Distinctive roles of different beta-amyloid 42 aggregates in modulation of synaptic functions.

To determine how endogenously secreted beta-amyloid 42 (Abeta42) aggregates regulate synaptic functions, we examined effects of Abeta42 at the neuromuscular junction of Drosophila larvae. Voltage-clamp recordings of synaptic transmission and optical analysis of vesicle recycling at presynaptic terminals show that expression of Abeta42 in neurons leads to a reduction of neurotransmitter release. However, expression of Abeta42 in postsynaptic muscle cells enhanced neurotransmitter release. Both effects are neutralized by Abeta antibody, suggesting a role for secreted Abeta42 peptides. Application of exogenously prepared Abeta42 oligomers leads to a reduction in synaptic responses, whereas mixed Abeta42 aggregates with mainly fibrils elicit an opposite effect by increasing synaptic transmission. Further analysis of long-term depression (LTD) confirms differential effects of different Abeta42 aggregates. Taken together, our data suggest that Abeta42 is secreted from neurons primarily as oligomers that inhibit neurotransmitter release and exert no effect on LTD. Whereas larger-sized aggregates, possibly fibrils, are major components secreted from muscle cells, which enhance synaptic transmission and LTD. Thus, different types of cells may secrete distinct forms of Abeta42 aggregates, leading to different modulation of synaptic functions.