In order to further examine the role of chronic neuroinflammation in the pathogenesis of PD, we are studying additional pathophysiological changes that occur in the CNS of our systemic LPS models. The main purpose of this project is to use our models to delineate the mechanism of the progressive nature of inflammation-elicited DA neurodegeneration. Currently, we are investigating the role of chronic neuroinflammation, in both C57Bl/6 and human mutant alpha-synuclein (A53T) over-expressing transgenic mice, on non-motor lesions and changes in the neurovascular unit.
The etiology of PD and the precise mechanism of action underlying the destruction of the nigro-striatal DA pathway remain unknown. We and others have recently provided evidence indicating that neuroinflammation plays a pivotal role in the pathogenesis of PD. The goal of this project is to provide insight into the mechanisms underlying the delayed and progressive nature of PD based on our chronic neuroinflammation models.
Current therapies for PD patients provide temporary symptom relief (e.g., levodopa), but are ineffective at halting the progression of neurodegeneration. By targeting the “self-propelling cycle,” our group is developing a new class of anti-PD therapies. We have demonstrated that interventions that target this self-propelling cycle effectively prevent the progression of the neuronal death. Furthermore, we have focused our efforts to develop a “dual therapy” intervention strategy that:
- modulates microglial activation, so that neuroinflammation can be dampened to controllable levels, becoming beneficial for neuronal survival, and
- enhances the release of neurotrophic factors from astroglia, to elicit increased neuronal survival and to further minimize the intensity of neuroinflammation from reactive microglia.