Fox Foundation. critically important features of AD, there are many other components of the disease as well, some still unknown that should be considered equally in the search for a cure. Iron and oxidative stress: Iron (Fe) is one of the redox-active transition metals and Fe, along with other metals, has been shown to promote the formation of A plaques and engender neuronal oxidative stress . The ability of Fe to induce oxidative stress is attributed to the valence state of iron (Fe) being reduced from Fe (III) to Fe(II) and this reduction is coupled with hydroxyl radical formations in the brain through the Fenton reaction [15,18]. As shown in multiple studies, the radical formations reduce the proliferation of Neural Stem Cells (NSCs) and neurogenesis in an AD brain [22C24]. Furthermore, oxidative stress has been known to cause tau neurofibrils, neurogenesis deterioration and increased ferritin levels that have been correlated with cognitive decline [25C28]. Amyloid precursor protein: The Amyloid Precursor Protein (APP), which can generate Amyloid-beta (A) through proteolysis, plays a vital Rabbit Polyclonal to OR2B2 role in synaptic formation, iron regulation, neural plasticity and neurogenesis [9,29C33]. The R406 besylate 5 UTR region of the APP plays a role in APP expression and the formation of A and it remains a possibility that these processes are accelerated in the presence of iron through a 5-Untranslated Region (UTR) iron response element (IRE) in the APP transcript [34,35]. The 5 UTR specific IRE RNA stem loop was first reported in 2002 and has since proven to present a target for chelators and other drugs that inhibit APP translation, such as desferrioxamine, clioquinol, VK-28, piperazine-1, phenserine, tetrathiomolybdate, dimercaptopropanol, paroxetine, azithromycin and a high throughput benzimidazole 5UTR translation blocker designated as JTR-009 [35C39]. JTR-004, JTR-009, JTR-0013 were among the most potent compounds tested in the high throughput study that inhibit the 5 UTR APP translation, with JTR-009 being the most potent blocker, whereas other endogenous compounds or hormones and amyloid expression such as glucocorticoids have been implicated in increasing APP translation . -amyloid plaques: Beta-amyloid plaques are one of the two most distinguishing features of AD. There are two types of A subtypes which have been implicated in causing AD progression, these mutations are A1/40 and A1/42. In the context of AD, A has been known to cause R406 besylate insoluble plaques and inhibit neurogenesis by suppressing proliferation of NSCs, this suppression eventually leads to neuronal apoptosis [41C43]. The build-up of these plaques can create inflammation and oxidative stress [44,45]. A vast amount of research regarding the role of A in Alzheimers already exists and this research is ongoing. Tau and tauopathy: The second distinguishing feature of AD other than beta-amyloid plaques is the appearance of tau neurofibrillary tangles. Tau is highly soluble R406 besylate microtubules associated protein that is part of a superclass of Microtubule Associated Proteins (MAP) which regulates neuronal microtubule within axons and are localized in dendrites in AD neuropathology . AD is classified as a tauopathy, tauopathies are a group of neurodegenerative diseases that involve tau tangles. R406 besylate Some other tauopathies include ALS, FTD and Picks Disease [47C49]. Research about tau is ongoing; a recent report shows that tau protein causes a decline R406 besylate in neurogenesis. In this 12 month study, as tau levels increased, the level of neurogenesis in the hippocampus and Subventricular Zone (SVZ) decreased . Furthermore, prion proteins (PrPC), which prevent cells from oxidative stress, interact with tau, but the mechanism and effects of these proteins are unclear, some evidence shows that these proteins stabilize tau and A production, while other evidence suggests that the proteins can arrest APP translation and tau production [51,52]. Tau is regulated by 2 factors: Glycogen Synthase Kinase-3 (GSK-3) and Cyclin-Dependent Kinase 5 (CDK5). GSK-3 and CDK5 regulate the activation of tau phosphorylation and this phosphorylation leads to tauopathy [53C55]. Researchers studying the inverse effects of.