What Computational Methods Can Teach Us About The Alzheimer-Protective Nature Of A2v-And A2t-Mutant Amyloid-Beta Oligomers

Unlike the large set of risk genetic mutations causing the familial form of Alzheimer's disease (AD), recent mutations in the Amyloid-β (Aβ) protein have been discovered to confer protection against AD. The A2V mutation is such a protective mutation in its recessive form only (i.e. mixed with wild-type (WT) Aβ) by preventing the Aβ-WT peptide from forming fibrils and toxic aggregates while, surprisingly, the A2V mutation in its dominant form (pure Aβ-A2V) becomes more potent than Aβ-WT and displays an increased toxicity and self-aggregation propensity [1]. Accounts of another protective mutant, A2T, (in both its recessive and dominant form) have also been reported [2]. While these two mutants reduce the production of Aβ delivered in the brain, this is not enough to clearly explain their beneficial effects against AD. We aim here to understand the impact of these mutations at a molecular level via all-atom molecular dynamics simulations to follow up on the promising results previously obtained computationally for the Aβ(1-28)-A2V monomer, providing a first look at the mechanism behind this protective mutation [3]. Now studying four dimer systems (WT-WT, WT-A2V, A2V-A2V and WT-A2T) and two tetramer systems (WT-WT and WT-A2T), we are able to explain, via extensive conformational searches and detailed free-energy calculations, how a single-point mutation at the position 2 of Aβ is sufficient to induce protective or potent properties compared to the Aβ-WT. These first computational results on the A2V and A2T mutations demonstrate that their protective (or potent) effects are encoded already at the dimer and tetramer level. [1] Di Fede G et al. (2009). Science, 323(5920), 1473-1477. [2] Peacock ML et al. (1993). Neurology, 43:1254. [3] Nguyen,PH, Tarus, B and Derrreumaux, P. (2014). J Phys Chem B, 118:501-510