Soluble Aβ_1-42 increases the heterogeneity in synaptic vesicle pool size among synapses by suppressing intersynaptic vesicle sharing

Growing evidence has indicated that prefibrillar form of soluble amyloid beta (sAβ_1-42) is the major causative factor in the synaptic dysfunction associated with AD. The molecular changes leading to presynaptic dysfunction caused by sAβ_1-42, however, still remains elusive. Recently, we found that sAβ_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 sAβ_1-42 increases intracellular Ca²⁺ that induces hyperphosphorylation of CaMKIV and synapsin, and what is the functional consequences of sAβ_1-42-induced defects in intersynaptic vesicle trafficking in physiological conditions. In this study, we showed that sAβ_1-42elevated intracellular Ca²⁺ through not only extracellular Ca²⁺ influx but also Ca²⁺ release from mitochondria. Surprisingly, without Ca²⁺ release from mitochondria, sAβ_1-42 failed to increase intracellular Ca²⁺ even in the presence of normal extracellular Ca²⁺. We further found that sAβ_1-42-induced mitochondria Ca²⁺ release alone sufficiently increased Serine 9 phosphorylation of synapsin. By blocking synaptic vesicle reallocation, sAβ_1-42 significantly increased heterogeneity of total synaptic vesicle pool size among synapses. Together, our results suggested that by disrupting the axonal vesicle trafficking, sAβ_1-42 disabled neurons to adjust synaptic pool sizes among synapses, which might prevent homeostatic rescaling in synaptic strength of individual neurons.