Neuroscience Program Seminar
Michigan State University
Is BDNF Signaling Dysfunctional in the Aged Brain?
Parkinson’s disease (PD) is a chronic neurodegenerative disorder characterized by both motor and non-motor symptoms. Histologically, PD manifests primarily as degeneration of dopamine (DA) neurons projecting from the substantia nigra (SN) to the striatum. An experimental approach that has had longstanding interest for treatment of PD symptoms is replacement of striatal DA terminals. Two regenerative strategies that have shown promise in animal models of PD include 1) delivery of trophic factors to induce sprouting of remaining nigral DA neurons, and 2) engraftment of embryonic DA neurons to replace those lost to disease. However, despite relative success in animal models of PD, these experimental therapies did not translate well to the clinic. Indeed, in controlled clinical trials, both strategies failed to provide significant clinical improvement, particularly for older patients and those with more advanced pathology. Interestingly, in embryonic DA neuron grafting trials, a significant subpopulation of patients has shown limited or no benefit and/or development of significant graft-derived side effects, despite robust survival of transplanted cells – a surprising finding that also has been shown by our group in aged parkinsonian rats grafted with DA neurons. Overall, the cumulative evidence suggests that factors inherent to the aged striatum limit successful brain repair. However, the impact of the aged brain on the response to regenerative therapy has received limited attention in preclinical studies. Interestingly, while young animals show a robust compensatory neurotrophic response after striatal DA depletion, aged animals lack this response, indicating a possible aging-related disruption of neurotrophic activity in the striatum. One member of the mammalian neurotrophin family, brain derived neurotrophic factor (BDNF), is known to play an important role in spine dynamics and actin remodeling, and has been implicated as a critical factor controlling spine density in the striatum. Though current evidence generally supports the idea that BDNF protein expression in the brain does not change with age, studies have shown impaired ability of the aged brain to produce BDNF in response to stress and reduced expression of BDNF transcription factors compared to the young brain. Taken together these data may indicate diminished capacity of the aged brain to transcribe, release, and/or respond to BDNF. Thus, the overarching hypothesis of the proposed experiments is that dysfunctional BDNF signaling in the aging striatum reduces the number of striatal dendritic spines available for functional synaptic integration with new DA terminals. Ultimately, these studies will contribute to our understanding of whether and how BDNF dysfunction occurs in the aged parkinsonian brain, and importantly, will provide a first step toward understanding its impact on regenerative approaches for the treatment of PD.
Dr. Kathy Steece-Collier
Thursday, November 30th, 2017 at 12:30pm
Room 1425 BPS
This seminar will originate from room 1102 A&B Grand Rapids Research Center
This seminar is also available for viewing in BPS room 1425
Connect via zoom - https://msu.zoom.us/j/893113407