Phospholipase D1 Attenuation Therapeutics Promotes Resilience against Synaptotoxicity in 12-Month-Old 3xTg-AD Mouse Model of Progressive Neurodegeneration.
Phospholipase D1 Attenuation Therapeutics Promotes Resilience against Synaptotoxicity in 12-Month-Old 3xTg-AD Mouse Model of Progressive Neurodegeneration.
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DOI：
10.3390/ijms24043372
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发表时间：
2023-02-08
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
--
作者：
消除与年龄相关的神经退行性疾病中的突触毒性是一个非常有前途的研究领域，在包括阿尔茨海默病（AD）在内的tau蛋白病中具有重要的神经治疗意义。我们使用人类临床样本和小鼠模型的研究表明，磷脂酶D1（PLD 1）异常升高与淀粉样蛋白β（Aβ）和tau蛋白驱动的突触功能障碍和潜在的记忆缺陷相关。虽然敲除脂解PLD 1基因对跨物种的生存无害，但表达升高与癌症、心血管疾病和神经病理学有关，从而成功开发出耐受性良好的哺乳动物PLD亚型特异性小分子抑制剂。在这里，我们解决了PLD 1衰减的重要性，与年龄匹配的媒介物（0.9%盐水）注射的同胞相比，在3xTg-AD小鼠中，仅从约11个月大开始（tau驱动的损伤的影响更大），每隔一天重复1 mg/kg的VU 0155069（VU 01），持续一个月。涉及行为、电生理学和生物化学的多模式方法证实了这种临床前治疗干预的影响。VU 01被证明在后期有效预防AD样认知下降，影响嗅周皮质、海马和杏仁核依赖性行为。谷氨酸依赖性HFS-LTP和LFS-LTD改善。树突棘的形态表现出蘑菇状和丝状棘的特征。观察到差异性PLD 1免疫荧光和与Aβ的共定位。
Abrogating synaptotoxicity in age-related neurodegenerative disorders is an extremely promising area of research with significant neurotherapeutic implications in tauopathies including Alzheimer’s disease (AD). Our studies using human clinical samples and mouse models demonstrated that aberrantly elevated phospholipase D1 (PLD1) is associated with amyloid beta (Aβ) and tau-driven synaptic dysfunction and underlying memory deficits. While knocking out the lipolytic PLD1 gene is not detrimental to survival across species, elevated expression is implicated in cancer, cardiovascular conditions and neuropathologies, leading to the successful development of well-tolerated mammalian PLD isoform-specific small molecule inhibitors. Here, we address the importance of PLD1 attenuation, achieved using repeated 1 mg/kg of VU0155069 (VU01) intraperitoneally every alternate day for a month in 3xTg-AD mice beginning only from ~11 months of age (with greater influence of tau-driven insults) compared to age-matched vehicle (0.9% saline)-injected siblings. A multimodal approach involving behavior, electrophysiology and biochemistry corroborate the impact of this pre-clinical therapeutic intervention. VU01 proved efficacious in preventing in later stage AD-like cognitive decline affecting perirhinal cortex-, hippocampal- and amygdala-dependent behaviors. Glutamate-dependent HFS-LTP and LFS-LTD improved. Dendritic spine morphology showed the preservation of mushroom and filamentous spine characteristics. Differential PLD1 immunofluorescence and co-localization with Aβ were noted.
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磷脂酰肌醇 - 糖磷脂酶D参与病毒疾病的神经退行性。
影响因子：
3.7
作者：
Jin JK;Jang B;Jin HT;Choi EK;Jung CG;Akatsu H;Kim JI;Carp RI;Kim YS
通讯作者：
Kim YS
影响因子：
2.5
作者：
Burkhardt, Ute;Stegner, David;Klein, Jochen
通讯作者：
Klein, Jochen
表达人类野生型Tau的转基因小鼠的树突复杂性和脊柱形态的变化。
影响因子：
3.1
作者：
Dickstein, Dara L.;Brautigam, Hannah;Stockton, Steven D., Jr.;Schmeidler, James;Hof, Patrick R.
通讯作者：
Hof, Patrick R.
DOI：
10.1590/s1807-59322011001300002
发表时间：
2011
期刊：
Clinics (Sao Paulo, Brazil)
影响因子：
--
作者：
Bliss TV;Cooke SF
通讯作者：
Cooke SF
影响因子：
5.3
作者：
DeVos, Sarah L.;Goncharoff, Dustin K.;Miller, Timothy M.
通讯作者：
Miller, Timothy M.