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

1. Potential mechanisms by which TREM2
deficiency facilitates neurodegeneration
Marco Colonna
Washington University School of Medicine
in St Louis

2. 1. Defect of microglia response

3. Defect of microglia response
in 3-month old APPPS1-21 mice

4. Decreased plaque-associated microglia
in TREM2 heterozygote mice
Alexa568-HJ3.4-
stained plaque
GFP-expressing
microgliaTREM2 Het
TREM2 WT

5. • 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

6. 2. Defect of microglia survival

7. Reduced survival of DAP12-/-
macrophages during in vitro culture
WT DAP12-/-
Propidium iodide staining
CSF-1
Otero, Turnbull, Poliani
et al Nat Immunol.
2009;10:734

8. Decreased microglia numbers and apoptotic
morphology in 10 month-old DAP12-/-
mice
Basal ganglia Spinal cord
WT
DAP12-/-

9. 3. Excessive microglial
inflammatory response

10. TREM-2 deficiency augments TNF-α and IL-6
responses to LPS, Zymosan and CpG
Turnbull et al. J Immunol. 2006;177:3520

11. Is TREM2 inhibiting microglia
inflammatory response to Aβ?
Aβ
LDLRApoE
lysosome
TNF-α
IL-6
Aβ
Aβ
TREM2
DAP12

12. Acknowledgments
Luigi Poliani
Elena Fontana
William Vermi
Cristina Rossini
Fabio Facchetti
University of Brescia
John Cirrito
Jessica Restivo
Todd Davis
Katherine Young
Jason Ulrich
David Holtzman
Alison Goate
Carlos Cruchaga
David Brody
Rachel Smith
Laura Piccio
David Wozniak
Funding: ADRC
LIFA Lilly innovation
fellowship program
Yaming
Wang
Yoshinori
Yamanishi