Soluble A?1-42 increases the heterogeneity in synaptic vesicle pool size among synapses by suppressing intersynaptic vesicle sharing.
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ABSTRACT: Growing evidence has indicated that prefibrillar form of soluble amyloid beta (sA?1-42) is the major causative factor in the synaptic dysfunction associated with AD. The molecular changes leading to presynaptic dysfunction caused by sA?1-42, however, still remains elusive. Recently, we found that sA?1-42 inhibits chemically induced long-term potentiation-induced synaptogenesis by suppressing the intersynaptic vesicle trafficking through calcium (Ca2+) dependent hyperphosphorylation of synapsin and CaMKIV. However, it is still unclear how sA?1-42 increases intracellular Ca2+ that induces hyperphosphorylation of CaMKIV and synapsin, and what is the functional consequences of sA?1-42-induced defects in intersynaptic vesicle trafficking in physiological conditions. In this study, we showed that sA?1-42elevated intracellular Ca2+ through not only extracellular Ca2+ influx but also Ca2+ release from mitochondria. Surprisingly, without Ca2+ release from mitochondria, sA?1-42 failed to increase intracellular Ca2+ even in the presence of normal extracellular Ca2+. We further found that sA?1-42-induced mitochondria Ca2+ release alone sufficiently increased Serine 9 phosphorylation of synapsin. By blocking synaptic vesicle reallocation, sA?1-42 significantly increased heterogeneity of total synaptic vesicle pool size among synapses. Together, our results suggested that by disrupting the axonal vesicle trafficking, sA?1-42 disabled neurons to adjust synaptic pool sizes among synapses, which might prevent homeostatic rescaling in synaptic strength of individual neurons.
SUBMITTER: Park D
PROVIDER: S-EPMC5819658 | biostudies-literature | 2018 Feb
REPOSITORIES: biostudies-literature
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