A selective p38α/β MAPK inhibitor alleviates neuropathology and cognitive impairment, and modulates microglia function in 5XFAD mouse

Abstract

Background: Chronic 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. Methods: In 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. Results: NJK14047 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.

P38α MAPK Signaling—A Robust Therapeutic Target for Rab5-Mediated Neurodegenerative Disease

“…Specifically, the compound MW150 was active in APP-transgenic and tau-transgenic mice [121,123], the compounds MW181 and SB2399063 in aged tauopathy mice [122], and neflamapimod/VX-745 in aged rats [120]. In addition, a very recent publication demonstrated that oral administration of a selective p38 α/β inhibitor, NJK14047, to 9-month old 5XFAD (APP) transgenic mice reduced levels of amyloid-beta deposits, reduced spatial memory loss and reduced the number of degenerating neurons labeled with Fluoro-Jade B [41]. Moreover, genetic reduction of neuronal p38α in APP overexpressing transgenic mice improved synaptic transmission, decreased memory loss and reduced amyloid pathology [124,125].…”

“…During the last two decades, deregulated p38α has emerged as a leading therapeutic target for AD and has also been associated with the pathology of other neurodegenerative disorders, including PD, DLB, or ALS [ 4 , 19 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 ]. These therapeutic opportunities for treatment with selective, brain-penetrant p38α inhibitors will be discussed in more details in Section 6 .…”

c-Jun N-Terminal Kinase Inhibitors as Potential Leads for New Therapeutics for Alzheimer’s Diseases

“…In response to Aβ, NTF, or oxidative stress, also a common feature in AD brains, JNK and p38 induce NF-kβ, synaptic excitotoxicity, and neuroinflammation [ 123 , 124 , 125 , 126 , 127 ]. Corroborating these findings, it was demonstrated that NJK14047 (selective p38α/β inhibitor) reduced NOS, COX-2, TNF-α, and IL-1β in vitro, decreased microglia activation in vivo [ 128 ], and improved cognitive functions in an AD mouse model [ 129 ]. This could be explained by the fact that p38α expression stimulates BACE1 and, therefore, the Aβ generation, but also induces dysfunctional autophagy in neurons [ 129 ].…”

PM2.5 can Promote the Alzheimer's Disease-like Changes through Microglia Related Mechanism in Mice

“…Entry points, which were systematically used throughout the experiment, were in other three quadrants and spaced equally around the edge of the tank. Briefly, the animals were trained for 90 seconds repeatedly to find the platform using visual information around and time taken (escape latency) to find the hidden platform was recorded as the learning (acquisition) process [37]. Mice who can not find the platform within 90 seconds were guided to the platform and the escape latency of it was recorded as 90 seconds.…”