The effect of amyloid on microglia-neuron interactions before plaque onset occurs independently of TREM2 in a mouse model of Alzheimer's disease

Sep 5, 2020Neurobiology of disease

Amyloid changes how brain immune cells interact with neurons before plaques form, independent of TREM2, in a mouse model of Alzheimer's

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Abstract

Mutations in immune-related genes are linked to an increased risk of developing Alzheimer's disease (AD).

Microglia may play a key role in the pathology of Alzheimer's disease by responding to amyloid accumulation.
In 1-month-old 5XFAD mice, microglia preferentially engage with neurons that show early signs of amyloid accumulation.
Microglia increase their uptake of neurites when exposed to amyloid, even before the formation of plaques.
The receptor TREM2 is not necessary for enhanced microglial interactions with neurons or for the internalization of neurites at this early stage.
TREM2 is required for early morphological changes in microglia, indicating a separate mechanism of response to amyloid accumulation before plaque deposition.

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Genetic studies identified mutations in several immune-related genes that confer increased risk for developing Alzheimer's disease (AD), suggesting a key role for microglia in AD pathology. Microglia are recruited to and actively modulate the local toxicity of amyloid plaques in models of AD through these cells' transcriptional and functional reprogramming to a disease-associated phenotype. However, it remains unknown whether microglia actively respond to amyloid accumulation before plaque deposition in AD. We compared microglial interactions with neurons that exhibit amyloid accumulation to those that do not in 1-month-old 5XFAD mice to determine which aspects of microglial morphology and function are altered by early 6E10+ amyloid accumulation. We provide evidence of preferential microglial process engagement of amyloid laden neurons. Microglia, on exposure to amyloid, also increase their internalization of neurites even before plaque onset. Unexpectedly, we found that triggering receptor expressed on myeloid cells 2 (TREM2), which is critical for microglial responses to amyloid plaque pathology later in disease, is not required for enhanced microglial interactions with neurons or neurite internalization early in disease. However, TREM2 was still required for early morphological changes exhibited by microglia. These data demonstrate that microglia sense and respond to amyloid accumulation before plaques form using a distinct mechanism from the TREM2-dependent pathway required later in disease.

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The effect of amyloid on microglia-neuron interactions before plaque onset occurs independently of TREM2 in a mouse model of Alzheimer's disease

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