Early TGF-β3 Gene Therapy and Neuroinflammation: Therapeutic Potential for Motor and Non-Motor Impairments in Parkinson's Disease

Congreso; ISN-ASN 2025; 2025

International Society of Neurochemistry - American Society of Neurochemistry

Parkinson's disease (PD) is primarily marked by the degeneration of nigrostriatal dopaminergic neurons, leading to classic motor symptoms. However, the disease's etiology remains unclear, and research shows other brain regions, including the hippocampus and amygdala, are also affected, potentially causing non-motor symptoms before the motor ones emerge. Current treatments are administered after diagnosis and fail to stop neurodegeneration. Neuroinflammation, often characterized by cytokine release and glial cell activation, has been linked to the neurodegeneration process. Consequently, modulating neuroinflammation and dopaminergic neuron protection in early stages is viewed as a possible therapeutic strategy. The TGF-β protein family, known for anti-inflammatory effects, includes TGF-β3, which has also shown to promote the differentiation of neurons into a dopaminergic phenotype. This study investigates the effects of TGF-β3 overexpression via gene therapy on neurodegeneration in PD. Using Wistar rats with 6-hydroxydopamine (6-OHDA)-induced neurodegeneration to model PD, we noted that early motor symptoms developed 28 days post-infusion, while non-motor impairments appeared sooner. Open Field test at 28 days post 6-OHDA revealed a reduction in vertical movements and anxiety-like behavior in affected rats. Additionally, 21 days post 6-OHDA, these animals demonstrated impaired spatial memory in the Barnes Maze, and pro-inflammatory factors were elevated in the hippocampus. To test TGF-β3's effects, we administered a TGF-β3 gene using an adenoviral vector intracisternally into the rats' brains 14 days post-6-OHDA infusion. Results showed that 2 weeks later, TGF-β3-treated animals had higher striatal tyrosine hydroxylase (TH) expression, improved vertical movement, and reduced anxiety-like behavior. Moreover, 1 week after treatment, pro-inflammatory factors in the hippocampus decreased, and cognitive function improved in the treated animals. These findings suggest that early-stage TGF-β3 gene therapy can reduce neuroinflammation in the hippocampus and protect dopaminergic neurons, making it a promising early treatment approach for Parkinson's disease.