Harnessing endogenous pathways and metabolites to treat or prevent neurodegenerative disease

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Title:
Harnessing endogenous pathways and metabolites to treat or prevent neurodegenerative disease
Physical Description:
Mixed Material
Language:
English
Creator:
Golde, Todd E.
Felsenstein, Kevin
Chakrabarty, Paramita
Li, Andy
Moore, Brenda
In, Jung Joo
Cruz, Pedor
Publisher:
Bio-Med Central (Molecular Neurodegeneration)
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Notes

Abstract:
From Molecular Neurodegeneration: Basic biology and disease pathways Cannes, France. 10-12 September 2013
General Note:
Golde et al. Molecular Neurodegeneration 2013, 8(Suppl 1):O36 http://www.molecularneurodegeneration.com/content/8/S1/O36
General Note:
doi:10.1186/1750-1326-8-S1-O36 Cite this article as: Golde et al.: Harnessing endogenous pathways and metabolites to treat or prevent neurodegenerative disease. Molecular Neurodegeneration 2013 8(Suppl 1):O36.

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University of Florida
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University of Florida
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All rights reserved by the source institution.
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AA00018710:00001


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au ca yes id A1 snm Goldemi Efnm Toddinsr iid I1
A2 FelsensteinKevin
A3 ChakrabartyParamita
A4 LiAndy
A5 MooreBrenda
A6 Inmnm JooJung
A7 CruzPedor
A8 PriceAshely
A9 BorcheltDavid
A10 JanusChristopher
A11 Cebballos-DiazCarolina
A12 RosarioAwilda
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ins Center for Translational Research in Neurodegenerative Disease, Department of Neuroscience, McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL, USA
source Molecular Neurodegeneration
supplement Molecular Neurodegeneration: Basic biology and disease pathwayssponsor note Publication costs for this supplement were funded by the publisher.Meeting abstractsconference Molecular Neurodegeneration: Basic biology and disease pathwayslocation Cannes, Francedate-range 10-12 September 2013url http://conf.molecularneurodegeneration.com/issn 1750-1326
pubdate 2013
volume 8
issue Suppl 1
fpage O36
http://www.molecularneurodegeneration.com/content/8/S1/O36
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cpyrt 2013collab Golde et al; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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As the field moves towards earlier interventions in preclinical stages of AD or even envisions true primary prevention strategies, the therapeutic strategies employed must be “safe enough”. Whether any current therapeutic (e.g., β-secretase inhibitors, γ-secretase modulators (GSM) or anti-Aβ immunotherapies) being tested for disease modification is sufficiently safe is not known. In order to try and identify “safe enough” therapeutics, we have been evaluating whether endogenous regulators of Aβ can be harnessed as therapeutics. We have identified a cholesterol metabolite, cholestenoic acid (CA), as potent GSM, and have genetic data from mice that are consistent with a role for CA in regulating Aβ42 levels in the brain. We will discuss our ongoing studies exploring how we might utilize CA or the CA metabolic pathway to safely lower Aβ42 levels. In addition, we have been evaluating how we can use soluble forms of endogenous innate immune receptors to alter Aβ deposition and modulate neuroinflammation in mouse models of AD. We have also been exploring the utility of such strategy in other neurodegenerative models. Effects of soluble toll-like receptors and soluble TREM2 will be presented. Our current data establish that soluble TLR4 and 5 both dramatically inhibit Aβ deposition but that soluble TLR2 and 6 do not. We also have data that suggest the utility of these soluble receptors in α-synucleinopathies. By using endogenous metabolites and receptors, we hope that the likelihood of adverse toxicities will be diminished and that these or endogenous factors can be safely developed for prophylactic or early intervention in AD and perhaps other neurodegenerative disorders.



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ORALPRESENTATION OpenAccessHarnessingendogenouspathwaysand metabolitestotreatorprevent neurodegenerativediseaseToddEGolde*,KevinFelsenstein,ParamitaChakrabarty,AndyLi,BrendaMoore,JungJooIn,PedorCruz, AshelyPrice,DavidBorchelt,ChristopherJanus,CarolinaCebballos-Diaz,AwildaRosarioFrom MolecularNeurodegeneration:Basicbiologyanddiseasepathways Cannes,France.10-12September2013AsthefieldmovestowardsearlierinterventionsinpreclinicalstagesofADorevenenvisionstrueprimarypreventionstrategies,thetherapeuticstrategiesemployedmust be safeenough .Whetheranycurrenttherapeutic(e.g., b -secretaseinhibitors, g -secretasemodulators(GSM)or anti-A b immunotherapies)beingtestedfordiseasemodificationissufficientlysafeisnotknown.Inordertotry andidentify safeenough therapeutics,wehavebeen evaluatingwhetherendogenousregulatorsofA b canbe harnessedastherapeutics.Wehaveidentifiedacholesterol metabolite,cholestenoicacid(CA),aspotentGSM,and havegeneticdatafrommicethatareconsistentwitharole forCAinregulatingAb 42levelsinthebrain.Wewill discussourongoingstudiesexploringhowwemight utilizeCAortheCAmetabolicpathwaytosafelylower Ab 42levels.Inaddition,wehavebeenevaluatinghowwe canusesolubleformsofendogenousinnateimmune receptorstoalterA b depositionandmodulateneuroinflammationinmousemodelsofAD.Wehavealsobeen exploringtheutilityofsuchstrategyinotherneurodegenerativemodels.Effectsofsol ubletoll-likereceptorsand solubleTREM2willbepresented.OurcurrentdataestablishthatsolubleTLR4and5bothdramaticallyinhibit A b depositionbutthatsolubleTLR2and6donot.We alsohavedatathatsuggestth eutilityofthesesoluble receptorsin a -synucleinopathies.Byusingendogenous metabolitesandreceptors,wehopethatthelikelihoodof adversetoxicitieswillbediminishedandthattheseor endogenousfactorscanbesafelydevelopedforprophylactic orearlyinterventioninADandperhapsotherneurodegenerativedisorders.Published:13September2013doi:10.1186/1750-1326-8-S1-O36 Citethisarticleas: Golde etal .: Harnessingendogenouspathwaysand metabolitestotreatorpreventneurodegenerativedisease. Molecular Neurodegeneration 2013 8 (Suppl1):O36. Submit your next manuscript to BioMed Central and take full advantage of: Convenient online submission Thorough peer review No space constraints or color gure charges Immediate publication on acceptance Inclusion in PubMed, CAS, Scopus and Google Scholar Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit CenterforTranslationalResearchinNeurodegenerativeDisease,Department ofNeuroscience,McKnightBrainInstitute,CollegeofMedicine,Universityof Florida,Gainesville,FL,USAGolde etal MolecularNeurodegeneration 2013, 8 (Suppl1):O36 http://www.molecularneurodegeneration.com/content/8/S1/O36 2013Goldeetal;licenseeBioMedCentralLtd.ThisisanOpenAccessarticledistributedunderthetermsoftheCreativeCommons AttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse,distribution,andreproductionin anymedium,providedtheoriginalworkisproperlycited.


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