Loss-of-TREM2 function increases amyloid seeding but reduces plaque-associated ApoE
Samira Parhizkar1, Thomas Arzberger2, Mathias Brendel3, Gernot Kleinberger1, Maximilian Deussing3, Carola Focke3, Brigitte Nuscher1, Monica Xiong4, Alireza Ghasemi5, Natalie Katzmarski6, Axel Rominger2,3, Ali Ertürk5, David M. Holtzman4, Melanie Meyer-Luehmann5*, Christian Haass1,2,3*
1Biomedical Center (BMC), Biochemistry, LMU Munich, and DZNE, Munich, Germany; 2Center for Neuropathology and Prion Research, LMU Munich, Munich, Germany; 3Department of Nuclear Medicine, LMU Munich, Munich, Germany; 4Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA; 5Institute for Stroke and Dementia Research, Klinikum der Universität München, Munich, Germany; 6Department of Neurology, Medical Center University of Freiburg, Freiburg, Germany
Variants in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2) are associated with late onset Alzheimer's disease (AD) and other neurodegenerative diseases. The TREM2 p.T66M variant found in Frontotemporal Dementia-like disorder results in impaired maturation and shedding of TREM2, lipid sensing and reduced microglial phagocytosis. Although loss-of-Trem2 results in decreased amyloid plaque (Aβ)-associated microglia, contradictory effects on Aβ pathology were reported. Our aim was to investigate whether Trem2-expressing microglia affect Aβ seeding in APPPS1/Trem2+/+ compared to loss-of-Trem2 function APPPS1/Trem2-/- and APPPS1/Trem2T66M mice. We induced Aβ seeding by intracerebrally injecting plaque-bearing brain extracts into asymptomatic APPPS1 hosts. We show that in the absence of functional TREM2, Aβ plaque density increased with accelerated kinetics of amyloidogenesis at early stages; eventually showing similar amyloid burden as APPPS1/Trem2+/+ at later stages. Whereas IBA1+ and CD68+ microglia clustering around seeded Aβ showed increased Trem2 expression, loss-of-Trem2 function microglia displayed impaired clustering and phagocytosis. We also found that amyloid plaques accumulated less ApoE, the strongest genetic risk factor of AD, in patients carrying TREM2 p.R47H, p.R62H, p.R62C or p.D87N variants suggesting that plaque-associated microglia are a source for co-deposited ApoE. Our findings suggest that, in the absence of functional TREM2, early amyloidogenesis is accelerated due to reduced phagocytic clearance while later during progression amyloidogenesis is slowed due to reduced ApoE.