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Webinar presentation made by Dr. Marco Colonna, July 8, 2014 http://www.alzforum.org/webinars/mutations-impair-trem2-maturation-processing-and-microglial-phagocytosis
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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