Targeting Substance P Pathway as an Emerging Novel Therapeutic Mechanism for Modulating Amyloid Beta in APP/PS1 Mouse Model

Abstract Background Neurodegeneration associated with Alzheimer’s disease (AD) is well established to be mediated by amyloid β (Aβ) plaques and neurofibrillary tangles (NFTs) of Tau protein in the brain. However, there are a multitude of underlying processes that individually contribute to the development of these aberrant Aβ aggregations and NFTs over time that are still being elucidated. The substance P/neurokinin‐1 receptor signaling pathways play an important role in regulating neuroinflammation and have recently been demonstrated to also influence mechanisms responsible for Aβ amyloidogenesis and toxicity 1,2,3 . Accordingly, HT‐ALZ is under development as a novel AD therapeutic to target the SP/NK1R pathway. Method Using microdialysis, Aβ levels in the interstitial fluid (ISF) of the hippocampus were measured in male and female APP/PS1 mice (3‐4 months old). ISF samples were collected every hour for 6 hours prior to treatment to establish a baseline, HT‐ALZ or vehicle was administered via oral gavage, and samples were collected continuously for 12‐15 hours following treatment. Aβ levels were measured using ELISA and changes from baseline were calculated for each mouse. Result We observed a significant change from baseline in mice treated with HT‐ALZ, but not in vehicle treated mice. Mice treated with HT‐ALZ show a decrease in average ISF Aβ following treatment. Conclusion Results of our microdialysis study indicate targeting the SP/NK1R pathway has a beneficial effect on circulating Aβ levels in the mouse brain, which may lead to lower plaque load with longer term treatment. We are currently investigating the impact of HT‐ALZ on the cognitive and behavioral impairments in APP/PS1 mice; the results of these studies will be provided at the time of presentation. References : 1. Martinez AN, Philipp MT. Substance P and Antagonists of the Neurokinin‐1 Receptor in Neuroinflammation Associated with Infectious and Neurodegenerative Diseases of the Central Nervous System. J Neurol Neuromedicine. 2016;1(2):29‐36. doi:10.29245/2572.942x/2016/2.1020 2. Severini C, Petrella C, Calissano P. Substance P and Alzheimer’s Disease: Emerging Novel Roles. Curr Alzheimer Res. 2016;13(9):964‐72. https://doi.org/10.2174/1567205013666160401114039. PMID: 27033058. 3. Chen XY, Du YF, Chen L. Neuropeptides Exert Neuroprotective Effects in Alzheimer’s Disease. Front Mol Neurosci. 2019;11:493. Published 2019 Jan 11. https://doi.org/10.3389/fnmol.2018.00493