning, is reduced for the A2T Aβ1-42 mutant, in comparison with the wild type and A2V Aβ1-42 mutant3. (vii) Blocking the N-terminus with sequence specific antibodies prevents LTP deficit whereas blocking the hydrophobic central core and C-terminus have minimal effects. (viii) Fragments of APP induce LTP deficits only when the N-terminus is included in the fragment1. (ix) A promising recombinant human monoclonal antibody, aducanumab, binds to the N-terminus of Aβ oligomers. (x) Recently reported experimental structures also show a flexible/exposed N-terminal region (Aβ1-14) in the disease relevant Aβ1-42 fibril6. 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 (≥2) of Aβ oligomers with glutamate N-methyl D-aspartate receptors. Unpublished MD simulations demonstrate increased flexibility of the protective versus the causative variants for N-termini in dimers. Taken together, these collective findings strongly suggest that the N-terminus of Aβ oligomers could be causative for AD.
Host: Angel Garcia