This document discusses the role of TREM2, a receptor expressed on myeloid cells and microglia, in neurodegenerative diseases. It notes that loss-of-function mutations in TREM2 are associated with Nasu-Hakola disease and increased risk for late-onset Alzheimer's disease. Heterozygous mutations are also linked to frontotemporal dementia and related syndromes, as well as amyotrophic lateral sclerosis and Parkinson's disease. The document describes how FTD-linked mutations impair TREM2 maturation and shedding, inhibiting its transport to the cell surface. This reduces phagocytic functions of microglia, including uptake of amyloid-beta, bacterial particles, and apopt

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. 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. 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. 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. TREM2 variants

6. Shedding of TREM2 by ADAM10
Gernot Kleinberger
Wunderlich et al., J Biol Chem, 2013
Kleinberger et al., Science Translational Medicine, 2014

7. FTD and FTD-like associated missense mutations impair TREM2
maturation and shedding

8. Mutations inhibit cell surface transport of TREM2

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

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

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. Reduced Amyloid b-peptide uptake

13. Reduced levels of soluble TREM2 in CSF of
AD and FTD patients

14. Therapeutic modulation of TREM2 function?