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

Hsueh-Cheng Chiang^*,, Koichi Iijima^*,1, Inessa Hakker^* and Yi Zhong^*,2

^* Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA; and

Department of Neuroscience, State University of New York, Stony Brook, New York, USA

²Correspondence: Cold Spring Harbor Laboratory, P.O. Box 100, Cold Spring Harbor, NY 11724, USA. E-mail: zhongyi{at}cshl.edu

To determine how endogenously secreted β-amyloid 42 (Aβ42) aggregates regulate synaptic functions, we examined effects of Aβ42 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 Aβ42 in neurons leads to a reduction of neurotransmitter release. However, expression of Aβ42 in postsynaptic muscle cells enhanced neurotransmitter release. Both effects are neutralized by Aβ antibody, suggesting a role for secreted Aβ42 peptides. Application of exogenously prepared Aβ42 oligomers leads to a reduction in synaptic responses, whereas mixed Aβ42 aggregates with mainly fibrils elicit an opposite effect by increasing synaptic transmission. Further analysis of long-term depression (LTD) confirms differential effects of different Aβ42 aggregates. Taken together, our data suggest that Aβ42 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 Aβ42 aggregates, leading to different modulation of synaptic functions.—Chiang, H.-C., Iijima, K., Hakker, I., Zhong, Y. Distinctive roles of different β-amyloid 42 aggregates in modulation of synaptic functions.

Key Words: Alzheimer’s disease • Drosophila • neuromuscular junction • endogenous