Department of Geriatrics, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, 1111 XianXia Road, Shanghai, 200336, China.
Mol Brain. 2024 Nov 19;17(1):81. doi: 10.1186/s13041-024-01156-9.
Alzheimer's disease (AD), an age-related neurodegenerative disorder, is characterized by irreversible brain tissue degeneration. The amyloid-β (Aβ) cascade hypothesis stands as the predominant paradigm explaining AD pathogenesis. This study aimed to elucidate the mechanisms underlying Aβ-induced pyroptosis in AD. AD models were established using amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice and Aβ-treated BV-2 cells (5 µM, 24 h). NEK7 expression was evaluated in vitro and in vivo. Cell pyroptosis was assessed before and after NEK7 expression was inhibited in BV-2 cells. Adeno-associated virus (AAV) vectors carrying short hairpin RNA (shRNA) against NEK7 (AAV-sh-NEK7) were administered to mice to knockdown NEK7 in vivo. Spatial learning and memory abilities were evaluated using the Morris water maze test. The interaction between NEK7 and histone H4 lysine 12 lactylation (H4K12la) were then investigated. The results suggested that NEK7 expression was markedly elevated in both in vitro and in vivo AD models. Treatment with Aβ significantly reduced cell viability and enhanced pyroptosis in BV-2 cells; these effects were reversed by inhibiting NEK7. Furthermore, AD mice with NEK7 knockdown exhibited shorter escape latencies and increased time spent in the target quadrant, suggesting that NEK7 inhibition improved cognitive function and memory retention. Mechanistically, Aβ treatment induced histone lactylation in BV-2 cells, and suppression of lactylation attenuated NEK7 transcriptional activity and mRNA levels. In summary, elevated NEK7 expression promoted histone lactylation in BV-2 cells, thereby facilitating pyroptosis. Inhibition of NEK7 conferred protection against Aβ-induced cellular damage and enhanced cognitive performance and memory retention in AD model mice. Collectively, targeting NEK7 represents a potential therapeutic strategy for alleviating AD symptoms.
阿尔茨海默病（AD）是一种与年龄相关的神经退行性疾病，其特征是脑组织不可逆转的退化。淀粉样蛋白-β（Aβ）级联假说被认为是解释 AD 发病机制的主要范例。本研究旨在阐明 Aβ诱导 AD 中细胞焦亡的机制。使用淀粉样前体蛋白/早老素 1（APP/PS1）转基因小鼠和 Aβ处理的 BV-2 细胞（5 μM，24 h）建立 AD 模型。在体外和体内评估 NEK7 的表达。在抑制 BV-2 细胞中的 NEK7 表达前后评估细胞焦亡。体内给予携带针对 NEK7 的短发夹 RNA（shRNA）的腺相关病毒（AAV）载体（AAV-sh-NEK7）以敲低体内的 NEK7。使用 Morris 水迷宫测试评估空间学习和记忆能力。然后研究了 NEK7 和组蛋白 H4 赖氨酸 12 乳酰化（H4K12la）之间的相互作用。结果表明，在体外和体内 AD 模型中，NEK7 的表达均明显升高。Aβ 处理显著降低了 BV-2 细胞的活力并增强了细胞焦亡；抑制 NEK7 可逆转这些作用。此外，敲低 NEK7 的 AD 小鼠的逃避潜伏期更短，在目标象限花费的时间更多，表明抑制 NEK7 可改善认知功能和记忆保留。从机制上讲，Aβ处理诱导了 BV-2 细胞中的组蛋白乳酰化，抑制乳酰化减弱了 NEK7 的转录活性和 mRNA 水平。总之，升高的 NEK7 表达促进了 BV-2 细胞中的组蛋白乳酰化，从而促进了细胞焦亡。抑制 NEK7 可防止 Aβ 诱导的细胞损伤，并提高 AD 模型小鼠的认知表现和记忆保留。总之，靶向 NEK7 可能是缓解 AD 症状的一种治疗策略。
