Christian Haas Webinar July 2014

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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-phagocytosis

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Christian Haas Webinar July 2014

  1. 1. 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
  2. 2. 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
  3. 3. 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
  4. 4. 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
  5. 5. TREM2 variants
  6. 6. Shedding of TREM2 by ADAM10 Gernot Kleinberger Wunderlich et al., J Biol Chem, 2013 Kleinberger et al., Science Translational Medicine, 2014
  7. 7. FTD and FTD-like associated missense mutations impair TREM2 maturation and shedding
  8. 8. Mutations inhibit cell surface transport of TREM2
  9. 9. TREM2 mutations block phagocytosis (bead uptake assay in HEK 293)
  10. 10. TREM2 mutations block phagocytosis of E. coli (HEK 293)
  11. 11. 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)
  12. 12. Reduced Amyloid b-peptide uptake
  13. 13. Reduced levels of soluble TREM2 in CSF of AD and FTD patients
  14. 14. Therapeutic modulation of TREM2 function?

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