IN SILICO EVALUATION OF NATURAL POLYPHENOLS AS POTENTIAL MODULATORS OF TREM 2 IN ALZHEIMER’S DISEASES

Abstract

The Alzheimer’s Disease in today’s world is one of the most leading and progressively debilitating neurodegenerative diseases characterized due to the deposition of beta-amyloid plaques, and presence of tau tangles, and neuroinflammation. Although years of research have been put into finding out a cure for this progressive disease, very little success has been achieved, thus necessitating the need for new targets to be discovered. Triggering Receptor Expressed found on Myeloid Cells-2 (TREM2) has proven to be recognized as an important immunoreceptor which is expressed mainly on microglia innate immune cells which are found on the Central Nervous System (CNS) and they act as the brain's first responders to pathological stimuli. TREM2 acts as a vital regulatory receptor of microglial homeostasis by controlling various neuroprotective mechanisms such as phagocytosis of Amyloid-Beta deposits, regulation of neuroinflammatory processes, microglial survival/proliferation, and synapse preservation. There are many considerable evidence based on genetic studies and functional analysis which proves that a lack of function mutations or improper regulation of TREM2 signaling pathways results in poor phagocytosis, persistent neuroinflammation, and faster progression of Alzheimer's Disease (AD). In contrast to this, it also proves that enhancing TREM2 activity improves neuroprotective responses of microglial cells; hence, TREM2 is considered as an appealing candidate for pharmacological modulation to achieve disease modification therapies for AD. In light of the increasing attention paid to natural bioactive molecules as novel neurotherapeutic agents, this study explores the ability of naturally occurring plant polyphenols as potential TREM2 regulators. Epigallocatechin Gallate (EGCG), apigenin, curcumin, and resveratrol are widely recognized to possess potent natural reductive phytocompounds, inflammation suppressing effects, the ability to pass through the Blood Brain Barrier, and neuroprotective properties. By evaluating the molecular interactions between TREM2 and these polyphenolic compounds, a computational in silico approach employing molecular docking was adopted in the present study. The 3D crystal configuration of TREM2 (PDB ID: 5ELI) was derived from the RCSB PDB i.e Protein Data Bank and used as the macromolecular target. In Silico docking activation were stimulated to systematically Evaluate the binding energies, interaction patterns and structural complementarity of EGCG, apigenin, curcumin, and resveratrol within the TREM2 binding site. The docking analysis revealed a distinct hierarchy of binding affinities among the four polyphenols. Apigenin exhibited the highest binding affinity of −8.6 kcal/mol followed closely by EGCG at −8.5 kcal/mol, indicating that both compounds form thermodynamically favorable, stable, and highly specific interactions with TREM2. The strong binding energies observed for apigenin and EGCG suggest their capacity to engage critical residues within the TREM2 active site through multiple non-covalent interactions, H-bond mediated stabilization, apolar molecular contacts, and van der Waals forces, thereby stabilizing the receptor-ligand complex. Curcumin exhibited a moderate binding affinity of −7.1 kcal/mol, indicating reasonable but comparatively weaker interaction, while resveratrol recorded the lowest binding affinity of −6.3 kcal/mol among the tested compounds, suggesting limited binding efficiency with TREM2. The superior binding affinities of apigenin and EGCG highlight their strong potential to modulate TREM2 receptor activity and, consequently, influence downstream microglial functional responses central to AD pathology — most notably neuroinflammation regulation and amyloid-β phagocytic clearance. These findings suggest that both apigenin and EGCG can be taken as lead phytochemical scaffolds for the evolution of TREM2-targeted neuroprotective therapeutics. While the results of this in silico molecular docking study are preliminary in nature, they provide a robust computational foundation and mechanistic rationale for advancing these polyphenolic candidates into subsequent stages of experimental validation, including in silico binding, cell-based operative studies in microglial models, and ultimately in vivo preclinical investigations. Collectively, this study contributes meaningful insights into the therapeutic modulation of TREM2 signaling through natural polyphenols and paves new pathways for the advancement of effective, plant-based interventional strategies for Alzheimer's disease.