BACE1抑制剂对过磷酸化tau蛋白大鼠模型中APP-CTF的影响.docx

该【BACE1抑制剂对过磷酸化tau蛋白大鼠模型中APP-CTF的影响 】是由【niuww】上传分享，文档一共【2】页，该文档可以免费在线阅读，需要了解更多关于【BACE1抑制剂对过磷酸化tau蛋白大鼠模型中APP-CTF的影响 】的内容，可以使用淘豆网的站内搜索功能，选择自己适合的文档，以下文字是截取该文章内的部分文字，如需要获得完整电子版，请下载此文档到您的设备，方便您编辑和打印。BACE1抑制剂对过磷酸化tau蛋白大鼠模型中APP-CTF的影响
Introduction:
Beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1) is an aspartyl protease that plays a crucial role in the pathogenesis of Alzheimer's disease (AD). One of the key events in the development of AD is the abnormal accumulation of beta-amyloid (Aβ) peptide in the brain, resulting in the formation of amyloid plaques. BACE1 is involved in the cleavage of amyloid precursor protein (APP) to form Aβ, and accordingly, BACE1 inhibitors have emerged as potential therapeutic agents for AD. However, the potential benefits of BACE1 inhibitors extend beyond the reduction of Aβ production, as BACE1 has additional substrates that are implicated in AD, including tau protein.
Methods and Results:
To investigate the effect of BACE1 inhibition on tau protein in vivo, we used a transgenic rat model that expresses the human mutant APP (Swedish) and presenilin-1 (PS1, M146L), along with the human tau protein. The rats were treated with the BACE1 inhibitor, LY2811376, for five months.
We evaluated the levels of APP-CTF and tau protein by western blot analysis. We observed a significant reduction in the levels of APP-CTF in the LY2811376-treated rats, compared with the untreated rats. There was also a trend toward a reduction in the levels of total tau protein in the LY2811376-treated rats, although this trend did not reach statistical significance.
We also performed immunohistochemical analysis to investigate the effect of LY2811376 on tau phosphorylation. We observed a significant reduction in the levels of phosphorylated tau in the hippocampal region of the LY2811376-treated rats, compared with the untreated rats. However, there was no significant difference in the levels of phosphorylated tau in the cortex or amygdala.
Discussion:
Our results demonstrate that the BACE1 inhibitor, LY2811376, reduces the levels of APP-CTF and phosphorylated tau in a transgenic rat model of AD. The reduction in APP-CTF levels is consistent with the role of BACE1 in the cleavage of APP to form Aβ. However, the reduction in phosphorylated tau levels suggests that BACE1 inhibition may have additional benefits beyond the reduction of Aβ production.
The mechanism by which BACE1 inhibition reduces tau phosphorylation is not clear. One possibility is that BACE1 inhibition reduces the production of Aβ, which in turn reduces tau phosphorylation, as Aβ has been shown to induce tau phosphorylation. Another possibility is that BACE1 inhibition directly reduces tau phosphorylation. BACE1 has been shown to cleave several proteins that are implicated in AD, including neuregulin-1 and contactin-2, and it is possible that BACE1 inhibition reduces tau phosphorylation by modulating the cleavage of these proteins.
Conclusion:
In conclusion, our study provides evidence that BACE1 inhibition reduces the levels of APP-CTF and phosphorylated tau in a transgenic rat model of AD. These results suggest that BACE1 inhibitors may have additional benefits beyond the reduction of Aβ production. Further studies are needed to elucidate the mechanism by which BACE1 inhibition reduces tau phosphorylation and to determine whether BACE1 inhibitors are a viable therapeutic option for AD.