Amyloid-β(1-40) inhibits amyloid-β(1-42) induced activation of cytoplasmic phospholipase A2 and synapse degeneration.
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.[1]References
- Amyloid-β(1-40) inhibits amyloid-β(1-42) induced activation of cytoplasmic phospholipase A2 and synapse degeneration. Bate, C., Williams, A. J. Alzheimers Dis. (2010) [Pubmed]
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