TREM2 variants: new keys to decipher Alzheimer disease pathogenesis

Area of Science:

• Neuroimmunology
• Genetics of neurodegenerative diseases

Background:

• Genome-wide association studies (GWAS) identified rare variants in the gene for Triggering Receptor Expressed on Myeloid cells 2 (TREM2) as risk factors for non-familial Alzheimer disease (AD).
• TREM2 is an immune receptor predominantly expressed in brain microglia, the primary immune cells of the central nervous system.
• Animal studies suggest microglia play a critical role in the brain's response to amyloid-beta (Aβ) plaques, a hallmark of AD, and that TREM2 variants may influence this function.

Purpose of the Study:

• To discuss the potential mechanisms by which TREM2 influences microglial responses to amyloid-beta (Aβ) pathology in Alzheimer disease.
• To explore the impact of TREM2 on microglial senescence and its implications for AD pathogenesis.
• To examine the interactions between TREM2 and other AD-associated genetic risk factors and the functional consequences of TREM2 shedding.

Main Methods:

• Review and synthesis of existing literature from genome-wide association studies (GWAS) and animal models.
• Discussion of molecular mechanisms involving TREM2, amyloid-beta (Aβ), and microglial function.
• Hypothetical modeling of TREM2 shedding and its potential impact on AD.

Main Results:

• TREM2 variants are confirmed genetic risk factors for Alzheimer disease, highlighting the role of microglia in AD.
• TREM2 signaling is implicated in modulating microglial responses to amyloid plaques, potentially affecting plaque clearance and neuroinflammation.
• TREM2 may influence microglial senescence, a process that can contribute to age-related cognitive decline and AD.

Conclusions:

• TREM2 plays a significant role in the microglial response to Alzheimer disease pathology, particularly in relation to amyloid-beta plaques.
• Dysfunctional TREM2 signaling, due to rare variants or altered shedding, may contribute to AD pathogenesis by impairing microglial protective functions.
• Further research into TREM2 function and its interactions is crucial for understanding Alzheimer disease and developing targeted therapies.