Amyloid-β 1–40 Inhibits Amyloid-β 1–42 Induced Activation of Cytoplasmic Phospholipase A 2 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 Aβ_1–42 reduced the amount of synaptophysin in cultured cortical neurons in a model of AD-induced synapse degeneration. Aβ_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 Aβ_1–40 with Aβ_1–42 significantly reduced the effects of Aβ_1–42 on synapses; it increased both synaptic vesicle recycling and synaptophysin content. These results are consistent with reports that Aβ_1–40 forms oligomers with Aβ_1–42 and that these are less toxic than Aβ_1–42 alone. In contrast, the addition of Aβ_1–40 did not affect the synapse degeneration induced by the prion-derived peptide PrP82-146. The addition of Aβ_1–40 reduced Aβ_1–42 induced activation of cytoplasmic phospholipase A₂ (cPLA₂) within synapses consistent with the hypothesis that Aβ_1–42 induced synapse degeneration is mediated by aberrant activation of synaptic cPLA₂. Such observations raise the possibility that the amount of Aβ_1–40 produced within the brain is critical in determining the synapse damaging effects of Aβ_1–42 and possibly the cognitive loss seen during the early stages of AD.