De La Cruz Priscilla M, Lockett Angelia, Gomes Marta T, Banerjee Somanshu, Razee Asif, Fisher Amanda, Cook Todd, Lloyd Christopher D, Magaki Shino, Umar Soban, Oblak Adrian L, Machado Roberto F
Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Indiana University, Indianapolis.
Division of Pulmonary, Critical Care, and Sleep Medicine, University of New Mexico, Albuquerque.
bioRxiv. 2025 Sep 8:2025.09.02.673803. doi: 10.1101/2025.09.02.673803.
Pulmonary arterial hypertension (PAH) is associated with neurocognitive deficits and abnormal brain MRI. Little is known about the mechanisms underlying these clinical observations. TDP-43 is a proteinopathy associated with frontotemporal lobar degeneration (FTLD), Alzheimer's Disease, and Amyotrophic Lateral Sclerosis (ALS). In this study, we hypothesize PAH will result in gliosis, reduced neuronal density, and increased TDP-43 mislocalization.
Sprague Dawley rats were randomly assigned to receive Vehicle (DMSO) Monocrotaline, or Sugen/Hypoxia to induce PH. Right heart catheterization was used to confirm PAH. Brain tissue was fixed and probed for microglia (Iba1), astrocytes (GFAP), neurons (NeuN), and TDP-43. Human PH vs control brain tissue was also probed for NeuN and TDP-43.
We identify an increase in microglia and astrocyte density in the frontal cortex along with reduced neuronal density and neuronal TDP-43 mislocalization in rat models of PH. In addition, human PH frontal cortex demonstrated neuronal TDP-43 mislocalization. This is the first evidence of TDP-43 proteinopathy in PH.
肺动脉高压（PAH）与神经认知缺陷及脑部MRI异常有关。对于这些临床观察结果背后的机制知之甚少。TDP-43是一种与额颞叶痴呆（FTLD）、阿尔茨海默病和肌萎缩侧索硬化症（ALS）相关的蛋白病。在本研究中，我们假设PAH会导致胶质细胞增生、神经元密度降低以及TDP-43错误定位增加。
将Sprague Dawley大鼠随机分为接受载体（二甲基亚砜）、野百合碱或苏金/低氧以诱导肺动脉高压的组。使用右心导管插入术确认PAH。固定脑组织并检测小胶质细胞（Iba1）、星形胶质细胞（GFAP）、神经元（NeuN）和TDP-43。对人类PAH与对照脑组织也检测NeuN和TDP-43。
我们发现在PAH大鼠模型中，额叶皮质的小胶质细胞和星形胶质细胞密度增加，同时神经元密度降低且神经元TDP-43错误定位。此外，人类PAH额叶皮质显示出神经元TDP-43错误定位。这是PAH中TDP-43蛋白病的首个证据。
