The Prognostic and Therapeutic Role of Tumor Necrosis Factor-Alpha (TNF-α) in Type 2 Diabetes Mellitus and Alzheimer’s Disease: Neuroimmune Mechanisms and Selective TNFR1 Targeting

Tumor necrosis factor-alpha (TNF-α) is considered as a key pro-inflammatory cytokine which plays a critical role in the pathophysiology of type 2 diabetes mellitus (T2DM) besides Alzheimer’s disease (AD). The current study investigates that the dual involvement of TNF-α in metabolic impairment and neurodegeneration, highlighting its molecular signaling mechanism achieved by two receptor interactions: TNFR1 with TNFR2, along with downstream inflammatory cascades. TNF-α is related to insulin resistance via serine phosphorylation of the insulin receptor substrate-1, and promotes pancreatic β-cell dysfunction, subsequently can disrupt blood–brain barrier integrity, and facilitate neuroinflammatory state. Within human central nervous system, TNF-α enhances the amyloid-β accumulation, tau hyperphosphorylation, in addition to synaptic impairment through activation of NF-κB with JNK pathways. The results of molecular docking analysis illustrated that the favorable binding affinities of TNF-α inhibitors toward the receptor TNFR1, of the binding energies ranging between −8.4 to −9.1 kcal/mol, are strongly indicating stable ligand–receptor interactions among them. Key amino acid residues which involved in this binding include Tyr151, Leu120, with Glu143 that supported by hydrogen bonding with hydrophobic interactions. These findings demonstrate that the structural basis of selective TNFR1 can be inhibited during preserving TNFR2-mediated neuroprotective signaling. Furthermore, integrated bioinformatics besides clinical data revealed the elevated TNF-α overexpression in both T2DM along with AD, supporting TNF-α role as a molecular bridge between neurodegeneration and systemic inflammation. Moreover, TNF-α can represent a promising biomarker. Selective modulation of TNFR1 might offer a novel strategy to mitigate both cognitive and metabolic decline.