Affiliations: Department of Pathology and Infectious Diseases, Royal Veterinary College, Hawkshead Lane, North Mymms, Herts, UK
Correspondence:
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Correspondence to: Dr. Clive Bate, Department of Pathology and Infectious Diseases, Royal Veterinary College, Hawkshead Lane, North Mymms, Herts AL9 7TA, UK. Tel.: +44 1707 666550; E-mail: [email protected].
Note: [1] Present address: Department of Veterinary Medicine, University of Cambridge, Cambridge, UK.
Note: [] Handling Associate Editor: James Bamburg
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.
