Exploring the Role of Tau Proteins in Alzheimer’s Disease from Typical Functioning MAPs to Aberrant Fibrillary Deposits in the Brain

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that leads to memory loss and cognitive function deficits in affected individuals, eventually affecting their motor functions. Among many other neurodegenerative conditions, AD is the leading cause of disability and dependency in the elderly population. The two principal essential markers of AD pathology include abnormal deposition neurofibrillary tangles (tau proteins) and amyloid plaques (Aβ peptides). Thus, tau proteins are of critical interest as the prominent indicator of disease mechanisms. Understanding the normal biological functions of tau and the role of PTMs (posttranslational modifications) is essential. In AD, the alteration of physi-ological tau proteins into aberrant misfolded proteins, such as oligomers, PHFs, and NFTs, due to the PTMs, leads to its interneuronal propagation along with Aβ plaques. It results in synapse loss, neurotoxicity, and neurodegeneration. Since extensive research has shown that Aβ-targeting medicines are toxic and less effective at attenuating AD pathology, tau-directed therapeutics have gained significant reme-dial focus in recent decades. Although current tau-related therapies provide transient symptomatic comfort, they do not treat the illness overall. Hence, modern research has focused on analyzing tau protein’s mechanisms and complexities to produce effective disease-modifying drugs. This review presents a thorough understanding of tau proteins in AD pathogenesis, their origin, and their essential roles in physiolog-ical conditions. Additionally, various effective therapeutics targeting tau-associated PTMs such as hyperphosphorylation, acetylation, and methylation are described. Moreover, novel therapeutic strategies such as immunotherapy and oligonucleotide therapy have been mentioned. The clinical trials surrounding tau-related medications have also been highlighted.