Loss of TREM2 Function Increases Amyloid Seeding but Reduces Plaque-Associated ApoE

Identification: Haass, Christian


Description

Loss of TREM2 Function Increases Amyloid Seeding but Reduces Plaque Associated ApoE
 
Samira Parhizkar1, Thomas Arzberger2, Mathias Brendel3 , Gernot Kleinberger1, Maximilian Deussing3, Carola Focke3, Monica Xiong4, Alireza Ghazemi5, Natalie Katzmarski6, Axel Rominger3, Ali Ertürk5, David M. Holtzman4, Melanie Meyer-Luehmann6 & Christian Haass1
 
1Biomedical Center (BMC), Ludwig-Maximilians-Universität München, and DZNE, Munich, Germany; 2Center for Neuropathology and Prion Research, Ludwig-Maximilians-Universität München, Munich, Germany; 3Department of Nuclear Medicine, University Hospital, Ludwig-Maximilians-Universität München; 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
 
Coding variants in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2) are associated with late onset Alzheimer's disease (AD). Using an in vivo seeding paradigm we found that amyloid plaque seeding increased in the absence of functional TREM2.  Increased amyloid plaque seeding was accompanied by decreased microglia clustering around newly seeded plaques and suppression of Apolipoprotein E (ApoE), and CD68.  Upon loss of TREM2, seeded amyloid plaques, but also non-experimentally seeded cortical plaques, accumulated less ApoE suggesting that plaque-associated microglia are a source for the co-deposited ApoE. Reduced ApoE deposition in amyloid plaques was also confirmed in brains of AD patients carrying disease associated TREM2 variants. Longitudinal amyloid small animal PET demonstrated accelerated kinetics of amyloidogenesis in TREM2 loss-of-function mutants at early stages, which progressed at a lower rate during aging such that late during progression wild type and mutant animals showed the same amyloid burden. These 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 a reduced ApoE load of amyloid plaques. Thus, microglial mediated plaque clearance and ApoE-dependent amyloid β-peptide deposition may counteract each other, a process which must be considered for any attempt to therapeutically modulate TREM2 and microglia function.
 

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