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

To determine how endogenously secreted beta-amyloid 42 (A beta 42) aggregates regulate synaptic functions, we examined effects of A beta 42 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 A beta 42 in neurons leads to a reduction of neurotransmitter release. However, expression of A beta 42 in postsynaptic muscle cells enhanced neurotransmitter release. Both effects are neutralized by A beta antibody, suggesting a role for secreted A beta 42 peptides. Application of exogenously prepared A beta 42 oligomers leads to a reduction in synaptic responses, whereas mixed A beta 42 aggregates with mainly fibrils elicit an opposite effect by increasing synaptic transmission. Further analysis of long-term depression (LTD) confirms differential effects of different A beta 42 aggregates. Taken together, our data suggest that A beta 42 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 A beta 42 aggregates, leading to different modulation of synaptic functions.-Chiang, H.-C., Iijima, K., Hakker, I., Zhong, Y. Distinctive roles of different beta-amyloid 42 aggregates in modulation of synaptic functions. FASEB J. 23, 1969-1977 (2009)