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) 过度表达会对 AD-cog- 产生渐进性有害影响 为了减少初始赤字，我们发表了两篇论文，重点介绍了降低 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提高突触弹性 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 在促进突触保存方面仍然有效。令人惊讶的是，当使用免疫荧光时 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 特定海马亚区域的 Aβ 水平降低。此外，这种减少还 改变斑块的形态。因此，我们建议研究这一机制 行动，扩展了 PLD1 减弱对淀粉样蛋白影响的领域 疾病状态下的蛋白质化学。在本补充的前提下，我们请求补充： 国家资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

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

• DOI: 10.3390/ijms22073668
• 发表时间: 2021-04-01
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Krishnan B;Natarajan C;Bourne KZ;Alikhani L;Wang J;Sowa A;Groen K;Perry B;Dickstein DL;Baulch JE;Limoli CL;Britten RA
• 通讯作者: Britten RA

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.

• DOI: 10.3233/jad-200716
• 发表时间: 2020
• 期刊: Journal of Alzheimer's disease : JAD
• 作者: Singh A;Allen D;Fracassi A;Tumurbaatar B;Natarajan C;Scaduto P;Woltjer R;Kayed R;Limon A;Krishnan B;Taglialatela G
• 通讯作者: Taglialatela G

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

• DOI: 10.3390/ijms24043372
• 发表时间: 2023-02-08
• 期刊: International journal of molecular sciences
• 影响因子: 5.6