BAP31 deficiency contributes to the formation of amyloid-β plaques in Alzheimer’s disease by reducing the stability of RTN3
BAP31 deficiency contributes to the formation of amyloid-β plaques in Alzheimer’s disease by reducing the stability of RTN3
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BAP31 缺陷通过降低 RTN3 的稳定性，导致阿尔茨海默病中淀粉样β斑块的形成
DOI：
10.1096/fj.201801702r
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通讯作者：
Tianyi Wang
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作者：
Tianyi Wang
Reticulon 3（RTN 3）通过负性调节β-分泌酶1（BACE 1）活性来减少淀粉样蛋白-β斑块（AP）。然而，RTN 3容易聚集，这抵消了RTN 3对BACE 1活性的抑制作用，并加剧了AP沉积。我们发现BAP 31是RTN 3的结合伴侣，并且与RTN 3的表达水平正相关。为了进一步探讨BAP 31与阿尔茨海默病（AD）的关系，本研究建立了海马和大脑皮层BAP 31基因敲除（B-KO）小鼠模型，并与APP/PS1转基因（AD模型）小鼠杂交，获得B-KO-AD小鼠。原代海马神经元中的BAP 31敲除降低了RTN 3单体的可用性并提高了RTN 3聚集体的水平，表明BAP 31缺陷增加了RTN 3的不稳定性。更重要的是，这些作用促进了BACE 1介导的淀粉样前体蛋白（APP）加工，并导致B-KO-AD小鼠海马和大脑皮层中AP的增加。因此，人脑中BAP 31的表达升高可能通过增强RTN 3的稳定性来减少RTN 3聚集体和淀粉样蛋白-β（Aβ）的形成。
Reticulon 3 (RTN3) reduces amyloid-β plaques (APs) by negatively modulating of β-secretase 1 (BACE1) activity. However, RTN3 aggregates easily, which offsets RTN3’s inhibitory effect on BACE1 activity and exacerbates AP deposition. We found that BAP31 was a binding partner of RTN3 and positively correlated with the expression level of RTN3. To further explore how BAP31 is involved in Alzheimer’s disease (AD), conditional knockout mice with targeted BAP31 deletion (B-KO) in the hippocampus and cerebral cortex were generated and hybridized with APP/PS1 transgenic (AD model) mice to obtain B-KO-AD mice. BAP31 knockout in primary hippocampal neurons decreased RTN3 monomer availability and enhanced the level of RTN3 aggregates, indicating that BAP31 deficiency increases the instability of RTN3. More importantly, these effects contributed to BACE1-mediated amyloid precursor protein (APP) processing, and were responsible for the increased APs in the hippocampus and cerebral cortex of B-KO-AD mice. Thus, elevated expression of BAP31 in the human brain is likely to reduce the formation of both RTN3 aggregates and amyloid-β (Aβ) by enhancing the stability of RTN3..