Abstract
The therapeutic value of inhibiting translation of the amyloid precursor protein (APP) offers the possibility to reduce neurotoxic amyloid formation, particularly in cases of familial Alzheimer’s disease (AD) caused by APP gene duplications (Dup–APP) and in aging Down syndrome individuals. APP mRNA translation inhibitors such as the anticholinesterase phenserine, and high throughput screened molecules, selectively inhibited the uniquely folded iron-response element (IRE) sequences in the 5’untranslated region (5’UTR) of APP mRNA and this class of drug continues to be tested in a clinical trial as an anti-amyloid treatment for AD. By contrast, in younger age groups, APP expression is not associated with amyloidosis, instead it acts solely as a neuroprotectant while facilitating cellular ferroportin-dependent iron efflux. We have reported that the environmental metallotoxins Lead (Pb) and manganese (Mn) cause neuronal death by interfering with IRE dependent translation of APP and ferritin. The loss of these iron homeostatic neuroprotectants thereby caused an embargo of iron (Fe) export from neurons as associated with excess unstored intracellular iron and the formation of toxic reactive oxidative species (ROS). We propose that APP 5’UTR directed translation activators can be employed therapeutically to protect neurons exposed to high acute Pb and/or Mn exposure. Certainly, high potency APP translation activators, exemplified by the Food and Drug Administration (FDA) pre-approved M1 muscarinic agonist AF102B and high throughput-screened APP 5’UTR translation activators, are available for drug development to treat acute toxicity caused by Pb/Mn exposure to neurons. We conclude that APP translation activators can be predicted to prevent acute metal toxicity to neurons by a mechanism related to the 5’UTR specific yohimbine which binds and targets the canonical IRE RNA stem loop as an H-ferritin translation activator.
Highlights
This paper described the interaction between iron-regulatory protein-1 (IRP1) in conjunction with miR-346 to bind and modulate the activity of the 5’untranslated region (5’UTR) of amyloid precursor protein (APP)–mRNA with implications for its role when iron interfaces with neural levels of APP and amyloidosis in Alzheimer’s disease (AD) [11]
We reported that translational control events generated both by inflammation [26] and iron excess can increase both intracellular APP and Aβ dose by increasing translation via a fully functional iron-responsive element (IRE) RNA stem loop in the 5’UTR of the precursor transcript [11,17,27]
Pharmacological lowering of APP levels is appropriate when associated with anti-amyloid efficacy and when excess APP is present in rare trisomy APP mutants of AD [3,97,98]
Summary
We reported that translational control events generated both by inflammation [26] and iron excess can increase both intracellular APP and Aβ dose by increasing translation via a fully functional iron-responsive element (IRE) RNA stem loop in the 5’UTR of the precursor transcript [11,17,27]. This strategy is applicable for patients before an age of increased risk for the onset of amyloidosis. From a chemical viewpoint, (±)-cis-2-methyl-spiro(1,3-oxathiolane-5,3 ) quinuclidine (AF102B) was a proven M1 agonist that attenuated cognitive dysfunction in AF64A-treated rats [50] Such M1 muscarinic agonists appear to be disease-modifying agents in AD [51] while cholinergic modulation of APP via the M1 muscarinic receptor has offered a potential therapeutic route to activate alpha-secretase and reduce amyloid and increase the secretion of neuroprotective APP(s) [52,53,54,55,56]. AF102B w(aans asuhtoowimnmtuonegedniseeraastee aesnsohcainatceeddwniethurdoipffircouteltcytibvreeaAthPiPng, ,ldikreylymoruesthu,ltainndg cforuogmhinalgp)h[5a7-s]e. cAreFt1a0s2eB awctaivsasthioonwnoftothgeenneorna-taemenyhloaindcoegdenneicuraonpdronteecutriovperAoPtePc,tliivkeelpyartehswulatyingoffrAomPPalepxhpar-essesciroenta[s5e1a,5c8ti]v. aWtioen reopf otrhteednothna-tatmhyisloMid1omgeunsiccarainndic nageuornoisptrcootencfteirvsenpeuatrhowpraoyteocftioAnPwP heixlepriensdsuiocning[5A1,P58P].traWneslaretipoonrtaesd wthelaltatshaisctMiva1tminugsaclaprhina-isceacgreotnaisset tcoognefenresranteeuirnocpreroasteecdtisoencrwethioilneoinf dAuPcPin(sg) fAroPmP tnreaunrsallactieolnl liansews [e5l7l ]a.s activInatiFnigguarleph2a, -wseecreextapseeritmo egnentaelrlyateeminpcrloeyaseeddasetcrraentsiofenctoifonA-PbPas(se)dfraosmsaynetuoraclocneflilrmlinethsa[t57A].F102B indeedIninFcigreuarsees2,AwPeP e5x’pUeTrRimdeinretacltleydeemxpprloesyseidonaotfraanlsufeccifteiorans-ebarseepdoratsesragyetnoe c(oFnigfiurrme 2th) a[t57A].FS10H2-B SiYn5dYeecdelilnscwreearseetsraAnPsPfe5c’tUedTRwidthireacPteSdVe2x(AprPePss5io’UnToRf )a–lluucciiffeerraasseerceopnosrttreurcgteinnew(hFiicghurtehe2)5[’U57T].RSoHf-ASYP5PY dcreivllesswleurceifteraranssefecetxepdrewsistihona.PFSoVr2(tAhPePp5u’UrpToRs)e–loufciaferpaosesictiovnesteruxpcteirnimwehnitcahl tchoem5’pUaTriRsoonf,AtPhPe darnivtie-s chluocliifneersatseeraesxepprehsesniosner. iFnoeratchteedpuasrpaonsAe PofPa5p’UoTsiRtivineheixbpiteorrimineFnitgaul rceom2 [p2a0r]i.sTohne, tdhaetaaninti-Fcihgoulrineses1tearnadse 2pshheonwsesrtihnaetaActFe1d02aBs aenxeAmPpPli5fi’eUsTaRsminahlilbmitoorleincuFleigtuhraet 2ac[t2i0v]a.tTeshethdeaAtaPiPn 5F’iugnutrreasn1slaantedd2reshgioowns[5th7a] t wAhFil1e02pBroemxeomtipnlgifineesuarsompraolltemcotilveecuallepthhaa-tsaecctrievtaatsees ethxepArePssPio5n’u.nTthrains selxaetemdprleigfiieosna[5c7l]awsshoilfedprruogmothtiantg ancteiuvraotepsroAtePcPtiv5e’UaTlpRhat-osetcrraentsalsaeteexhpirgehsesriolne.vTelhsisoefxAemPPplaifiseas anecularsosporfodtercutgantht,aat apcrtiovpaetretsyAtPhPat5m’UaTyR etxopltarainnsiltasteprhoi-gchoegrnlietivveelsfuofnActiPoPnsaswahnileeuarolsporogteencetarantti,nagparnotpiearmtyytlhoaidt mefafyiceaxcyplvaiina iatlspphrao--sceocgrentiatsivee [5fu3–n5c5ti]o. ns while generating anti amyloid efficacy via alpha-secretase [53,54,55]
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