Department of Neurology, The 2nd Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, P.R. China.
Institute of Neuroscience, Nanchang University, Nanchang, Jiangxi Province, P.R. China.
CNS Neurosci Ther. 2024 Nov;30(11):e70095. doi: 10.1111/cns.70095.
The hyperphosphorylation of Tau protein is considered an important cause of neuronal degeneration in Alzheimer's disease (AD). The disruption of neuronal histone acetylation homeostasis mediated by Tip60 HAT is a common early event in neurodegenerative diseases, but the deeper regulatory mechanism on β-amyloid peptide (Aβ)-induced neurotoxicity and autophagic function in AD is still unclear.
AD models were established both in APP/PS1 mice and Aβ-treated SH-SY5Y cells. The Morris water maze test (MWM) was performed to examine mouse cognitive function. Neurological damage in the hippocampus was observed by hematoxylin-eosin (H&E), Nissl's, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), and NeuN staining. Autophagosome-lysosome fusion was detected by immunohistochemistry, immunofluorescence, and Lyso-Tracker Red staining. Cell viability and apoptosis were evaluated by CCK-8 assay and flow cytometry. The molecular interactions were verified by co-immunoprecipitation (Co-IP), dual luciferase assays, and ChIP detections. The RNA and autophagy-lysosome-related proteins were assessed by Western blot and RT-qPCR.
TIP60 overexpression improved cognitive deficits and neurological damage and restored the impairment of autophagy-lysosomes fusion in vivo. Similarly, the upregulation of TIP60 in Aβ-treated SH-SY5Y cells suppressed neuronal apoptosis and tau phosphorylation through the activating autophagy-lysosome pathway. Mechanistically, TIP60 activated IKKβ transcription by promoting SOX4 acetylation, thus leading to the translocation of SNAP23 to STX17-contained autophagosomes. Moreover, the protective roles of TIP60 in neuron damage were abolished by the inhibition of SOX4/IKKβ signaling.
Collectively, our results highlighted the potential of the TIP60 target for AD and provided new insights into the mechanisms underlying neuroprotection in this disorder.
Tau 蛋白的过度磷酸化被认为是阿尔茨海默病（AD）神经元退行性变的重要原因。Tip60 HAT 介导的神经元组蛋白乙酰化平衡的破坏是神经退行性疾病的常见早期事件，但 AD 中β-淀粉样肽（Aβ）诱导的神经毒性和自噬功能的更深层次调节机制仍不清楚。
在 APP/PS1 小鼠和 Aβ处理的 SH-SY5Y 细胞中建立 AD 模型。通过 Morris 水迷宫测试（MWM）检查小鼠认知功能。通过苏木精-伊红（H&E）、尼氏、末端脱氧核苷酸转移酶 dUTP 缺口末端标记（TUNEL）和 NeuN 染色观察海马神经损伤。通过免疫组化、免疫荧光和 Lyso-Tracker Red 染色检测自噬体-溶酶体融合。通过 CCK-8 测定法和流式细胞术评估细胞活力和细胞凋亡。通过共免疫沉淀（Co-IP）、双荧光素酶测定和 ChIP 检测验证分子相互作用。通过 Western blot 和 RT-qPCR 评估 RNA 和自噬-溶酶体相关蛋白。
TIP60 过表达改善了认知缺陷和神经损伤，并恢复了体内自噬体-溶酶体融合的损伤。同样，在 Aβ处理的 SH-SY5Y 细胞中上调 TIP60 通过激活自噬体-溶酶体途径抑制神经元凋亡和 Tau 磷酸化。机制上，TIP60 通过促进 SOX4 乙酰化激活 IKKβ 转录，从而导致 SNAP23 易位到含有 STX17 的自噬体。此外，SOX4/IKKβ 信号的抑制消除了 TIP60 在神经元损伤中的保护作用。
总之，我们的研究结果强调了 TIP60 靶标在 AD 中的潜力，并为该疾病的神经保护机制提供了新的见解。
