christian haas webinar july 2014

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

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

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

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

TREM2 variants

Shedding of TREM2 by ADAM10Gernot Kleinberger

Wunderlich et al., J Biol Chem, 2013

Kleinberger et al., Science Translational Medicine, 2014

FTD and FTD-like associated missense mutations impair TREM2

maturation and shedding

Mutations inhibit cell surface transport of TREM2

TREM2 mutations block phagocytosis(bead uptake assay in HEK 293)

TREM2 mutations block phagocytosis of E. coli(HEK 293)

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)

Reduced Amyloid b-peptide uptake

Reduced levels of soluble TREM2 in CSF of

AD and FTD patients

Therapeutic modulation of TREM2 function?