Based on our preliminary data of the 3-years NSC grant (NSC96-2628-B-038-004-MY3) entitled “Molecular pathogenetic mechanism of neurotoxocariasis potentially develops into Alzheimer’s-like diseases”, a further hypothesis is proposed that Tachykinins substance P (SP) may cause tight junction proteins (TJPs) changes of cerebral endothelial cells (CECs) located in blood-brain barrier (BBB) or trigger microglial cell or astrocytes to produce inflammatory cytokines (ICs) thus leading to the increased BBB permeability through interaction of NK-1R on the surface of CECs, microglial cell or astrocytes. Following Toxocara canis larval (TcL) invasion into the brains, TcL antigens may stimulate microglial cell or astrocytes to produce significant SP and neuroinjury associated factors (NIAFs) and in the meanwhile, because the functions of both BBB and ubiquitin-proteosome system (UPS) persistently work abnormally make persistent inflammation in the brains due to excess accumulation of neurotoxic β-amyloid (Aβ) which can not be cleaned up or expelled out the brain that all of those evidences proposed a high possibility of neurotoxocariasis may develop into Alzheimer’s-like diseases. However, three important issues should be clarified that may prove our hypothesis. The 1st year protocol: To investigate the relationship between increased BBB permeability, UPS impairment, expressions of SP/NK-1R, TJPs, ICs, as well as NIAFs by what kind of Tc infection intensity and neurodegeneration. The 2nd year protocol: To investigate whether inhibition of SP/NK-1R expression may improve murine neurodegenerative syndrome caused due to increased BBB permeability and UPS impairment possibly through manipulation of TJPs、ICs, and NIAFs expressions. The 3rd year protocol: To investigate (A) whether TcL antigens per se may trigger (1) the production of SP/NK-1R and TJPs changes from CECs, (2) the production of SP/NK-1R, ICs, and NIAFs from microglial cell or astrocytes. (B) If SP/NK-1R antagonist CP-96,345 was added into the co-cultures of TcL antigens and CECs, microglial cell or astrocytes, how are the TJPs expressions of CECs as well as expressions of ICs, and NIAFs of microglial cell or astrocytes.
|Effective start/end date||8/1/10 → 7/31/11|