Potential mechanisms by which TREM2 deficiency facilitates neurodegeneration

Marco Colonna

Washington University School of Medicine in St Louis

1. Defect of microglia response

Defect of microglia response

in 3-month old APPPS1-21 mice

Decreased plaque-associated microglia in TREM2 heterozygote mice

Alexa568-HJ3.4-stained plaque

GFP-expressing microgliaTREM2 Het

TREM2 WT

• No impact of TREM2 haploinsufficiency on Aβ plaque deposition in 3-month old APPPS1-21 mice

• No impact of TREM2 haploinsufficiency on Aβ-induced inflammatory milieu

2. Defect of microglia survival

Reduced survival of DAP12-/-

macrophages during in vitro culture

WT DAP12-/-

Propidium iodide staining

CSF-1Otero, Turnbull, Poliani

et al Nat Immunol. 2009;10:734

Decreased microglia numbers and apoptotic morphology in 10 month-old DAP12-/- mice

Basal ganglia Spinal cord

WT

DAP12-/-

3. Excessive microglial inflammatory response

TREM-2 deficiency augments TNF-α and IL-6 responses to LPS, Zymosan and CpG

Turnbull et al. J Immunol. 2006;177:3520

Is TREM2 inhibiting microglia inflammatory response to Aβ?

Aβ

LDLRApoE

lysosomeTNF-α

IL-6

AβAβ

TREM2

DAP12

Acknowledgments

Luigi PolianiElena FontanaWilliam Vermi

Cristina RossiniFabio Facchetti

University of Brescia

John CirritoJessica Restivo Todd DavisKatherine Young

Jason UlrichDavid HoltzmanAlison GoateCarlos CruchagaDavid BrodyRachel SmithLaura Piccio

David Wozniak

Funding: ADRC

LIFA Lilly innovation fellowship program

Yaming Wang

Yoshinori Yamanishi