(631g) A Causative Link Between Abeta Binding and Its Clearance and Toxicity for Alzheimer's Disease

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 (Aβ_1-42) 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 Aβ_1-42, the purported AD reversal in a mouse model due to overproduction of ApoE with augmented Aβclearance, and the findings that Aβ_1-42 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 Aβ_1-42.  The prevailing protective hypothesis is that the mutation (A673T in amyloid precursor protein or A2T in Aβ_1-42), 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 Aβ_1-42 demonstrate marked differences compared with each other and the wild-type Aβ_1-42 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.