Recent advances in the molecular signaling pathways of Substance P in Alzheimer's disease: Link to neuroinflammation associated with toll-like receptors

A significant quantity of substance P (SP) and its receptor, the neurokinin 1 (NK1) receptors are found in the brain. SP is a neuropeptide distributed in the central nervous system and functions as a neurotransmitter, neuromodulator, and neurotrophic factor. The concentrations of SP in the brain and cerebrospinal fluid fluctuate in individuals with Alzheimer's disease (AD). SP is an endogenous ligand for NK1 receptor, enhancing the expression of toll-like receptors (TLR) and vice versa. So, both pathways are interconnected, where activation of one pathway activates the second pathway. Researchers have observed the interaction of TLR with SP in the pathophysiology of AD. Thus, this review discusses various TLRs involved in regulating amyloid processing and its interaction with SP in AD. Further, in AD pathology, SP can regulate the non-amyloidogenic pathway. Recent studies have also demonstrated the capacity of SP in regulating voltage-gated potassium channel currents, emphasizing SP's neuroprotective ability. Therefore, we corroborate the findings linking the SP, NK1R, and TLRs in AD.