Abstract
BackgroundChronic neuroinflammation, aggressive amyloid beta (Aβ) deposition, neuronal cell loss, and cognitive impairment are pathological presentations of Alzheimer’s disease (AD). Therefore, resolution of neuroinflammation and inhibition of Aβ-driven pathology have been suggested to be important strategies for AD therapy. Previous efforts to prevent AD progression have identified p38 mitogen-activated protein kinases (MAPKs) as a promising target for AD therapy. Recent studies showed pharmacological inhibition of p38α MAPK improved memory impairment in AD mouse models.MethodsIn this study, we used an AD mouse model, 5XFAD, to explore the therapeutic potential of NJK14047 which is a novel, selective p38α/β MAPK inhibitor. The mice were injected with 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, respectively. In vitro studies were conducted to measure the cytotoxicity of microglia- and astrocyte-conditioned medium on primary neurons using the MTT assay and TUNEL assay.ResultsNJK14047 treatment downregulated phospho-p38 MAPK levels, decreased the amount of Aβ deposits, and reduced spatial learning memory loss in 9-month-old 5XFAD mice. While the pro-inflammatory conditions were decreased, the expression of alternatively activated microglial markers and microglial phagocytic receptors was increased. Furthermore, NJK14047 treatment reduced the number of degenerating neurons labeled with Fluoro-Jade B in the brains of 5XFAD mice. The neuroprotective effect of NJK14047 was further confirmed by in vitro studies.ConclusionTaken together, a selective p38α/β MAPK inhibitor NJK14047 successfully showed therapeutic effects for AD in 5XFAD mice. Based on our data, p38 MAPK inhibition is a potential strategy for AD therapy, suggesting NJK14047 as one of the promising candidates for AD therapeutics targeting p38 MAPKs.
Highlights
Chronic neuroinflammation, aggressive amyloid beta (Aβ) deposition, neuronal cell loss, and cognitive impairment are pathological presentations of Alzheimer’s disease (AD)
P38 mitogen-activated protein kinases (MAPKs) inhibition is a potential strategy for AD therapy, suggesting NJK14047 as one of the promising candidates for AD therapeutics targeting p38 MAPKs
NJK14047 as a selective p38α/β MAPK inhibitor reduces the level of phospho-p38 MAPKs in the brain and attenuates spatial memory loss in 9-month-old 5XFAD mice The phospho-p38 MAPK level was upregulated in the brain of 9-month-old 5XFAD mice in both cortex and hippocampus regions of the brain compared to the wildtype mice (Fig. 1a)
Summary
Aggressive amyloid beta (Aβ) deposition, neuronal cell loss, and cognitive impairment are pathological presentations of Alzheimer’s disease (AD). Alzheimer’s disease (AD) is a common progressive neurodegenerative disorder characterized by severe neuronal loss leading to cognitive dysfunction. Microglial cells are involved in various functions, including the regulation of brain development, the maintenance of homeostasis, and the clearance of old synapses or other debris such as Aβ peptides. In AD, microglia has been known to be chronically activated, resulting in impairment of Aβ clearance, overexpression of pro-inflammatory signals, and neurotoxicity [8, 9]. The regulation of microglial activation may be an important therapeutic strategy of AD by lowering excessive pro-inflammatory immune chemotaxis and enhancing neuroprotective function, leading to the modulation of neuroinflammation [10, 11]
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