Kamikubo Yuji, Takasugi Nobumasa, Niisato Kazue, Hashimoto Yoshie, Sakurai Takashi
J Alzheimers Dis. 2017;56(2):641-653. doi: 10.3233/JAD-160806.
The amyloid-β protein precursor (AβPP) is cleaved by a transmembrane protease termed β-site AβPP cleavage enzyme (BACE1), which is being explored as a target for therapy and prevention of Alzheimer's disease (AD). Although genetic deletion of BACE1 results in abolished amyloid pathology in AD model mice, it also results in neurodevelopmental phenotypes such as hypomyelination and synaptic loss, observed in schizophrenia and autism-like phenotype. These lines of evidence indicate that the inhibition of BACE1 causes adverse side effects during the neurodevelopmental stage. However, the effects of the inhibition of BACE1 activity on already developed neurons remain unclear. Here, we utilized hippocampal slice cultures as an ex vivo model that enabled continuous and long-term analysis for the effect of BACE1 inhibition on neuronal circuits and synapses. Temporal changes in synaptic proteins in hippocampal slices indicated acute synaptic loss, followed by synapse formation and maintenance phases. Long-term BACE1 inhibition in the neurodevelopmental stage caused the loss of synaptic proteins but failed to alter synaptic proteins in the already developed maintenance stage. These data indicate that BACE1 function on synapses is dependent on synaptic developmental stages, and our study provides a useful model to observe the long-term effect of BACE1 activity in the brain, and to evaluate adverse effects of BACE inhibitors.
淀粉样前体蛋白（AβPP）由一种跨膜蛋白酶β-位点淀粉样前体蛋白裂解酶1（BACE1）进行裂解，目前BACE1正作为治疗和预防阿尔茨海默病（AD）的靶点进行研究。虽然在AD模型小鼠中基因敲除BACE1可消除淀粉样病变，但也会导致神经发育表型，如髓鞘形成不足和突触丧失，这些表型在精神分裂症和自闭症样表型中也有观察到。这些证据表明，抑制BACE1在神经发育阶段会引起不良副作用。然而，抑制BACE1活性对已发育成熟的神经元的影响仍不清楚。在此，我们利用海马脑片培养作为一种体外模型，能够对BACE1抑制对神经回路和突触的影响进行持续和长期分析。海马脑片中突触蛋白的时间变化表明，先是急性突触丧失，随后是突触形成和维持阶段。在神经发育阶段长期抑制BACE1会导致突触蛋白丧失，但在已发育成熟的维持阶段未能改变突触蛋白。这些数据表明，BACE1在突触上的功能取决于突触发育阶段，我们的研究提供了一个有用的模型，用于观察BACE1活性在大脑中的长期影响，并评估BACE抑制剂得不良影响。
