Role of Autophagy Inhibition in Development of Alzheimer’s Disease: Resumption of Autophagy Leads to Neuronal Survival
Standing
Undergraduate
Type of Proposal
Oral Presentation
Faculty
Faculty of Science
Faculty Sponsor
Dr. Siyaram Pandey
Proposal
Alzheimer’s Disease (AD) is the most common neurodegenerative disorder associated with impaired memory, affecting 48 million people worldwide. Currently, the only treatments available are for symptomatic relief, rather than inhibiting its progression. The possible biochemical reasons for AD pathologies are inflammation, mitochondrial dysfunction, increased oxidative stress, and inhibition of autophagy. Autophagy is the cell’s mechanism for removing defective proteins and organelles; however, the role of autophagy in AD is not well understood. It has been shown that Ubisol-Q10 (water-soluble formulation of coenzyme-Q10) stabilizes mitochondria and reduces oxidative stress. This results in the inhibition of premature aging (senescence) in fibroblasts from Alzheimer’s disease (AD) patients with the presenilin-1 (PS-1) mutation. This PS-1 mutation leads to the build-up of defective proteins including amyloid-beta plaques which can induce oxidative stress and mitochondrial destabilization. Since Ubisol-Q10 was shown to reduce these AD pathologies, it was hypothesized that it may lead to the resumption of autophagy in AD fibroblasts. Through gene expression analysis, we observed that Ubisol-Q10 resulted in the upregulation of autophagy related genes at the mRNA level. We have also confirmed the expression of these genes at the protein level using Western Blotting and immunofluorescence. Ubisol-Q10 treatment led to increased expression of autophagy genes in AD fibroblasts compared to untreated AD fibroblasts. The autophagy gene expression profile of Ubisol-Q10 treated AD cells was observed and was comparable to fibroblasts from healthy subjects. Ubisol-Q10 was shown to prevent the formation of amyloid-beta plaques in the brains of transgenic AD mice as well as improve their long term and spatial memory. To confirm the fibroblast model results are transferable to an in-vivo neuronal model, transgenic mouse brains were examined for upregulation of autophagy in Ubisol-Q10 treated mice. Indeed, there was activation of autophagy. Therefore, autophagy seems to play a key role in neuronal health and its inhibition can lead to Alzheimer’s Disease. These results indicate that Ubisol-Q10 could be a potential therapeutic to ameliorate the progression of the disease.
Location
University of Windsor
Grand Challenges
Viable, Healthy and Safe Communities
Role of Autophagy Inhibition in Development of Alzheimer’s Disease: Resumption of Autophagy Leads to Neuronal Survival
University of Windsor
Alzheimer’s Disease (AD) is the most common neurodegenerative disorder associated with impaired memory, affecting 48 million people worldwide. Currently, the only treatments available are for symptomatic relief, rather than inhibiting its progression. The possible biochemical reasons for AD pathologies are inflammation, mitochondrial dysfunction, increased oxidative stress, and inhibition of autophagy. Autophagy is the cell’s mechanism for removing defective proteins and organelles; however, the role of autophagy in AD is not well understood. It has been shown that Ubisol-Q10 (water-soluble formulation of coenzyme-Q10) stabilizes mitochondria and reduces oxidative stress. This results in the inhibition of premature aging (senescence) in fibroblasts from Alzheimer’s disease (AD) patients with the presenilin-1 (PS-1) mutation. This PS-1 mutation leads to the build-up of defective proteins including amyloid-beta plaques which can induce oxidative stress and mitochondrial destabilization. Since Ubisol-Q10 was shown to reduce these AD pathologies, it was hypothesized that it may lead to the resumption of autophagy in AD fibroblasts. Through gene expression analysis, we observed that Ubisol-Q10 resulted in the upregulation of autophagy related genes at the mRNA level. We have also confirmed the expression of these genes at the protein level using Western Blotting and immunofluorescence. Ubisol-Q10 treatment led to increased expression of autophagy genes in AD fibroblasts compared to untreated AD fibroblasts. The autophagy gene expression profile of Ubisol-Q10 treated AD cells was observed and was comparable to fibroblasts from healthy subjects. Ubisol-Q10 was shown to prevent the formation of amyloid-beta plaques in the brains of transgenic AD mice as well as improve their long term and spatial memory. To confirm the fibroblast model results are transferable to an in-vivo neuronal model, transgenic mouse brains were examined for upregulation of autophagy in Ubisol-Q10 treated mice. Indeed, there was activation of autophagy. Therefore, autophagy seems to play a key role in neuronal health and its inhibition can lead to Alzheimer’s Disease. These results indicate that Ubisol-Q10 could be a potential therapeutic to ameliorate the progression of the disease.