Inhibitors of MAPKs signaling pathways attenuated the cells death and restored the proteins levels of ADAM-10, BACE-1 and RAGE in varying degrees induced by acrolein. We found that acrolein activated MAPKs signaling pathways to mediate cells apoptosis, and then altered the levels of AD-associated proteins ADAM-10, BACE-1 and RAGE. In this study, we investigated whether acrolein-induced alterations of AD-associated proteins are relevant to MAPKs activation, and strategies to inhibit MAPKs activation yield benefits to acrolein-induced neurotoxicity in HT22 mouse hippocampal cells. Our previous data showed that acrolein changed the levels of key AD-associated proteins, including advanced glycation end products (RAGE), A-disintegrin and metalloprotease (ADAM-10), and beta-site amyloid-beta peptide cleaving enzyme 1(BACE-1). Acrolein, a ubiquitous pollutant, has been reported to implicate in the etiology of AD. Signal Transduction and Targeted Therapy (2019) 4:29 Activation of mitogen-activated protein kinases (MAPKs) in neurons may underlie the pathogenesis of Alzheimer’s disease (AD). We further propose that fluoxetine, a selective serotonin reuptake inhibitor, has the potential to treat AD. The combination of hypometabolism and autophagy deficiency is likely to be a causative factor for AD.
Wealthy puzzles and lessons have made it possible to develop explanatory theories and identify potential strategies for therapeutic interventions for AD. In this review, we discuss the main hypotheses of AD and related clinical trials. However, the ultimate etiology of AD remains obscure. There are various descriptive hypotheses regarding the causes of AD, including the cholinergic hypothesis, amyloid hypothesis, tau propagation hypothesis, mitochondrial cascade hypothesis, calcium homeostasis hypothesis, neurovascular hypothesis, inflammatory hypothesis, metal ion hypothesis, and lymphatic system hypothesis. Its main pathological features are cerebral atrophy, amyloid plaques, and neurofibrillary tangles in the brains of patients.
The present review summarizes the evidence justifying a novel therapeutic approach focused on inhibition of RAGE signaling in order to arrest or halt the development of neuronal dysfunction in AD.Īlzheimer's disease (AD) is a neurodegenerative disease characterized by progressive memory loss along with neuropsychiatric symptoms and a decline in activities of daily life. In particular, changes in the phosphorylation state of various MAPKs by Abeta lead to synaptic dysfunction and cognitive decline, as well as development of inflammatory responses in AD. Recent results have shown that MAPKs are involved in neurodegenerative processes. The receptor for advanced glycation end products (RAGE), a multiligand receptor in the immunoglobulin superfamily, acts as a cell surface binding site for Abeta and mediates alternations in the phosphorylation state of mitogen-activated protein kinase (MAPKs). Growing evidence indicates that oligomeric soluble Abeta plays an important role in the development of synaptic dysfunction and the impairment of cognitive function in AD. Genetic and biological studies provide strong support for the hypothesis that accumulation of beta amyloid peptide (Abeta) contributes to the etiology of Alzheimer's disease (AD).
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