## 1 Introduction  
Tau protein is a microtubule-associated protein known to stabilize microtubules in neurons and other cells, and it plays a major role in cellular differentiation, neurite outgrowth and polarization [1]. In a recent study, [PERSON] and co-workers showed through computational studies that Tau's capacity to facilitate lateral interactions with microtubules plays a significant role in microtubule stabilization by crosslinking protofilaments. Furthermore, Tau competes with the microtubule-binding protein EB1 for binding to microtubules [2]. Additionally, [PERSON] and co-workers were able to computationally predict the three-dimensional structure of Tau protein both under simulated intracellular fluid and microtubule associated conditions. They showed that Tau can adopt different secondary structures depending on whether or not it is associated with microtubules. It was shown that tau adopts a more compact structure with few helical motifs closer to the microtubule-binding regions in simulated intracellular fluid, while when associated with microtubules, it adopts an extended conformation, with helical conformation at the microtubule-binding region, and the N- and C-terminals remain apart from each other [3]. In order to examine the mechanistic aspects involved in Tau binding to microtubules, and the impact of post-translational modifications, the group created acetylated Lys residues and phosphorylated Ser/Thr/Tyr residues and generated various acetylated and phosphorylated Tau analogs. Using molecular dynamics simulations, they demonstrated that the electrostatic changes due to the loss of positively charged Lys residues result in the disassociation from the microtubules [4]. While tau is found in healthy brain tissues, it is well-known that hyper-phosphorylated intracellular filamentous aggregates of tau lead to the formation of neurofibrillary tangles (NFTs). The formation of these aggregates has been implicated in several neurodegenerative diseases, including Alzheimer's disease, Pick disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and in dementia related to Parkinson's disease [5]. Additionally, tau has been known to upsurge amyloid-\(\beta\) toxicity by modifying the activity of tyrosine kinase (Fyn), which plays a key role in tau aggregation [6]. Recent studies have also shown that in the case of synucleinopathies, in addition to the accumulation of \(\alpha\)-synuclein, tau oligomers accumulate in diseased brains due to the formation of hybrid tau-alpha-synuclein aggregates [7]. Thus, several studies have been conducted to investigate the aggregation and spread of tau protein to elucidate neurological disease mechanisms and develop potential treatments. In one study, it was reported that changes in the microtubule-binding domain of tau protein due to hyperphosphorylation lead to its dysregulation and separation of tau from microtubules [8]. Upon separation, tau starts to misfold and aggregate intracellular in neurons. Furthermore, the intracellular tau can not only aggregate within neurons, but those aggregates can also be transmitted between cells, leading to the spread of the aggregates. The major constituents of Tau NFTs are the paired helical filaments (PHF) and SF (straight filaments), both of which tend to form C-shaped structural subunits [9; 10]. Studies using steered molecular dynamics simulations have demonstrated that the 306-311 segment of Tau that contains the sequence VQIVYK motif plays an important role in docking of soluble Tau to PHF fibrils, and further folding of Tau along the PHF fibrils occurs with the formation of \(\beta\)3, \(\beta\)4 and \(\beta\)5 regions [11]. Several studies have shown that tau is not only present in the cytoplasm of neurons, but it is also actively released into the extracellular regions. To that end, it has been shown that this cell-to-cell propagation of tau is promoted by the uptake of extracellular tau, which can act as a seed for soluble tau in cells and lead to the propagation and spread of tauopathies [12].