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

磷脂酶 D1 介导影响阿尔茨海默病和相关痴呆症突触功能障碍的早期事件

• 批准号: 10812084
• 负责人: BALAJI KRISHNAN
• 金额: $ 3.45万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10812084
• 关键词: 3xTg-AD mouse; Address; Affect; Alzheimer' s disease model; Alzheimer' s disease related dementia; Amyloid Proteins; Amyloid beta-Protein; Chronic; Cognitive deficits; Creativeness; Dementia; Dendritic Spines; Development; Disease; Event; Fostering; Functional disorder; Funding; Health; Immunofluorescence Immunologic; Measurable; Mediating; Memory; Microscopy; Mission; Morphology; Outcome; Paper; Phospholipase D; Protein Chemistry; Public Health; Publishing; Quality of life; Research; Resources; Synapses; Testing; Therapeutic; United States National Institutes of Health; attenuation; design; effective therapy; hippocampal subregions; improved; overexpression; phospholipase D1; preservation; prevent; recruit; resilience; sex; sound; tau Proteins

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.

项目概要/摘要 在我们的治疗/机制研究中，为了解决我们的假设，即诱导性 磷脂酶 D (PLD1) 过度表达会导致 AD-cog- 的渐进性痛苦影响 为了减少初始赤字，我们发表了两篇论文，强调了降低 PLD1 水平如何发挥作用 通过保留在突触水平观察到的树突棘来增强突触弹性 能够使用两种不同类型的痴呆症记忆测试此外，使用 3xTg-AD 模型， 我们评估了一种针对性别和时间设计的慢性衰减方法，证实了 我们的假设是 Aβ 和 tau 在早期和晚期抑制 PLD1 的募集 令人惊讶的是，当使用免疫荧光时，它仍然有效地促进突触保存。 为了确认 PLD1 和这些淀粉样蛋白形成威胁的共定位减少，我们还观察到 此外，特定海马亚区域的 Aβ 水平也明显降低。 因此，我们建议研究这种机制。 行动，扩展了 PLD1 减弱对淀粉样蛋白影响的领域 在此补充的前提下，我们要求补充蛋白质化学。 国家基金，这将提高我们现有的显微镜资源的分辨率 米切尔中心，使我们能够以更好的定性和定量方法剖析该机制 ner 导致人们对与我们的方法相关的治疗能力更有信心。

项目成果

Functional Integrity of Synapses in the Central Nervous System of Cognitively Intact Individuals with High Alzheimer's Disease Neuropathology Is Associated with Absence of Synaptic Tau Oligomers.

患有高度阿尔茨海默氏病神经病理学的认知完整个体的中枢神经系统中突触的功能完整性与突触 Tau 寡聚物的缺失有关。

• 发表时间: 2020
• 作者: Singh, Ayush;Allen, Dyron;Fracassi, Anna;Tumurbaatar, Batbayar;Natarajan, Chandramouli;Scaduto, Pietro;Woltjer, Randy;Kayed, Rakez;Limon, Agenor;Krishnan, Balaji;Taglialatela, Giulio
• 通讯作者: Taglialatela, Giulio

Phospholipase D1 Attenuation Therapeutics Promotes Resilience against Synaptotoxicity in 12-Month-Old 3xTg-AD Mouse Model of Progressive Neurodegeneration.

磷脂酶 D1 减弱疗法可促进 12 个月大的进行性神经退行性变的 3xTg-AD 小鼠模型对突触毒性的抵抗力。

• 发表时间: 2023-02-08
• 影响因子: 5.6
• 作者: Natarajan, Chandramouli;Cook, Charles;Ramaswamy, Karthik;Krishnan, Balaji
• 通讯作者: Krishnan, Balaji

Suppressing aberrant phospholipase D1 signaling in 3xTg Alzheimer's disease mouse model promotes synaptic resilience.

抑制 3xTg 阿尔茨海默病小鼠模型中异常的磷脂酶 D1 信号传导可促进突触弹性。

• 发表时间: 2019-12-04
• 影响因子: 4.6
• 作者: Bourne, Krystyn Z;Natarajan, Chandramouli;Perez, Carlos X Medina;Tumurbaatar, Batbayar;Taglialatela, Giulio;Krishnan, Balaji
• 通讯作者: Krishnan, Balaji

Chronic Low Dose Neutron Exposure Results in Altered Neurotransmission Properties of the Hippocampus-Prefrontal Cortex Axis in Both Mice and Rats.

慢性低剂量中子暴露会导致小鼠和大鼠海马-前额皮质轴神经传递特性的改变。

• 发表时间: 2021-04-01
• 影响因子: 5.6
• 作者: Krishnan, Balaji;Natarajan, Chandramouli;Bourne, Krystyn Z;Alikhani, Leila;Wang, Juan;Sowa, Allison;Groen, Katherine;Perry, Bayley;Dickstein, Dara L;Baulch, Janet E;Limoli, Charles L;Britten, Richard A
• 通讯作者: Britten, Richard A