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  • 1. AlzheimerAlzheimer’’s Disease Risk Genes Disease Risk Gene CD33CD33Inhibits Microglial Uptake of Amyloid BetaInhibits Microglial Uptake of Amyloid BetaAna Griciuc, Ph.D.Ana Griciuc, Ph.D.Massachusetts General HospitalMassachusetts General HospitalHarvard Medical SchoolHarvard Medical School
  • 2. Alzheimer’s Disease Risk Gene CD33Inhibits Microglial Uptake of Amyloid BetaResearch in the Tanzi LaboratoryDiscoveryGenetics of familial and late-onset ADMutations in APP, PS1, PS2 linked to FADUBQLN1, ADAM10, ATXN1 and CD33 genes linked to LOADBasic and pre-clinical researchNovel animal and in vitro models of ADMolecular mechanisms of brain aging and ADNovel therapies: γ-secretase modulators, metal chelatorsClinical research collaborationsSeveral compounds currently in clinical trials
  • 3. CD33 is a Novel Risk Factor for LOADThe minor “G” allele of thers3826656 is a risk allele (Bertramet al., 2008)The minor “T” allele of thers3865444 is protective (Naj et al.,2011; Hollingworth et al., 2011)CD33 is activated by sialic acids,and regulates inflammatoryresponses of the innate immunesystem
  • 4. Increased Numbers of CD33-positive Microglia in ADCD33CD33Iba1Iba1CD33/Iba1/DAPICD33/Iba1/DAPICTRLADCD33CD33CD33+microglia/mm2Aβplaqueburden(%) r=0.471p=0.01704080120**CD33+microglia/mm2G/G G/T T/TCD33+microglia/mm2CTRL AD***
  • 5. Decreased Numbers of CD33-Immunoreactive Microgliain Carriers of the Minor Protective Allele “T” of rs3865444CD33 Localizes Around the Core of AmyloidPlaques in AD BrainThioS CD33 ThioS/CD33 Iba1ThioS CD33 ThioS/CD33 Iba1
  • 6. WTCD33-/-CD33CD33 Aβ42Aβ42CD33/Aβ42CD33/Aβ42Iba1Iba1CD33 Inactivation Promotes the Uptake of Amyloid Betaby MicrogliaCD33-/-WT0123InternalizedAβ42(a.u.)**
  • 7. CD33 inhibits microglial uptake of amyloid betaCD33-mediated Inhibition of Amyloid Beta Uptake byMicroglia Requires Sialic Acid BindingInhibitionof Amyloid Beta UptakeNo Inhibitionof Amyloid Beta UptakeCD33 Aβ42CD33 Aβ42CD33 Aβ42EmptyvectorCD33WTCD33ΔV-IgCD33/Aβ42CD33/Aβ42CD33/Aβ42
  • 8. CD33 Inactivation Mitigates Amyloid Beta PlaquePathology in APP/PS1 MiceAPP/PS1                                      APP/PS1/CD33‐/‐APP/PS1 (n=11)APP/PS1/CD33-/-(n=9)βplaqueburden(%)Cortex**CortexHippocampusAβplaqueburden(%)Hippocampus*
  • 9. ConclusionsCD33 activity in microglial cells strongly impairs their ability toclear brain amyloid.Novel pathway linking CD33 activity in microglial cells toamyloid accumulation in the aging brain.Targeting CD33 activity might delay or arrest cognitive declineand AD?
  • 10. Rudy TanziRudy TanziSeSe HoonHoon ChoiChoiAndreaAndrea LesinskiLesinskiCarolineCaroline AsselinAsselinTonyTony ParradoParradoKristina MullinKristina MullinRajRaj HooliHooliJaehongJaehong SuhSuhCan ZhangCan ZhangZhongcongZhongcong XieXieBradley HymanBradley Hyman -- MGH/HarvardMGH/HarvardAlberto SerranoAlberto Serrano--PozoPozo -- MGH/HarvardMGH/HarvardLars BertramLars Bertram -- Max PlanckMax PlanckCure AlzheimerCure Alzheimer’’s Funds FundNational Institutes of HealthNational Institutes of HealthDeutsche ForschungsgemeinschaftDeutsche ForschungsgemeinschaftACKNOWLEDGEMENTSACKNOWLEDGEMENTSTHANK YOU!THANK YOU!