Regorafenib Regulates AD Pathology, Neuroinflammation, and Dendritic Spinogenesis in Cells and a Mouse Model of AD

Abstract

<jats:p>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.</jats:p>

Ibrutinib modulates Aβ/tau pathology, neuroinflammation, and cognitive function in mouse models of Alzheimer's disease

“…For instance, ibrutinib may directly and/or indirectly interact with EGFR to inhibit EGFR signaling and therefore modulate Aβ pathology. Consistent with this notion, we recently reported that the EGFR inhibitor regorafenib significantly reduces Aβ pathogenesis, suggesting that EGFR might be a potential off‐target of ibrutinib for Aβ inhibition (Han et al, 2020). Another possibility is that ibrutinib regulates Aβ‐degrading enzymes such as neprilysin and insulin‐degrading enzyme to reduce Aβ accumulation.…”

“…How does ibrutinib regulate Aβ and tau‐mediated neuroinflammatory responses in mouse models of AD? Interestingly, we and others have reported that the EGFR inhibitors regorafenib and dasatinib downregulate peripheral and central inflammation in wild‐type mice and 5xFAD mice (Han et al, 2020; Liu et al, 2020; Ryu et al, 2019). These reports suggest that ibrutinib might suppress Aβ‐ and tau‐evoked neuroinflammation in mouse models of AD via EGFR and BTK inhibition.…”

“…Surprisingly, we found that ibrutinib affects tau phosphorylation in a BTK‐independent manner (Figure ). Importantly, we recently demonstrated that the EGFR inhibitor regorafenib significantly reduces tau phosphorylation at Thr 212 /Ser 214 (Han et al, 2020). Based on the literature and our findings, we hypothesize that ibrutinib decreases tau pathology through EGFR inhibition, but other off‐targets of ibrutinib may be associated with these processes.…”

Diarylureas as Antitumor Agents

“…The pivotal RESORCE (NCT01774344) phase III trial studied regorafenib therapy in patients with HCC who were tolerant to sorafenib, but who had progressed during sorafenib treatment [58]. Regorafenib has been demonstrated to inhibit glioblastoma multiforme (GBM) growth through PSAT1-mediated autophagy arrest [59], and to have beneficial effect in Alzheimer's disease (AD) and formation of dendritic spine in vitro and in vivo [60].…”

Sorafenib Modulates the LPS- and Aβ-Induced Neuroinflammatory Response in Cells, Wild-Type Mice, and 5xFAD Mice

“…In turn, the activation of these pathways initiates proinflammatory cytokine release and neuroinflammation in glial cells. Emerging evidence indicates that proinflammatory cytokine release by glial cells is a crucial marker of neuroinflammation (6)(7)(8). Thus, inhibiting the LPS-evoked neuroinflammatory response may prevent neuroinflammation.…”