The acetylcholinesterase inhibitors donepezil and rivastigmine have been used as therapeutic drugs for Alzheimer’s disease (AD), but their effects on LPS- and Aβ-induced neuroinflammatory responses and the underlying molecular pathways have not been studied in detail in vitro and in vivo. In the present study, we found that 10 or 50 μM donepezil significantly decreased the LPS-induced increases in the mRNA levels of a number of proinflammatory cytokines in BV2 microglial cells, whereas 50 μM rivastigmine significantly diminished only LPS-stimulated IL-6 mRNA levels. In subsequent experiments in primary astrocytes, donepezil suppressed only LPS-stimulated iNOS mRNA levels. To identify the molecular mechanisms by which donepezil regulates LPS-induced neuroinflammation, we examined whether donepezil alters LPS-stimulated proinflammatory responses by modulating LPS-induced downstream signaling and the NLRP3 inflammasome. Importantly, we found that donepezil suppressed LPS-induced AKT/MAPK signaling, the NLRP3 inflammasome, and transcription factor NF-kB/STAT3 phosphorylation to reduce neuroinflammatory responses. In LPS-treated wild-type mice, a model of neuroinflammatory disease, donepezil significantly attenuated LPS-induced microglial activation, microglial density/morphology, and proinflammatory cytokine COX-2 and IL-6 levels. In a mouse model of AD (5xFAD mice), donepezil significantly reduced Aβ-induced microglial and astrocytic activation, density, and morphology. Taken together, our findings indicate that donepezil significantly downregulates LPS- and Aβ-evoked neuroinflammatory responses in vitro and in vivo and may be a therapeutic agent for neuroinflammation-associated diseases such as AD.

The oral multi-target kinase inhibitor regorafenib, which targets the oncogenic receptor tyrosine kinase (RTK), is an effective therapeutic for patients with advanced gastrointestinal stromal tumors or metastatic colorectal cancer. However, whether regorafenib treatment has beneficial effects on neuroinflammation and Alzheimer’s disease (AD) pathology has not been carefully addressed. Here, we report the regulatory function of regorafenib in neuroinflammatory responses and AD-related pathology in vitro and in vivo. Regorafenib affected AKT signaling to attenuate lipopolysaccharide (LPS)-mediated expression of proinflammatory cytokines in BV2 microglial cells and primary cultured microglia and astrocytes. In addition, regorafenib suppressed LPS-induced neuroinflammatory responses in LPS-injected wild-type mice. In 5x FAD mice (a mouse model of AD), regorafenib ameliorated AD pathology, as evidenced by increased dendritic spine density and decreased Aβ plaque levels, by modulating APP processing and APP processing-associated proteins. Furthermore, regorafenib-injected 5x FAD mice displayed significantly reduced tau phosphorylation at T212 and S214 (AT100) due to the downregulation of glycogen synthase kinase-3 beta (GSK3β) activity. Taken together, our results indicate that regorafenib has beneficial effects on neuroinflammation, AD pathology, and dendritic spine formation in vitro and in vivo.

Monoamine oxidase (MAO) has been implicated in neuroinflammation, and therapies targeting MAO are of interest for neurodegenerative diseases. The small-molecule drug tranylcypromine, an inhibitor of MAO, is currently used as an antidepressant and in the treatment of cancer. However, whether tranylcypromine can regulate LPS- and/or Aβ-induced neuroinflammation in the brain has not been well-studied. In the present study, we found that tranylcypromine selectively altered LPS-induced proinflammatory cytokine levels in BV2 microglial cells but not primary astrocytes. In addition, tranylcypromine modulated LPS-mediated TLR4/ERK/STAT3 signaling to alter neuroinflammatory responses in BV2 microglial cells. Importantly, tranylcypromine significantly reduced microglial activation as well as proinflammatory cytokine levels in LPS-injected wild-type mice. Moreover, injection of tranylcypromine in 5xFAD mice (a mouse model of AD) significantly decreased microglial activation but had smaller effects on astrocyte activation. Taken together, our results suggest that tranylcypromine can suppress LPS- and Aβ-induced neuroinflammatory responses in vitro and in vivo.

The coenzyme Q10 analogue idebenone is an FDA-approved antioxidant that can cross the blood–brain barrier (BBB). The effects of idebenone on the pathology of Alzheimer’s disease (AD) and the underlying molecular mechanisms have not been comprehensively investigated. Here, we examined the impact of idebenone treatment on AD pathology in 5xFAD mice, a model of AD. Idebenone significantly downregulated Aβ plaque number via multi-directional pathways in this model. Specifically, idebenone reduced the RAGE/caspase-3 signaling pathway and increased levels of the Aβ degradation enzyme NEP and α-secretase ADAM17 in 5xFAD mice. Importantly, idebenone significantly suppressed tau kinase p-GSK3β^Y216 levels, thereby inhibiting tau hyperphosphorylation at Thr231 and total tau levels in 5xFAD mice. Taken together, the present study indicates that idebenone modulates amyloidopathy and tauopathy in 5xFAD mice, suggesting therapeutic potential for AD.

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by Aβ deposition, tauopathy, neuroinflammation, and impaired cognition. The recent identification of associations between protein kinases and AD pathology has spurred interest in tyrosine kinase inhibitors (TKIs) as potential strategic therapeutic agents for AD. In the present study, we investigated whether the TKIs ibrutinib, PD180970, and cabozantinib, which have different on-targets, selectively regulate AD pathology in 3.5- to 4-month-old 5xFAD mice (a model of the early phase of AD). Ibrutinib (10 mg/kg, i.p.) effectively reduced amyloid-β (Aβ) plaque number, tau hyperphosphorylation and neuroinflammation in 5xFAD mice. Surprisingly, PD180970 (10 mg/kg, i.p.) did not alter Aβ plaque number or neuroinflammatory responses and exacerbated tau hyperphosphorylation in 5xFAD mice. Cabozantinib (10 mg/kg, i.p.) had no effect on amyloidopathy but partially relieved tau hyperphosphorylation and astrogliosis. Taken together, our results suggest that not all TKIs have therapeutic effects on AD pathology in a mouse model of AD. Consequently, optimization of drug dosage, injection periods and administration routes should be considered when repurposing TKIs as novel AD therapeutics.