The Role of Amyloids and Glycated Protein Adducts in Immune Regulation and Homeostasis: Unraveling the Molecular Interplay Between Diabetes and Neurodegeneration

The convergence of metabolic disorders such as diabetes with neurodegenerative diseases forms an urgent and intricate clinical challenge—one underpinned by the accumulation of amyloid and glycated protein adducts. One of the principal molecular consequences of chronic hyperglycemia is the non-enzymatic glycation of proteins, resulting in the formation of Advanced Glycation End products (AGEs). AGEs, displaying high structural and functional diversity, exert their pathophysiological roles primarily via engagement with the Receptor for AGEs (RAGE) expressed on a wide array of immune effector cells, including T cells, monocytes, and macrophages. This interaction is known to drive pro-inflammatory cytokine release, immunometabolic dysfunction, cell cycle arrest, and apoptosis, bearing implications for both systemic inflammation (as seen in obesity and diabetes) and organ-specific damage (such as neurodegeneration and liver disease).

Importantly, AGEs and amyloidogenic protein species share conformational and aggregative properties, with certain AGE species morphologically mimicking amyloid. Both AGEs and amyloids interact with pattern recognition receptors—including the RAGE and Toll-Like Receptors (TLRs)—converging on the activation of inflammasome complexes such as NLRP3 and thereby orchestrating complex immune signaling cascades. Notably, amyloids (such as β-amyloid) and their interaction with T regulatory (Treg) cells point to dual roles in modulating both inflammatory and anti-inflammatory axes, thus impacting immune homeostasis, self-tolerance, and resilience to chronic insults.

Recent advances in molecular biology, neuroendocrinology, immunology, and clinical nutrition have opened major avenues for:

Identification of structural motifs of glycated proteins that determine binding affinity to RAGE;

Molecular dissection of inflammasome activation and its downstream effectors in the context of metabolic and infectious diseases;

Understanding the crosstalk between immune and metabolic systems in modulating proteopathic stress and immune resilience;

Developing precision intervention strategies that offer neuroprotection or counteract glycation stress by regulating immune homeostasis.

This Research Topic invites high-quality original research, reviews, and perspectives focused on, but not limited to:

• Molecular signatures of AGE-RAGE interaction
• Extracellular proteome surveillance and amyloid profiling
• Novel inflammasome complexes
• Immune modulation by amyloids and AGEs
• High-throughput screening and signaling analyses
• Diet, nutraceuticals, and metabolic regulation
• Infectious disease intersections

We seek:

• Submissions that bridge molecular mechanisms to translational, clinical, or public health insights.Contributions showcasing integrative 'bench to bedside' or 'omics to intervention' workflows.
• Studies on therapeutic targeting of the AGE-RAGE/amyloid axis for improved neuroimmune and metabolic outcomes.
• Potential contributors are encouraged to leverage recent advances in structural biology, high-throughput omics, molecular immunology, nutritional science, nanoformulations, and computational biology.

Together, we aim to deepen our understanding of how glycation and amyloidogenesis shape the 'immune-metabolic-neural' landscape and foster innovations in disease prevention, diagnosis, and treatment.

Manuscript that are not focusing on immunological mechanisms or immunological parameters are out of scope for this section; manuscripts describing the pharmacological action of drugs, including those used in traditional medicine, are not in scope unless they have a strong focus on the immune system.