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.
Bate
Clive
C
Department of Pathology and Infectious Diseases, Royal Veterinary College, North Mymms, Herts, UK. cbate@rvc.ac.uk
Williams
Alun
A
D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D051379:Mice; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology*; D054467:Phospholipases A2 / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013572:Synaptic Vesicles / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016708:Synaptophysin / Q000378:metabolism
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D016708:Synaptophysin; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D054467:Phospholipases A2