An in Silico Approach to Study Tauopathies in Alzheimer's Disease and Modeling of Neuroprotective Compounds Targeting Neurofibrillary Tangles

Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline and memory impairment, closely associated with the pathological aggregation of Tau protein into neurofibrillary tangles (NFTs). Advances in cryo-electron microscopy (cryo-EM) have resolved Tau filament structures at near-atomic resolution, revealing disease-specific conformers such as paired helical filaments (PHFs) in AD (PDB: 7QKY, 6HRE), straight filaments in Pick's disease (PDB: 7P6Z), and C-shaped folds in chronic traumatic encephalopathy (CTE). These fibrils are stabilized by the PHF6 hexapeptide motif (\textsuperscript{306VQIVYK}311), which mediates steric zipper interactions through hydrophobic residues (V306, I308, Y310) and electrostatic contacts (K311). Genomic studies implicate MAPT haplotypes ($\text{H1} / \text{H2}$) and mutations (e.g., P301L) in altering 4R/3R Tau isoform ratios and accelerating fibrillization kinetics Tyrosine Protein Kinase (FYN AFP06241). Epigenetic modifications, including MAPT promoter hypomethylation and miR-132 depletion, further elevate Tau expression. Post-translational modifications such as hyperphosphorylation, acetylation at K280, and caspase cleavage at D421 induce conformational rearrangements that expose aggregation-prone domains. This study integrates computational biology, structural data, and modeling therapeutic strategies to target Tau pathology and FYN protein cascade mechanism interactions. Small molecules like epigallocatechin-3-gallate (EGCG, $\mathrm{Kd} =160 \text{nM}$) and curcumin inhibit Tau aggregation by modulating oxidative stress and steric interfaces, validated through molecular docking and hydrogen bond interaction analysis. Immunotherapies (e.g., semorinemab) and antisense oligonucleotides (ASOs) have demonstrated reduction in Tau levels in both preclinical and clinical settings. Emerging diagnostics such as Tau-PET tracers ([18F] MK-6240, SUVR = 2.43) and plasma p-Tau217 assays enable early detection and stratification of patients. We advocate a multi-target therapeutic approach combining structural biology and computational chemistry of natural bioactive compounds (omega-3 fatty acid, Hericenone C, Bilobalide (Ginkgo biloba), Epigallocatechin Gallate, curcumin, and resveratrol) to address hyperphosphorylation of Tau pathology. Future directions include CRISPR-based exon skipping and nanoparticle-based delivery systems to enhance blood-brain barrier penetration and therapeutic specificity. The results suggest Ginkgo Biloba, Hericenone C, Resveratrol, Curcumin, Epigallocatechin Gallate were shown the top binding affinity respectively with the Tau protein and FYN interactions.