Abstract
Growing evidence has indicated that prefibrillar form of soluble amyloid beta (sAβ1-42) is the major causative factor in the synaptic dysfunction associated with AD. The molecular changes leading to presynaptic dysfunction caused by sAβ1-42, however, still remains elusive. Recently, we found that sAβ1-42 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 sAβ1-42 increases intracellular Ca2+ that induces hyperphosphorylation of CaMKIV and synapsin, and what is the functional consequences of sAβ1-42-induced defects in intersynaptic vesicle trafficking in physiological conditions. In this study, we showed that sAβ1-42elevated intracellular Ca2+ through not only extracellular Ca2+ influx but also Ca2+ release from mitochondria. Surprisingly, without Ca2+ release from mitochondria, sAβ1-42 failed to increase intracellular Ca2+ even in the presence of normal extracellular Ca2+. We further found that sAβ1-42-induced mitochondria Ca2+ release alone sufficiently increased Serine 9 phosphorylation of synapsin. By blocking synaptic vesicle reallocation, sAβ1-42 significantly increased heterogeneity of total synaptic vesicle pool size among synapses. Together, our results suggested that by disrupting the axonal vesicle trafficking, sAβ1-42 disabled neurons to adjust synaptic pool sizes among synapses, which might prevent homeostatic rescaling in synaptic strength of individual neurons.