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AD-linked R47H-TREM2 mutation induces disease-enhancing microglial states via AKT hyperactivation.

Faten A Sayed1,2, Lay Kodama1,2,3,4, Li Fan3

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Science Translational Medicine
|December 1, 2021
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Summary
This summary is machine-generated.

The R47H variant of TREM2 gene exacerbates Alzheimer's disease by increasing inflammation and AKT signaling in microglia. Inhibiting AKT signaling may offer a therapeutic strategy for Alzheimer's disease.

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Area of Science:

  • Neuroscience
  • Genetics
  • Immunology

Background:

  • The R47H variant of TREM2 (triggering receptor expressed on myeloid cells 2) is a genetic risk factor for late-onset Alzheimer's disease (AD).
  • TREM2 is a microglia-specific gene crucial for brain immune responses.
  • Microglia play a significant role in AD pathogenesis, and their dysfunction is implicated in disease progression.

Purpose of the Study:

  • To investigate the functional consequences of the TREM2 R47H variant on microglial activity and Alzheimer's disease pathology.
  • To explore the role of AKT signaling in R47H-associated microglial dysfunction.
  • To evaluate the therapeutic potential of targeting AKT signaling in AD.

Main Methods:

  • Transcriptomic analysis of single nuclei from human AD brain tissues and microglia from a novel tauopathy mouse model.
  • Establishment of a tauopathy mouse model with heterozygous knock-in of human TREM2 R47H or common variant (CV).
  • Pharmacological inhibition of AKT signaling using MK-2206 in primary microglia and in the mouse model.

Main Results:

  • R47H-associated microglia exhibit enhanced inflammatory signatures and AKT signaling activation, resembling disease-associated microglia (DAM).
  • The R47H mutation exacerbates tau-mediated spatial memory deficits in female mice, with conserved transcriptomic changes observed in mouse and human microglia.
  • Pharmacological AKT inhibition reversed inflammatory signatures in R47H microglia and rescued synapse loss and microglial alterations in R47H tauopathy mice.

Conclusions:

  • The TREM2 R47H mutation promotes AD pathogenesis through microglial hyperinflammation and AKT pathway activation.
  • AKT signaling is a key mediator of R47H-induced microglial dysfunction and AD-related cognitive deficits.
  • Inhibitors of AKT signaling represent a promising microglial-modulating therapeutic strategy for Alzheimer's disease.