Phospholipase D1 Mediated Early Events Affecting Synaptic Dysfunction in Alzheimer's Disease and Related Dementia

项目总结/摘要 在追求我们的治疗/机制研究，以解决我们的假设，诱导 磷脂酶D（PLD 1）过表达有助于对AD-cog的进行性有害影响。 为了解决这一问题，我们发表了两篇论文，强调了减弱PLD 1水平的作用 通过保留在突触水平观察到的树突棘和测量， 能够使用两种不同的记忆测试影响痴呆症。此外，使用3xTg-AD模型， 我们评估了一种性别特异性和时间设计的慢性衰减方法， 我们的假设是，在早期和晚期抑制Aβ和tau蛋白对PLD 1的募集， 仍然有效地促进突触的保存。令人惊讶的是，当使用免疫荧光 为了证实PLD 1和这些淀粉样蛋白生成威胁的共定位减少，我们还观察到 特定海马亚区Aβ水平降低。此外，这一减少也是由 改变了斑块的形态因此，我们建议研究这种机制， 行动，这在PLD 1衰减对淀粉样蛋白的影响方面扩大了领域 在疾病状态下的蛋白质化学在此补充的前提下，我们要求增- 国家基金，将提高我们现有的显微镜资源的分辨率， 米切尔中心，使我们能够更好地定性和定量地剖析机制- 从而增加了对与我们的方法相关的治疗能力的信心。

PROJECT SUMMARY/ABSTRACT In the pursuit of our therapeutic/mechanistic study to address our hypothesis that inducible phospholipase D (PLD1) overexpression contributes to the progressive detrimental impact on AD-cog- nitive deficits, we have published two papers that highlights how attenuating PLD1 levels contributes to synaptic resilience by preserving dendritic spines that is observed at the synaptic level and measur- able using two different kind of memory tests affected in dementia. Moreover, using the 3xTg-AD model, we assessed a sex-specific and a temporally designed approach of chronic attenuation that confirmed our hypothesis that inhibiting the recruitment of PLD1 by Aβ and tau both at early stages and late stages remains efficacious in promoting synaptic preservation. Surprisingly, when using immunofluorescence to confirm the reduced co-localization of PLD1 and these amyloidogenic threats, we also observed a reduction in the Aβ levels in specific hippocampal subregions. Moreover, this reduction was also ob- served in altered morphology of the plaques. As a result, we propose to investigate this mechanism of action, which extends the field ahead in terms of what outcomes the PLD1 attenuation has on amyloid protein chemistry in diseased states. Under the premise of this supplement, we are requesting addi- tional funds that would increasing the resolving power of our already existing microscopy resource at the Mitchell Center and allow us to dissect the mechanism in a better qualitative and quantitative man- ner leading to increased confidence in the therapeutic abilities associated with our approach.