NATURAL POLYPHENOLS AS POTENTIAL TREM2 MODULATORS IN ALZHEIMER’S DISEASE: AN IN SILICO DOCKING STUDY

Abstract

Alzheimer’s Disease is one of the most leading and progressively debilitating neurodegenerative diseases characterized due to the accumulation of beta-amyloid plaques, and presence of tau tangles, and neuroinflammation. While years of research have been dedicated to determining what causes the disease, and ultimately, a cure, there has been little to no success in finding one, and new targets must be discovered. Receptor present on Myeloid Cells-2 (TREM2) is an important immunoreceptor that is mainly expressed on microglial innate immune cells, which are the first to respond to Central Nervous System (CNS). TREM2 was considered an important receptor that regulates microglial homeostasis by regulating many neuroprotective mechanisms including phagocytosis of Amyloid-Beta deposits, regulation of neuro-inflammatory processes, microglial survival/proliferation and preservation of synapses. A number of significant evidence both from the genetic and functional analyses indicate that failure to acquire function mutations or impaired TREM2 signaling pathways leads to impaired phagocytosis, chronic neuroinflammation, and accelerated Alzheimer's Disease (AD) progression. Contrary to this, it also demonstrates that stimulating TREM2 activity leads to better microglial neuroprotective responses, making TREM2 a promising target for enhancing its activity to develop disease-modifying therapies for AD via pharmacologic interventions. Considering the high profile interest in natural bioactive molecules as novel neurotherapeutic agents, the capacity of naturally occurring plant polyphenols to be potential regulators of TREM2 is addressed in this study. Epigallocatechin Gallate (EGCG), apigenin, curcumin and resveratrol are known to have important properties for eg - potent antioxidant, anti inflammatory properties. Also have the ability to cross the Blood Brain Barrier, and possess neuroprotective properties. In the present study, a computational molecular docking approach was used to explore the molecular interactions between TREM2 and these polyphenolic compounds. The target, a macromolecule, was obtained from the Protein Data Bank, and it was the three-dimensional crystal structure of TREM2 (PDB ID: 5ELI). The binding affinities, interaction profiles, and structural complementarities of EGCG, apigenin, curcumin, and resveratrol were systematically evaluated in the TREM2 binding site using molecular docking simulations. Based on the docking analysis, the four polyphenols showed a definite order of binding affinities. Apigenin showed binding affinity of −8.6 kcal/mol, and EGCG with an affinity of −8.5 kcal/mol, suggesting high specificity, stability, and thermodynamic favorability of their interactions with TREM2. The high binding energy of apigenin and EGCG implies that they can make multiple non-covalent interactions with the receptor, which help to stabilize the receptor-ligand complex. Curcumin showed moderate binding affinity (−7.1 kcal/mol), which is comparatively less, while resveratrol was found with the lowest binding affinity (−6.3 kcal/mol) in comparison to the other tested compounds with TREM2. These superior binding affinities of apigenin and EGCG suggest that they possess a high potential for modulating the activity of the TREM2 receptor and, therefore, the functional responses of microglia that are central to the pathology of AD such as the regulation of inflammation and the clearance of amyloid-β. Both apigenin and EGCG could present promising neuroprotective therapeutic leads based on their ability to target TREM2. Though this in silico molecular docking study gives preliminary results, it serves as a solid computational groundwork and a mechanistic explanation for the further in vivo preclinical and in vitro binding studies of these polyphenolic candidates in microglial models and in vivo studies. In summary, this study provides valuable insights into the therapeutic regulation of TREM2 signaling by natural polyphenols and suggests new drug development approaches using plant-derived polyphenols in the context of AD.

The keywords used are TREM2, Alzheimer's disease, neuroinflammation, microglia, molecular docking, polyphenols, apigenin, EGCG, curcumin, resveratrol, amyloid-β, neuroprotection and in silico.