Epigenetic Reprogramming as a Treatment for Alzheimer's Disease
This review paper lumps together thoughts on the prospects for both epigenetic reprogramming and upregulation of autophagy as approaches to the treatment of Alzheimer's disease, the former a much more recent development in the research community, and the latter a long-running goal that has seen less concrete progress than desired. The long, slow path to any sort of success in the development of Alzheimer's therapies based on clearance of amyloid-β has led to considerable pressure to try other other avenues, but despite numerous trials and development programs, few of those have made much progress towards the clinic as of yet.
Age remains the largest risk factor in the development of neurodegenerative diseases such as Alzheimer's disease (AD). Numerous cellular hallmarks of aging contribute to the advancement of the pathologies associated with neurodegenerative disease. Not all cellular hallmarks of aging are independent and several fall into the broader category of cellular rejuvenation, which captures returning cells to a more youthful, improved functional state. Cellular rejuvenation is quickly becoming a hot topic in the development of novel therapeutic modalities for a range of diseases. Therapeutic approaches utilizing cellular rejuvenation technologies are rapidly advancing and will represent the next phase of AD therapeutics.
This review focuses on two important processes, epigenetic reprogramming, and chaperone-mediated autophagy (CMA) that play a critical role in aging and in neurodegenerative diseases and the potential therapeutic approaches (gene therapy, small molecule) towards targeting these mechanisms. In aging and in AD, epigenetic changes on DNA (e.g., hypermethylation on CpG islands) lead to alterations in gene expression. Partial epigenetic reprogramming utilizes transcription factors to remove the epigenetic marks and to rejuvenate cells to a more youthful state. During aging and in neurodegenerative disorders, CMA becomes impaired resulting in a buildup of proteins known to be associated with neurodegenerative pathologies. The protein buildups lead to aggregates that preclude proteostasis leading to cell toxicity. Small-molecule CMA activators restore proteostasis and limit toxicity enabling cellular rejuvenation.