## 1 Introduction
Thus, the targeting and mitigation of cellular internalization of extracellular tau is one of the therapeutic routes that may be utilized to combat the propagation of tau pathology. Several mechanisms are involved in regulating the levels of extracellular tau, and internalization pathways have been put forward. Both monomeric and oligomeric tau have been shown to enter neurons through dynamin-dependent processes [13]. Studies have also shown that extracellular misfolded tau can be internalized through heparin sulfate proteoglycan (HSPGs) present on cell surfaces, in a similar manner as prion proteins [14]. Additionally, Tau monomers, dimers and trimers are also internalized through clathrin-mediated endocytosis and that internalization is also dependent upon HSPGs as Tau contains heparin-binding regions [15]. Several receptors such as alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) [16] and muscarinic receptors (M1, M3) have been implicated in the internalization of tau [17]. Moreover, studies conducted by [PERSON] et al. have demonstrated that soluble extracellular Tau can interact with muscarinic receptors, while PHF tau does not [18]. It has also been shown that there is an increase in microglia that express M1 and M3 muscarinic receptors in [PERSON]'s disease mice models, implicating their role in the clearance of Tau. Other proteins including leucine-rich repeat serine/threonine-protein kinase 2 (LRRK2) as well as phosphatidylinositol 3-kinase subunit type 4, which regulate endocytosis and autophagy, have also been shown to be involved in neuronal uptake of monomeric and fibrillar tau [19; 20]. In another study, it was shown that over-expression of Rab-5, a Ras-related protein, also promotes tau internalization of vesicle-free tau, which subsequently accumulates in endosomes [21]. Furthermore, it has been demonstrated that beta amyloid (A\(\beta\)) peptide-induced signaling can bolster tau phosphorylation, leading to hyperphosphorylation and tau pathology [22]. In a contrasting study, however, [PERSON] et al. showed that site-specific phosphorylation of tau mediatedby neuronal p38 mitogen activated protein kinase p38y-mitigated A\(\beta\) toxicity [23]. In a recent study, it was also shown that tau interacts with cell membranes by binding to membrane proteins, which may lead to misfolding of tau, causing cellular dysfunction and disease [24]. While internalization of normal tau is necessary for regulated neuronal processes, the internalization of pathological forms of tau such as misfolded, pseudo-phosphorylated tau proteins disrupts normal neuronal processes and causes aggregation and propagation of tauopathies. Research focusing on the mechanisms by which healthy neurons uptake extracellular misfolded tau during trans-synaptic seeding has aimed to study both the cellular components and specific tau morphologies involved in this process. Anti-tau antibodies have been developed to deter the uptake and spread of pathological extracellular tau [25]. Antibodies that can distinguish between healthy and diseased tau and block the uptake of diseased tau have also been developed [26]. Furthermore, antibodies developed against the first-in-man tau vaccine, AADvac1, were shown to promote uptake of diseased tau proteins that that were subsequently removed by microglial cells. In a pioneering study by [PERSON], it was reported that the endocytic cell surface apo E receptor, low-density lipoprotein-related receptor protein 1 (LRP1), can regulate tau uptake and spread across cells [27], and that lysine residues in the microtubule-binding domain of tau play a key role in binding with LRP1. Because LRP1 is expressed not only in neurons, astrocytes, endothelial cells and microglia, but also other tissues such as liver, lungs and adipose tissue, it can recognize a variety of ligands, thus making the investigation of tau internalization processes through LRP1 highly significant [28].