The hidden players: Shedding light on the significance of post-translational modifications and miRNAs in Alzheimer's disease development

Alzheimer's disease (AD) is the most prevalent, expensive, lethal, and burdening neurodegenerative disease of this century. The initial stages of this disease are characterized by a reduced ability to encode and store new memories. Subsequent cognitive and behavioral deterioration occurs during the later stages. Abnormal cleavage of amyloid precursor protein (APP) resulting in amyloid-beta (Aβ) accumulation along with hyperphosphorylation of tau protein are the two characteristic hallmarks of AD. Recently, several post-translational modifications (PTMs) have been identified on both Aβ as well as tau proteins. However, a complete understanding of how different PTMs influence the structure and function of proteins in both healthy and diseased conditions is still lacking. It has been speculated that these PTMs might play vital roles in the progression of AD. In addition, several short non-coding microRNA (miRNA) sequences have been found to be deregulated in the peripheral blood of Alzheimer patients. The miRNAs are single-stranded RNAs that control gene expression by causing mRNA degradation, deadenylation, or translational repression and have been implicated in the regulation of several neuronal and glial activities. The lack of comprehensive understanding regarding disease mechanisms, biomarkers, and therapeutic targets greatly hampers the development of effective strategies for early diagnosis and the identification of viable therapeutic targets. Moreover, existing treatment options for managing the disease have proven to be ineffective and provide only temporary relief. Therefore, understanding the role of miRNAs and PTMs in AD can provide valuable insights into disease mechanisms, aid in the identification of biomarkers, facilitate the discovery of novel therapeutic targets, and inspire innovative treatments for this challenging condition.