christian haas webinar july 2014
DESCRIPTION
Presentation made by Christian Haas at the Alzforum webinar of July 8, 2014 - http://www.alzforum.org/webinars/mutations-impair-trem2-maturation-processing-and-microglial-phagocytosisTRANSCRIPT
![Page 1: Christian Haas Webinar July 2014](https://reader034.vdocuments.net/reader034/viewer/2022052508/559ac6701a28abe3138b4703/html5/thumbnails/1.jpg)
Ludwig-Maximilians-University Munich
DZNE - German Center for Neurodegenerative Diseases, Munich & Adolf-Butenandt-Institute, Biochemistry, Ludwig-Maximilians University Munich
TREM2 – a general player in
neurodegeneration?
Christian Haass & Gernot Kleinberger
![Page 2: Christian Haas Webinar July 2014](https://reader034.vdocuments.net/reader034/viewer/2022052508/559ac6701a28abe3138b4703/html5/thumbnails/2.jpg)
Haass, Nat. Med., 2010; Haass & Aguzzi, Science, 2003
Haass & Selkoe, Nature Reviews Mol. Cell Biology, 2007; Winklhofer, Tatzelt & Haass, EMBO J., 2008
A RIP substrate affected in several neurodegenerative
disorders: a novel common mechanism?
Prion Disorders
PrP
PD and others
a-synuclein
FTLD/ALS
TDP-
43/FUS/DP
R
AD FTLD
ta
u
Ab/tau
![Page 3: Christian Haas Webinar July 2014](https://reader034.vdocuments.net/reader034/viewer/2022052508/559ac6701a28abe3138b4703/html5/thumbnails/3.jpg)
Regulated Intramembrane Proteolysis (RIP)
Prion Disorders PD and others FTLD-U/ALSAD FTLD
Nucleus
transcription
Trscr.
Factor
1. shedding
2. intramem.
cleavage
Haass, EMBO J, 2004
![Page 4: Christian Haas Webinar July 2014](https://reader034.vdocuments.net/reader034/viewer/2022052508/559ac6701a28abe3138b4703/html5/thumbnails/4.jpg)
Triggering Receptor Expressed on Myeloid cells 2
(TREM2)• Attenuating inflammatory reactions
• Promoting phagocytosis
• selectively expressed in myeloid cells and microglia
• Homozygous loss-of-function mutations in TREM2
are associated with Nasu-Hakola disease / polycystic
lipomembraneous osteodysplasia (PLOSL)
• Heterozygous mutations are associated with
increased risk for late-onset AD
• Linkage to FTD-like syndrome without bone
involvement
• Linkage to FTD
• Linkage to ALS
• Linkage to PD
![Page 5: Christian Haas Webinar July 2014](https://reader034.vdocuments.net/reader034/viewer/2022052508/559ac6701a28abe3138b4703/html5/thumbnails/5.jpg)
TREM2 variants
![Page 6: Christian Haas Webinar July 2014](https://reader034.vdocuments.net/reader034/viewer/2022052508/559ac6701a28abe3138b4703/html5/thumbnails/6.jpg)
Shedding of TREM2 by ADAM10Gernot Kleinberger
Wunderlich et al., J Biol Chem, 2013
Kleinberger et al., Science Translational Medicine, 2014
![Page 7: Christian Haas Webinar July 2014](https://reader034.vdocuments.net/reader034/viewer/2022052508/559ac6701a28abe3138b4703/html5/thumbnails/7.jpg)
FTD and FTD-like associated missense mutations impair TREM2
maturation and shedding
![Page 8: Christian Haas Webinar July 2014](https://reader034.vdocuments.net/reader034/viewer/2022052508/559ac6701a28abe3138b4703/html5/thumbnails/8.jpg)
Mutations inhibit cell surface transport of TREM2
![Page 9: Christian Haas Webinar July 2014](https://reader034.vdocuments.net/reader034/viewer/2022052508/559ac6701a28abe3138b4703/html5/thumbnails/9.jpg)
TREM2 mutations block phagocytosis(bead uptake assay in HEK 293)
![Page 10: Christian Haas Webinar July 2014](https://reader034.vdocuments.net/reader034/viewer/2022052508/559ac6701a28abe3138b4703/html5/thumbnails/10.jpg)
TREM2 mutations block phagocytosis of E. coli(HEK 293)
![Page 11: Christian Haas Webinar July 2014](https://reader034.vdocuments.net/reader034/viewer/2022052508/559ac6701a28abe3138b4703/html5/thumbnails/11.jpg)
TREM2 loss of function reduces phagocytosis in
primary microglia
pHrodo E.coli assay
• In accordance with reduced uptake of neuronal apoptotic cell debris upon Trem2
knockdown (Takahashi K. et al. JEM 2005)
![Page 12: Christian Haas Webinar July 2014](https://reader034.vdocuments.net/reader034/viewer/2022052508/559ac6701a28abe3138b4703/html5/thumbnails/12.jpg)
Reduced Amyloid b-peptide uptake
![Page 13: Christian Haas Webinar July 2014](https://reader034.vdocuments.net/reader034/viewer/2022052508/559ac6701a28abe3138b4703/html5/thumbnails/13.jpg)
Reduced levels of soluble TREM2 in CSF of
AD and FTD patients
![Page 14: Christian Haas Webinar July 2014](https://reader034.vdocuments.net/reader034/viewer/2022052508/559ac6701a28abe3138b4703/html5/thumbnails/14.jpg)
Therapeutic modulation of TREM2 function?