Amyloid-β1-40 Inhibits Amyloid-β1-42 Induced Activation of Cytoplasmic Phospholipase A2 and Synapse Degeneration

The pathogenesis of Alzheimer's disease (AD) is associated with the accumulation of amyloid-beta (A beta) peptides and the loss of synapses. The addition of A beta(1-42) reduced the amount of synaptophysin in cultured cortical neurons in a model of AD-induced synapse degeneration. A beta(1-42) also reduced the uptake of the fluorescent dye FM1-43 into synaptic recycling vesicles, a measure of synaptic function. We report that pre-mixing A beta(1-40) with A beta(1-42) significantly reduced the effects of A beta(1-42) on synapses; it increased both synaptic vesicle recycling and synaptophysin content. These results are consistent with reports that A beta(1-40) forms oligomers with A beta(1-42) and that these are less toxic than A beta(1-42) alone. In contrast, the addition of A beta(1-40) did not affect the synapse degeneration induced by the prion-derived peptide PrP82-146. The addition of A beta(1-40) reduced A beta(1-42) induced activation of cytoplasmic phospholipase A(2) (cPLA(2)) within synapses consistent with the hypothesis that A beta(1-42) induced synapse degeneration is mediated by aberrant activation of synaptic cPLA(2). Such observations raise the possibility that the amount of A beta(1-40) produced within the brain is critical in determining the synapse damaging effects of A beta(1-42) and possibly the cognitive loss seen during the early stages of AD.