Pulmonary Hypertension Promotes Neuroinflammation and Neurodegeneration

Abstract

IntroductionPulmonary 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), Alzheimers Disease, and Amyotrophic Lateral Sclerosis (ALS). In this study, we hypothesize PAH will result in gliosis, reduced neuronal density, and increased TDP-43 mislocalization. MethodsSprague 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. Results and ConclusionsWe 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.