TREM2 modulates differential deposition of modified and non-modified A\u03b2 species in extracellular plaques and intraneuronal deposits

Pranav Joshi,Nàdia Villacampa,Sathish Kumar,Marco Colonna,Florian Riffel,Jochen Herms,Thomas Arzberger,Samira Parhizkar,Christian Haass,Jochen Walter,Michael T Heneka,Sandra Theil

doi:10.1186/s40478-021-01263-x

Abstract

Progressive accumulation of Amyloid-β (Aβ) deposits in the brain is a characteristic neuropathological hallmark of Alzheimer’s disease (AD). During disease progression, extracellular Aβ plaques undergo specific changes in their composition by the sequential deposition of different modified Aβ species. Microglia are implicated in the restriction of amyloid deposits and play a major role in internalization and degradation of Aβ. Recent studies showed that rare variants of the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) are associated with an increased risk for AD. Post-translational modifications of Aβ could modulate the interaction with TREM2, and the uptake by microglia. Here, we demonstrate that genetic deletion of TREM2 or expression of a disease associated TREM2 variant in mice lead to differential accumulation of modified and non-modified Aβ species in extracellular plaques and intraneuronal deposits. Human brains with rare TREM2 AD risk variants also showed altered deposition of modified Aβ species in the different brain lesions as compared to cases with the common variant of TREM2. These findings indicate that TREM2 plays a critical role in the development and the composition of Aβ deposits, not only in extracellular plaques, but also intraneuronally, that both could contribute to the pathogenesis of AD.

Highlights

Alzheimer’s disease (AD) is characterized neuropathologically by the combined occurrence of extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs) with abnormally phosphorylated tau (τ) protein in the brain [24, 65]
Selective accumulation of Ser8‐phosphorylated Aβ species upon loss of Triggering Receptor Expressed on Myeloid cells 2 (TREM2) function in brains of transgenic mice Phosphorylated Aβ variants were previously detected in brains of transgenic mouse models and human AD cases, and shown to exert increased toxicity in Drosophila models and human neurons derived from embryonic stem or induced pluripotent stem cells [11, 13, 38, 40, 41, 54]
Triple staining with mouse monoclonal 1E4E11, rat monoclonal 7H3D6, and rabbit polyclonal 2964 antibodies revealed that TREM2−/− mice at 15 months (15 M) of age had significantly more plaques detected by all three antibodies

Summary

Introduction

Alzheimer’s disease (AD) is characterized neuropathologically by the combined occurrence of extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs) with abnormally phosphorylated tau (τ) protein in the brain [24, 65]. Genome-wide association studies (GWAS) and exome sequencing have revealed genetic loci related to inflammatory pathways to be associated with an increased risk for AD [5, 18, 71]. Among these subsets of genes, rare variants of the microglial transmembrane receptor, Triggering Receptor Expressed on Myeloid cells (TREM2), confer a high risk for the development of AD, comparable to the risk exerted by the Apolipoprotein E4 allele (ApoE4) [18, 30]. TREM2 is proteolytically processed by ADAM proteases to generate soluble variants of TREM2 (sTREM2) [25, 34, 78], that can be detected in extracellular fluids. sTREM2 could act as a decoy receptor to negatively modulate TREM2 signaling and inflammatory responses of microglia, and shows trophic activity to promote microglial survival [35, 83]

Methods

Results

Conclusion