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Differential interaction with TREM2 modulates microglial uptake of modified Aβ species
Pranav Joshi1, Florian Riffel1, Kanayo Satoh2
1Department of Neurology, University of Bonn, Bonn, Germany.
Abstract:
Rare coding variants of the microglial triggering receptor expressed on myeloid cells 2 (TREM2) confer an increased risk for Alzheimer's disease (AD) characterized by the progressive accumulation of aggregated forms of amyloid β peptides (Aβ). Aβ peptides are generated by proteolytic processing of the amyloid precursor protein (APP). Heterogeneity in proteolytic cleavages and additional post-translational modifications result in the production of several distinct Aβ variants that could differ in their aggregation behavior and toxic properties. Here, we sought to assess whether post-translational modifications of Aβ affect the interaction with TREM2. Biophysical and biochemical methods revealed that TREM2 preferentially interacts with oligomeric Aβ, and that phosphorylation of Aβ increases this interaction. Phosphorylation of Aβ also affected the TREM2 dependent interaction and phagocytosis by primary microglia and in APP transgenic mouse models. Thus, TREM2 function is important for sensing phosphorylated Aβ variants in distinct aggregation states and reduces the accumulation and deposition of these toxic Aβ species in preclinical models of Alzheimer's disease.
Insights
Rare variants in TREM2 (triggering receptor expressed on myeloid cells 2) increase Alzheimer's risk. Microglial TREM2 senses phosphorylated amyloid-beta (Aβ) variants, reducing toxic Aβ accumulation in preclinical models.
Area of Science:
- Neuroscience
- Immunology
- Molecular Biology
Background:
- Rare coding variants in TREM2 (triggering receptor expressed on myeloid cells 2) are linked to increased Alzheimer's disease (AD) risk.
- Alzheimer's disease pathogenesis involves the aggregation of amyloid-beta (Aβ) peptides, derived from amyloid precursor protein (APP).
- Post-translational modifications of Aβ can alter its aggregation and toxicity.
Purpose of the Study:
- To investigate if post-translational modifications of Aβ influence its interaction with TREM2.
- To determine the impact of Aβ phosphorylation on TREM2 binding and microglial function.
Main Methods:
- Biophysical and biochemical assays to assess TREM2-Aβ interactions.
- Experiments using primary microglia and APP transgenic mouse models.
Main Results:
- TREM2 preferentially binds to oligomeric Aβ.
- Phosphorylation of Aβ enhances its interaction with TREM2.
- Phosphorylated Aβ affects TREM2-dependent microglial interaction and phagocytosis.
Conclusions:
- TREM2 plays a crucial role in sensing phosphorylated Aβ variants in various aggregation states.
- TREM2 signaling helps mitigate the accumulation and deposition of toxic Aβ species in Alzheimer's disease models.
