AlzheimerAlzheimer’’s Disease Risk Gene s Disease Risk Gene CD33CD33Inhibits Microglial Uptake of Amyloid BetaInhibits Microglial Uptake of Amyloid Beta

Ana Griciuc, Ph.D.Ana Griciuc, Ph.D.Massachusetts General Hospital Massachusetts General Hospital

Harvard Medical SchoolHarvard Medical School

Alzheimer’s Disease Risk Gene CD33Inhibits Microglial Uptake of Amyloid BetaResearch in the Tanzi Laboratory

DiscoveryGenetics of familial and late-onset AD

Mutations in APP, PS1, PS2 linked to FADUBQLN1, ADAM10, ATXN1 and CD33 genes linked to LOAD

Basic and pre-clinical researchNovel animal and in vitro models of AD

Molecular mechanisms of brain aging and ADNovel therapies: γ-secretase modulators, metal chelators

Clinical research collaborationsSeveral compounds currently in clinical trials

CD33 is a Novel Risk Factor for LOAD

The minor “G” allele of the rs3826656 is a risk allele (Bertram et al., 2008)

The minor “T” allele of the rs3865444 is protective (Naj et al., 2011; Hollingworth et al., 2011)

CD33 is activated by sialic acids, and regulates inflammatory responses of the innate immune system

Increased Numbers of CD33-positive Microglia in AD

CD33

CD33

Iba1

Iba1

CD33/Iba1/DAPI

CD33/Iba1/DAPI

CTR

LAD

CD33

CD33

CD33+ microglia/mm2

Aβpl

aque

bur

den

(%)

r=0.471p=0.017

0

40

80

120

**

CD

33+

mic

rogl

ia/m

m2

G/G G/T T/T

CD

33+

mic

rogl

ia/m

m2

CTRL AD

***

Decreased Numbers of CD33-Immunoreactive Microgliain Carriers of the Minor Protective Allele “T” of rs3865444

CD33 Localizes Around the Core of Amyloid Plaques in AD Brain

ThioS CD33 ThioS/CD33 Iba1

ThioS CD33 ThioS/CD33 Iba1

WT

CD

33-/-

CD33

CD33 Aβ42

Aβ42

CD33/Aβ42

CD33/Aβ42

Iba1

Iba1

CD33 Inactivation Promotes the Uptake of Amyloid Betaby Microglia

CD33-/-

WT

0

1

2

3

Inte

rnal

ized

Aβ4

2 (a

.u.) **

CD33 inhibits microglial uptake of amyloid beta CD33-mediated Inhibition of Amyloid Beta Uptake by Microglia Requires Sialic Acid Binding

Inhibition of Amyloid Beta Uptake

No Inhibition of Amyloid Beta Uptake

CD33 Aβ42

CD33 Aβ42

CD33 Aβ42

Empt

y ve

ctor

CD

33W

TC

D33

ΔV

-Ig

CD33/Aβ42

CD33/Aβ42

CD33/Aβ42

CD33 Inactivation Mitigates Amyloid Beta Plaque Pathology in APP/PS1 Mice

APP/PS1                                      APP/PS1/CD33‐/‐

APP/PS1 (n=11)APP/PS1/CD33-/- (n=9)

0

0.2

0.4

0.6

0.8

Aβpl

aque

bur

den

(%)

Cortex

**

Cortex

Hippo

campu

s

Aβpl

aque

bur

den

(%)

Hippocampus

*

0

0.1

0.2

0.3

0.4

Conclusions

CD33 activity in microglial cells strongly impairs their ability to clear brain amyloid.

Novel pathway linking CD33 activity in microglial cells to amyloid accumulation in the aging brain.

Targeting CD33 activity might delay or arrest cognitive decline and AD?

Rudy TanziRudy TanziSe Se HoonHoon ChoiChoiAndrea Andrea LesinskiLesinskiCaroline Caroline AsselinAsselinTony Tony ParradoParradoKristina MullinKristina MullinRaj Raj HooliHooliJaehongJaehong SuhSuhCan ZhangCan ZhangZhongcongZhongcong XieXie

Bradley Hyman Bradley Hyman -- MGH/HarvardMGH/HarvardAlberto SerranoAlberto Serrano--PozoPozo -- MGH/HarvardMGH/HarvardLars Bertram Lars Bertram -- Max PlanckMax Planck

Cure AlzheimerCure Alzheimer’’s Funds FundNational Institutes of HealthNational Institutes of HealthDeutsche ForschungsgemeinschaftDeutsche Forschungsgemeinschaft

ACKNOWLEDGEMENTSACKNOWLEDGEMENTS

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