Amyloid-β1-40 inhibits amyloid-β1-42 induced activation of cytoplasmic phospholipase A2 and synapse degeneration

Abstract

The pathogenesis of Alzheimer's disease (AD) is associated with the accumulation of amyloid-β (Aβ) peptides and the loss of synapses. The addition of Aβ1-42 reduced the amount of synaptophysin in cultured cortical neurons in a model of AD-induced synapse degeneration. Aβ1-42 also reduced the uptake of the fluorescent dye FM1-43 into synaptic recycling vesicles, a measure of synaptic function. We report that pre-mixing Aβ1-40 with Aβ1-42 significantly reduced the effects of Aβ1-42 on synapses; it increased both synaptic vesicle recycling and synaptophysin content. These results are consistent with reports that Aβ1-40 forms oligomers with Aβ1-42 and that these are less toxic than Aβ1-42 alone. In contrast, the addition of Aβ1-40 did not affect the synapse degeneration induced by the prion-derived peptide PrP82-146. The addition of Aβ1-40 reduced Aβ1-42 induced activation of cytoplasmic phospholipase A2 (cPLA2) within synapses consistent with the hypothesis that Aβ1-42 induced synapse degeneration is mediated by aberrant activation of synaptic cPLA2. Such observations raise the possibility that the amount of Aβ1-40 produced within the brain is critical in determining the synapse damaging effects of Aβ1-42 and possibly the cognitive loss seen during the early stages of AD. © 2010 - IOS Press and the authors. All rights reserved.