Title : A selective p38?/? MAPK inhibitor alleviates neuropathology and cognitive impairment, and modulates microglia function in 5xFAD mouse
Abstract:
Chronic neuroinflammation, aggressive amyloid beta (Aβ) deposition, neuronal cell loss and cognitive impairment are pathological symptoms of Alzheimer’s disease (AD). Regarding these symptoms, resolution of neuroinflammation and inhibition of Aβ-driven pathology might be a novel strategy for AD therapy. Efforts to prevent AD progression have identified that p38 mitogen-activated protein kinase (MAPK) is a promising target for AD therapy. However, the actual therapeutic effect of selective p38 MAPK inhibitors in AD has not been ascertained yet. In this study, we explored the therapeutic potential of NJK14047, a selective p38 MAPK inhibitor, using an Alzheimer’s disease mouse model, 5xFAD. The mice were injected 2.5 mg/kg NJK14047 or vehicle every other day for 3 months. Morris water maze task and histological imaging analysis were performed. Protein and mRNA expression levels were measured using immunoblotting and qRT-PCR. In in vitro studies, the cytotoxicity of microglial conditioned medium and astrocyte conditioned medium on primary neurons were measured using MTT assay and TUNEL assay. NJK14047 treatment downregulated phospho-p38 MAPK levels, decreased the amount of Aβ deposits, and improved spatial learning memory in 5xFAD mice. Interestingly, these effects were associated with the decrease of inflammatory responses and the increase of the phenotype markers of alternatively activated microglia which were effective for phagocytosis and degradation of Aβ peptides. Furthermore, NJK14047 treatment reduced the number of Fluoro-jade B positive cells, a class of degenerating neurons, in the brains of 5xFAD mice. The neuroprotective effect of NJK14047, achieved via the restoration of microglia function, was further confirmed by in vitro studies.
What will audience learn from your presentation?
(Try to list 3-5 specific items)
- Importance of neuroinflammation and glial phenotypes in Alzheimer’s disease (AD)
- The experimental procedures and tips for AD research using 5xFAD mouse
- The experimental procedures and tips for neuroinflammation research using primary neurons and glial cells
- Mouse behavior test procedures and tips
- Morris water maze test
- Novel objective recognition test
- Y-maze test
- Passive avoidance test
