Humanized TREM2 mice reveal microglia-intrinsic and -extrinsic effects of R47H polymorphism

Mice carrying R47H variation display impaired binding of TREM2 with anionic and zwitterionic lipids known to associate with fibrillar Aβ, leading to failure of microglia to cluster around Aβ plaques, apoptosis, augmented Aβ accumulation, and spread of neuritic plaque tau aggregates.

“Mice carrying R47H variation displayed impaired binding of TREM2 with anionic and zwitterionic lipids which are known to associate with fibrillar Aβ. As a result, microglia failed to cluster around Aβ plaques and became apoptotic, subsequently leading to augmented Aβ accumulation,198,199 and spread of neuritic plaque tau aggregates.200”

Loss of TREM2 function in Alzheimer's disease mouse models limits microglial plaque surrounding, proliferation, and conversion to disease-associated microglia, leading to more severe neuritic dystrophy.

“loss of TREM2 function in AD mouse models restricts the ability of microglia to surround Aβ plaques15,16, proliferate, and convert to DAM10,15,17, which in turn leads to more profound neuritic dystrophy18,19.”

In mouse models of Alzheimer's disease, the disease-associated microglia program depends on TREM2.

“activation of “disease-associated microglia” (DAM) is dependent on TREM2 in mouse models of AD.”

sTREM2 directly binds to neurons in mouse models of AD and inhibits LTP induction.

“experimental evidence revealed that sTREM2 directly bound to neurons in mouse models of AD194 and inhibited LTP induction.”

Aβ-induced microglial activation is impaired in humanized transgenic mice expressing human R47H TREM2, and the R47H mutation impairs TREM2 binding to anionic lipids.

“Aβ-induced microglial activation is impaired in humanized transgenic mice expressing human R47H TREM2 (REF.169), and the R47H mutation impairs TREM2 binding to anionic lipids166.”

Other studies have not revealed obvious phenotypes in young Trem2 R47H expressing mice, or even Trem2 knockout mice, unless they are aged or bred to amyloid mouse models.

“Other studies have not revealed obvious phenotypes in young Trem2 R47H expressing mice, or even Trem2 knockout mice, unless they are aged or bred to amyloid mouse models (35,61,85–87).”

Impaired or absent Trem2 function attenuates the microglial response to amyloid pathology by regulating microglial number around plaques, regulating microglial activity, and restricting neuritic damage.

“Recent important studies have also shown that impaired/absent Trem2 function attenuates the microglial response to amyloid pathology by regulating microglial number around plaques, regulating microglial activity, and restricting neuritic damage (37,61,84–87,95–99).”

Data from human genetics, particularly with respect to the hypomorphic R47H allele of TREM2 that strongly increases risk for AD, provide strong evidence for a protective role for microglia.

“Data from human genetics, particularly with respect to the hypomorphic R47H allele of TREM2 that strongly increases risk for AD (32, 33, 102), provide strong evidence for a protective role for microglia.”