Altered microglial response to Aβ plaques in APPPS1-21 mice heterozygous for TREM2

Jun 5, 2014Molecular neurodegeneration

Changed immune cell reactions to amyloid plaques in mice with one copy of TREM2 gene

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Abstract

Loss of a single copy of the trem2 gene did not affect Aβ plaque deposition in APPPS1-21 mice.

No significant difference in Aβ plaque levels was observed in 3-month old or 7-month old APPPS1-21 mice with one or two copies of trem2.
Mice with one copy of trem2 at 3 months showed a marked decrease in both the number and size of microglia associated with plaques.
Trends indicated decreased expression of certain inflammatory markers, including NOS2, C1qa, and IL1a, in 3-month old mice with one copy of trem2 compared to those with two copies.
These findings suggest TREM2 plays a role in shaping the response of microglia to Aβ deposition without influencing the overall Aβ plaque burden.

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BACKGROUND: Recent genome-wide association studies linked variants in TREM2 to a strong increase in the odds of developing Alzheimer's disease. The mechanism by which TREM2 influences the susceptibility to Alzheimer's disease is currently unknown. TREM2 is expressed by microglia and is thought to regulate phagocytic and inflammatory microglial responses to brain pathology. Given that a single allele of variant TREM2, likely resulting in a loss of function, conferred an increased risk of developing Alzheimer's disease, we tested whether loss of one functional trem2 allele would affect Aβ plaque deposition or the microglial response to Aβ pathology in APPPS1-21 mice.

RESULTS: There was no significant difference in Aβ deposition in 3-month old or 7-month old APPPS1-21 mice expressing one or two copies of trem2. However, 3-month old mice with one copy of trem2 exhibited a marked decrease in the number and size of plaque-associated microglia. While there were no statistically significant differences in cytokine levels or markers of microglial activation in 3- or 7-month old animals, there were trends towards decreased expression of NOS2, C1qa, and IL1a in 3-month old TREM2+/- vs. TREM2+/+ mice.

CONCLUSIONS: Loss of a single copy of trem2 had no effect on Aβ pathology, but altered the morphological phenotype of plaque-associated microglia. These data suggest that TREM2 is important for the microglial response to Aβ deposition but that a 50% decrease inTREM2 expression does not affect Aβ plaque burden.

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Altered microglial response to Aβ plaques in APPPS1-21 mice heterozygous for TREM2

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