Abstract

Alzheimer?sdisease(AD),thefourthleadingcauseofdeathindevelopedcountriesandoneof themostcommonformsofdementias,isknowntohaveastronggeneticcomponent.Late- onsetAD(LOAD),whichconstitutes>99%ofADcases,hasbeenestimatedtobeupto80% heritable.TheAPOEalleleisthemostprominentgeneticriskfactorforLOAD,accountingforup to30%ofLOADheritability,andappearstomodulateADriskinanisoform-dependentmanner: APOE4isthemajorrisk-conferringgenotypewhileAPOE2isprotectiveofdiseaseand positivelyassociatedwithcognitivelongevity.However,themechanismbywhichAPOEvariants modulateriskfororprotectionfromADandtheirinteractionwithothergeneticriskfactorsin mediatingLOADisstillpoorlyunderstood.Functionalperturbationtostudyhowmultiplegenetic hitscancollaboratetodevelopageneticriskprofileofLOADwouldbehighlyvaluablefor identifyingandprioritizingpotentialtherapeuticpathways.Todothis,wewillfirstdevelopanin vitroco-culturesystemforstudyingAPOE2andAPOE4variantsinisogenichumanEScell- derivedneuronsandastrocytes.Tounderstandthedifferentialcontributionofthesetwo isoformstoneuronaldeath,wewillemploygenome-scaleCRISPR-Cas9screensforthe systematicgeneticinterrogationoftheAPOEinteractome.Theseexperimentswillbethefirst geneticscreenlookingattheroleofAPOE2andAPOE4inahumanmodelof neurodegeneration,acentralphenotypeofAlzheimer?sdisease.
We aim toidentifykeygenes andpathwaysthatmediatethesystems-levelcellularandfunctionaldifferencescausedby APOEallelesthatcanprotectfromordriveneuronalatrophy.Thiswillhelpprovideinsightinto theunderlyingmechanismsofAPOE-mediatedneurodegenerationandhasthepotentialto providenoveltargetsfortherapeuticintervention.

Public Health Relevance

PublicHealthRelevance Alzheimer?sdisease(AD)isoneofthemostcommonformsofdementiaandaffectsmorethan 35millionpeopleworldwide,yetcurrentlytherearenoeffectivetreatmentsavailable;?forthe majority(>99%)ofADcases,categorizedaslate-onsetAD(LOAD),theAPOEallelehas consistentlyemergedasthemostimportantgeneticriskfactor.However,themechanismby whichAPOEvariantsmodulateriskfororprotectionfromADisstillrelativelypoorlyunderstood. Thisworkwilldevelopandgeneticallymanipulatehumancellculturemodelsofsporadic Alzheimer?sdiseasetoidentifygenesthatmayinteractwithAPOEtobeprotectiveof neurotoxicity,servingasanimportantfirststeptoidentifypromisingpointsofinterventionfor LOADtherapy.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AG056811-02
Application #
9532713
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Raghavachari, Nalini
Project Start
2017-08-01
Project End
2019-05-31
Budget Start
2018-06-01
Budget End
2019-05-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost

  Institution

Name
Salk Institute for Biological Studies
Department
Type
DUNS #
078731668
City
La Jolla
State
CA
Country
United States
Zip Code
92037

  Publications

Konermann, Silvana; Lotfy, Peter; Brideau, Nicholas J et al. (2018) Transcriptome Engineering with RNA-Targeting Type VI-D CRISPR Effectors. Cell 173:665-676.e14
Geraci, Lisa; McDaniel, Mark A; Manzano, Isabel et al. (2009) The influence of age on memory for distinctive events. Mem Cognit 37:175-80