Alzheimer's disease (AD) is a progressive neurodegenerative disorder (ND) mainly leading to memory loss, cognitive decline, and extensive neuronal damage, affecting millions of people worldwide, [1] especially older adults of age 65 years and above. [2], [3], [4], [5] The pathology of AD is characterized by the abnormal accumulation of amyloid-beta (Aβ) plaques, and hyperphosphorylated Tau proteins in different forms like monomers, oligomers, aggregates and Tau neurofibrillary tangles. [6], [7], [8], [9], [10], [11] Abnormal accumulation of Aβ peptide led to formation of Aβ plaques outside the neurons, disrupting communication between cells and contributing to cell death. [12], [13], [14], [15] According to Young-Pearse et al., there are many different proteins implicated in AD but Aβ and Tau have long been recognized as the primary ones contributing to key pathological process. [16] Tau proteins are associated to microtubules and help stabilize neurons. Tau protein structurally consists of 441 amino acids, with five important distinct regions, which are N-terminal domain, N-terminal inserts (N1, N2), proline-rich domains (PRD1, PRD2), a microtubule-binding domain (R1-R4), and a C-terminal domain. [6] When Tau undergoes aberrant post-translational modifications (PTMs) like hyperphosphorylation, it leads to the formation of neurofibrillary tangles that impair cellular transport thus leading to neuronal dysfunction. [17] Similarly, Acetylation also leads to impaired microtubule-binding and reduces its solubility, ultimately impairing protein degradation and truncation which allows Tau aggregation, further increasing Tau toxicity by reducing microtubule binding and enhancing synaptic dysfunction. [18] Alongside these structural changes of Tau protein, PTMs and prolonged activation of microglia leads to significant neuroinflammation, collectively manifesting the hallmark symptoms of AD and behavioural changes, which may progressively impair an individual’s ability to function independently. [19], [20], [21] G-protein coupled receptors (GPCRs) are important gatekeepers in AD; for a long period of time, studies focused on the clearance of Aß; however, recently the trend has shifted towards Tau clearance, especially via GPCRs because of their involvement in recognition, interaction and degradation.

Effective Tau clearance is an important mechanism involved in reducing neuroinflammation, neurotoxicity and maintaining synaptic architecture to ensure proper mitochondrial function. [22], [23], [24] Tau propagates in a prion-like fashion from cell-to-cell, current research is sparse in terms of outlining the mechanism of Tau clearance via G-protein coupled receptors (GPCRs), making it the need of the hour to unravel these mechanisms for reducing the build-up of toxic protein aggregates and oligomers and pave the way forward for therapeutic interventions. [25], [26], [27]