Author ORCID Identifier
https://orcid.org/0009-0009-8472-7672 : Caleb Vegh
Date of Award
Chemistry and Biochemistry
Alzheimer's Disease, Mitochondria, Neurodegeneration, Neuroinflammation, Oxidative stress, Parkinson's disease
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
Alzheimer’s Disease (AD) and Parkinson’s Disease (PD) are the two most common and devastating neurodegenerative diseases in the world. There is no cure for either disease and current treatments provide only symptomatic relief. Furthermore, current treatments for AD and PD have shown to exhibit adverse side effects when taken over long periods of time. With age being the greatest risk factor for developing AD and PD, the increase in the aging population has the potential to lead to a serious medical/economic crisis due to the amount of time and care required for patients with AD and PD. The exact aetiologias of PD and AD is unknown but pathological features of these AD and PD respectively include: formation of neuritic plaques and neurofibrillary tangles, and neuron loss in the hippocampus leading to memory impairment; loss of dopaminergic neurons in the substantia nigra (SN) leading to movement impairment. While the targets of AD and PD are different, the end result of both lead to morbidity and eventually death. We have found from previous research, there are several biochemical mechanisms shared between AD and PD which include the following: 1) increased oxidative stress; 2) impaired autophagy/proteasome activity and accumulation of defective proteins; 3) mitochondrial dysfunction; 4) inflammatory modulation of microglia/astroglia; 5) accumulation of senescent cells. As a result of these multiple mechanisms, AD and PD should be considered a multifactorial disease and targeting only one of the mechanisms may prove unsuccessful in treating the diseases. Furthermore, many of the therapies used to treat symptoms of AD and PD are chemo-modulators and extended use has shown to have toxic and adverse psychological side effects. Therefore, in order to successfully treat these two neurodegenerative diseases, a multifaceted approach using natural health products that are well tolerated would be preferable. Prior research has shown the neuroprotective effects of Ubisol-Q10, a water-soluble formulation of coenzyme-Q10, and extracts of ashwagandha root, a plant used in Ayurveda (traditional Indian school of medicine). Previously, Ubisol-Q10 has been demonstrated to target oxidative stress, mitochondrial dysfunction, resume autophagy, and prevent cell senescence in in-vitro and in-vivo models of AD and PD. Ashwagandha extracts have shown to possess potent anti-inflammatory properties, prevent apoptosis of dopaminergic neurons in PD rodent models, and eliminated beta-amyloid plaques and improved memory in the brains of transgenic AD mice. This work sought to investigate the therapeutic potential of combined Ubisol-Q10 and ashwagandha root extract to target the biochemical mechanisms of AD and PD in-vitro and in-vivo. Here Ubisol-Q10 and ashwagandha extract were combined for the first time to investigate whether these two well-tolerated natural health products are more efficacious when administered together compared to the agents alone at targeting AD and PD biochemical mechanisms. Dopaminergic neurons were better protected and motility improved with the combination of Ubisol-Q10 and ethanolic extract of ashwagandha root (compared to either agent alone) in a paraquat induced rat model of Parkinson’s Disease. This was due to the agents working together to target all biochemical mechanism of PD Ubisol-Q10 was shown to reduce oxidative stress and enhance autophagy in the SN of paraquat injected rats. Meanwhile, ashwagandha extract acted as a potent anti-inflammatory by reducing activation of pro-inflammatory microglia and increasing activation of pro-survival/supporting astroglia. Increases in active astroglia coincided with an increased expression of pro-survival neurotrophic factors. Also, Ubisol-Q10 and ashwagandha prevented cell senescence in brains of paraquat injected rats. Efficacy of ashwagandha extract was further improved by using the same technology used in Ubisol-Q10 to increase solubility leading to better absorption and bioavailability. In Alzheimer’s Diseased fibroblasts and double transgenic AD mice, Ubisol-Q10 reduced oxidative stress and enhanced expression of autophagy. Autophagy was shown to be essential at preventing stress induced premature senescence (SIPS) in these fibroblasts as SIPS returned when autophagy was inhibited using small molecule autophagy inhibitor SP600125. Ubisol-Q10 and ashwagandha extract were more effective at preventing the development of beta-amyloid plaques in the brains double transgenic mice compared to the agents alone. This was likely due to the combined agents targeting all biochemical mechanisms of AD. Ubisol-Q10 reduced oxidative stress and autophagy impairment in double transgenic AD mice brains. Ashwagandha extract reduced activation of pro-inflammatory microglia and increased activation of pro-survival astroglia which coincided with increased expression of pro-survival brain derived neurotrophic factor. Since Ubisol-Q10 and ashwagandha are simple nutraceuticals and GRAS-approved, they can also be taken over long periods of time without serious side effects and could prove to be a promising therapy for AD and PD that could halt neurodegeneration and improve quality of life.
Vegh, Caleb, "Development of novel therapies targeting biochemical mechanisms to halt progression of Alzheimer’s and Parkinson’s Disease" (2022). Electronic Theses and Dissertations. 9136.