Parkinson’s disease (PD) is the second most common neurodegenerative disorder behind Alzheimer’s disease, and is a major burden to society. PD is a progressive disorder resulting in a variety of symptoms including dementia, autonomic, and motor dysfunction; all contributing to a diminished quality of life for afflicted individuals. Current treatments help to restore motor function, however there are no disease-modifying treatments that halt or slow the progression of PD. The question of whether deep brain stimulation (DBS) of the subthalamic nucleus (STN) can be disease-modifying in PD remains unanswered. Preclinical studies link STN DBS-mediated neuroprotection of nigrostriatal dopamine neurons to brain-derived neurotrophic factor (BDNF) signaling. However, the impact of STN DBS on α-synuclein (α-syn) aggregation, inclusion-associated neuroinflammation, and BDNF levels have yet to be examined in the context of synucleinopathy.In this dissertation I examine the effects of STN DBS on BDNF in the preformed fibril synucleinopathy model. PFF injection resulted in accumulation of phosphorylated α-syn (pSyn) inclusions in the substantia nigra pars compacta (SNpc) and cortical areas. SNpc pSyn inclusions were associated with significantly increased major histocompatibility complex-II immunoreactive (MHC-II-ir) microglia, and intensity, complexity, and length of astrocytes. Rats with pSyn inclusions had less tyrosine hydroxylase (THir) SNpc neurons (≈18-33% decrease) reflecting loss of TH phenotype. STN DBS did not alter any of these pSyn inclusion-associated effects, and also did not impact the size or intensity of individual pSyn inclusions within the SNpc. The presence of pSyn inclusions did not alter total levels of BDNF protein in any of the structures evaluated. However, the normally positive association between nigrostriatal and corticostriatal BDNF levels was negatively impacted in PFF treated rats. Despite this, rats receiving both PFF injection and STN DBS exhibited significantly increased BDNF protein in the striatum, which partially restored the normal corticostriatal BDNF relationship.The rat α-syn PFF model provides a relevant preclinical platform to examine the impact of STN DBS on multiple potentially disease-modifying factors. Our results demonstrate that pSyn inclusions may alter anterograde BDNF transport. However, STN DBS retains the ability to increase BDNF within the context of synucleinopathy. Future studies will examine whether long-term STN DBS can prevent the nigrostriatal degeneration associated with longer post PFF injection intervals.
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