EGFR is a potential dual molecular target for cancer and Alzheimer's disease. Frontiers in pharmacology Many researchers are attempting to identify drugs that can be repurposed as effective therapies for Alzheimer's disease (AD). Several recent studies have highlighted epidermal growth factor receptor (EGFR) inhibitors approved for use as anti-cancer drugs as potential candidates for repurposing as AD therapeutics. In cancer, EGFR inhibitors target cell proliferation and angiogenesis, and studies in AD mouse models have shown that EGFR inhibitors can attenuate amyloid-beta (Aβ) pathology and improve cognitive function. In this review, we discuss the different functions of EGFR in cancer and AD and the potential of EGFR as a dual molecular target for AD diseases. In addition, we describe the effects of anti-cancer EGFR tyrosine kinase inhibitors (TKIs) on AD pathology and their prospects as therapeutic interventions for AD. By summarizing the physiological functions of EGFR in cancer and AD, this review emphasizes the significance of EGFR as an important molecular target for these diseases. 10.3389/fphar.2023.1238639

Potential Repositioning of Anti-cancer EGFR Inhibitors in Alzheimer's Disease: Current Perspectives and Challenging Prospects. Mansour Heba M,Fawzy Hala M,El-Khatib Aiman S,Khattab Mahmoud M Neuroscience Clinical trials of new drugs for Alzheimer's disease (AD) have ended with disappointing results, with tremendous resources and time. Repositioning of existing anti-cancer epidermal growth factor receptors (EGFR) inhibitors in various preclinical AD models has gained growing attention in recent years because hyperactivation of EGFR has been implicated in many neurodegenerative disorders, including AD. Many recent studies have established that EGFR inhibition suppresses reactive astrocytes, enhances autophagy, ameliorates Aβ toxicity, neuroinflammation, and regenerates axonal degradation. However, there is no incontrovertible neuroprotective proof using EGFR inhibitors due to many under-explored signaling transductions, poor blood-brain barrier (BBB) permeability of the most tested drugs, and disappointing outcomes of most clinical trials. This has caused debate about the possible involvement of EGFR inhibitors in future clinical trials. In this perspective article, we recap recent studies to merge data on the neuroprotective effects of EGFR inhibition. By consequent analysis of previous data, we notably find the under-investigated neuroprotective pathways that highlight the importance of additional research of EGFR inhibitors in attempts to be repurposed as burgeoning therapeutic strategies for AD. Finally, we will discuss future prospective challenges in the repositioning of EGFR inhibitors in AD. 10.1016/j.neuroscience.2021.06.013

Implicative role of epidermal growth factor receptor and its associated signaling partners in the pathogenesis of Alzheimer's disease. Ageing research reviews Epidermal growth factor receptor (EGFR) plays a pivotal role in early brain development, although its expression pattern declines in accordance with the maturation of the active nervous system. However, recurrence of EGFR expression in brain cells takes place during neural functioning decline and brain atrophy in order to maintain the homeostatic neuronal pool. As a consequence, neurotoxic lesions such as amyloid beta fragment (Aβ) formed during the alternative splicing of amyloid precursor protein in Alzheimer's disease (AD) elevate the expression of EGFR. This inappropriate peptide deposition on EGFR results in the sustained phosphorylation of the downstream signaling axis, leading to extensive Aβ production and tau phosphorylation as subsequent pathogenesis. Recent reports convey that the pathophysiology of AD is correlated with EGFR and its associated membrane receptor complex molecules. One such family of molecules is the annexin superfamily, which has synergistic relationships with EGFR and is known for membrane-bound signaling that contributes to a variety of inflammatory responses. Besides, Galectin-3, tissue-type activated plasminogen activator, and many more, which lineate the secretion of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, and IL-18) result in severe neuronal loss. Altogether, we emphasized the perspectives of cellular senescence up-regulated by EGFR and its associated membrane receptor molecules in the pathogenesis of AD as a target for a therapeutical alternative to intervene in AD. 10.1016/j.arr.2022.101791

[Effects of Huangpu Tongqiao Capsules on EGFR-PLCγ signal pathway of hippocampus in rats with Alzheimer's disease]. Wang Guo-Quan,Zhou Peng,Xie Dao-Jun,Ye Shu,Gao Hua-Wu,Wang Yan,Fang Zheng-Qing,Cai Biao Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica Huangpu Tongqiao Capsules(HPTQC), with the functions of invigorating Qi and kidney, eliminating phlegm and removing blood stasis, have the effect of treating Alzheimer's disease(AD), but its mechanism needs further exploration. To explore the relationship between the therapeutic mechanism of HPTQC on Alzheimer's disease and EGFR-PLCγ signal pathway, 40 healthy male SD rats were selected and divided into 4 groups randomly: sham operation group(sham), model group(model), HPTQC group(HPTQC), and nimodipine group(NMP). AD rat model was established by intraperitoneal injection of D-galactose combined with an intracerebral injection of amyloid-β peptide(25-35). After 28 days of administration, Morris water maze test and HE staining showed that the learning and memory ability of AD rats were significantly decreased(P<0.01), and hippocampal neurons were obviously da-maged. However, HPTQC could improve the learning and memory ability of AD rats(P<0.05) and reduce the damage of hippocampal neurons. Immunofluorescence test results showed that the expression levels of EGFR and p-Tau in hippocampal CA1 region of AD rats were significantly increased(P<0.01), and HPTQC could reduce the expression of EGFR and p-Tau in hippocampus of AD rats(P<0.01). Western blot results showed that the protein expression levels of EGFR, PLCγ, IP3 R and p-Tau in hippocampus of AD rats were significantly increased(P<0.01), and HPTQC could reduce the protein expression of EGFR, PLCγ, IP3 R and p-Tau in AD rats(P<0.05). RT-PCR results showed that the mRNA levels of EGFR, PLCγ, IP3 R and Tau in hippocampus of AD rats were significantly increased(P<0.01), and HPTQC could reduce the mRNA levels of EGFR, PLCγ, IP3 R and Tau in AD rats(P<0.05). The results indicate that HPTQC can improve the learning and memory ability of AD rats, and its mechanism of action may be related to regulating EGFR-PLCγ signal pathway. 10.19540/j.cnki.cjcmm.20191219.401

Liver-Brain Axis in Sporadic Alzheimer's Disease: Role of Ten Signature Genes in a Mouse Model. Jakhmola-Mani Ruchi,Islam Anam,Katare Deepshikha Pande CNS & neurological disorders drug targets AIM:Poor nutritional effect of junk food induces injuries to the liver and the brain but still most of the developing nations survive on these diets to compensate for the fast-paced lifestyle. The aim of the study is to infer the protein-connections behind the liver-brain axis and identify the role of these proteins in causing neurodegenerative disorders. BACKGROUND:Chronic consumption of fructose and fat-rich food works as a toxin in the body and has the ability to cause a negative metabolic shift. Recently a study was published in Annals of Internal Medicine (2019) citing the loss of vision and hearing in a 14-year-old boy whose diet was strictly restricted to fries and junk-food for almost a decade. This puts the entire body on insulin resistance and related co-morbidities and causes simultaneous damaging effects on the liver as well as the brain. This work provides insights into the liver-brain axis and explains how the liver is involved in brain related disorders. OBJECTIVE:In this study, transcriptomic data related to chronic eating of junk-food was analyzed and simultaneous damage that happens in the liver and the brain was assessed at the molecular level. METHODS:Transcriptomic study was taken from the GEO database and analysed to find out the genes dysregulated in both the liver and the brain during this metabolic stress. Cytoscapev3.7 was used to decipher the signalling between the liver and the brain. This connection between both is called as the liver-brain axis. RESULT:The results obtained from our study indicate the role of TUBB5-HYOU1-SDF2L1-DECR1- CDH1-EGFR-SKP2-SOD1-IRAK1-FOXO1 gene signature in the decline of concurrent liver and brain health. Dysregulated levels of these genes are linked to molecular processes like cellular senescence, hypoxia, glutathione synthesis, amino acid modification, increased nitrogen content, synthesis of BCAAs, cholesterol biosynthesis, steroid hormone signalling and VEGF pathway. CONCLUSION:We strongly advocate that prolonged consumption of junk food is a major culprit in brain related disorders like Alzheimer's disease and propose that receptors for brain diseases lie outside the brain and aiming them for drug discovery and design may be beneficial in future clinical studies. This study also discusses the connection between NAFLD (non-alcoholic fatty liver disease) and sAD (sporadic Alzheimer's disease) owing to liver-brain axis. 10.2174/1871527319666201209111006