388670 A Causative Link Between Abeta Binding and Its Clearance and Toxicity for Alzheimer's Disease

Thursday, November 20, 2014: 10:24 AM
205 (Hilton Atlanta)
Brian Murray, Howard P. Isermann Department of Chemcial and Biological Engineering, Rensselaer Polytechnic Institute, Troy, NY, Payel Das, Computational Biology Center, Soft Matter Theory and Simulations Group, IBM Thomas J. Watson Research Center, Yorktown Heights, NY and Georges Belfort, Howard P. Isermann Dept of Chemical & Biological Engineering, Rensselaer Polytechnic Institute, Troy, NY

Alzheimer’s disease (AD) is a major public health concern due to its prevalence, severity, cost and lack of mechanism-based treatments. The molecular process underlying AD involves an imbalance between production and clearance of the amyloid beta (Aβ1-42) peptide.  Several recent findings related to the Aβ peptide hypothesis are central to our focus on downstream molecular events of AD:  The discovery of a protective (A2T) and a causative (A2V) variant of Aβ1-42, the purported AD reversal in a mouse model due to overproduction of ApoE with augmented Aβ clearance, and the findings that Aβ1-42 binding to receptors causes synaptic impairment.  The protective variant is expressed with a wild-type copy of the gene, with only a 20% decrease in total Aβ1-42.  The prevailing protective hypothesis is that the mutation (A673T in amyloid precursor protein or A2T in Aβ1-42), close to the cleavage site of β-secretase, lowers Aβ production and hence balances production with clearance.  Here, we provide the first direct evidence supporting the hypothesis that protective and causative variants of Aβ1-42 demonstrate marked differences compared with each other and the wild-type Aβ1-42 in terms of aggregation, toxicity to neuronal cells, binding to ApoE molecules (with clearance implications) and to EphB2-FC chimera receptors (with synaptotoxic implications), and propensity to populate β-hairpin structures in the monomeric state (using molecular dynamics simulations).  Thus, stabilizing Aβ in the β-hairpin conformation by an A2V mutation promotes toxic oligomer formation and inhibits aggregation, whereas the A2T mutation acts inversely.  These findings, that the Aβ variants exert their protective/causative effects through their inherent biophysical properties, move the focus of a possible cause of AD from upstream cleavage and production to downstream aggregation, binding, and clearance, suggesting new routes to treatment through intervention of downstream events.

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See more of this Session: Fundamentals of Protein Folding in Diseases
See more of this Group/Topical: Food, Pharmaceutical & Bioengineering Division