Microglia TREM2 Alzheimer-linked variant enhances excitatory transmission and reduces LTP via increased TNF-α levels

Area of Science:

• Neuroscience
• Genetics
• Immunology

Background:

• The p.R47H variant of TREM2 (triggering receptor expressed on myeloid cells 2) is a significant genetic risk factor for Alzheimer's disease (AD).
• Microglia, the brain's immune cells, play a crucial role in AD pathogenesis, and TREM2 is a key microglial receptor.

Purpose of the Study:

• To elucidate the pathogenic mechanisms by which the TREM2 p.R47H variant increases dementia risk.
• To differentiate between human amyloid-beta (Aβ)-dependent and -independent pathways influenced by the TREM2 variant.

Main Methods:

• Creation of TREM2 knock-in (KI) rats engineered to express human Aβ.
• Assessment of brain TNF-α concentrations, glutamatergic transmission, and Long-term Potentiation (LTP) in young TREM2 KI rats.
• Administration of a neutralizing anti-TNF-α antibody to evaluate its effect on neuronal function.

Main Results:

• Young TREM2 KI rats exhibited elevated brain TNF-α, enhanced glutamatergic transmission, and suppressed LTP, despite normal Aβ levels.
• Treatment with an anti-TNF-α antibody reversed the augmented glutamatergic transmission and LTP suppression in young TREM2 KI rats.
• These findings indicate that the TREM2 variant directly impacts neuronal function via TNF-α, independent of Aβ.

Conclusions:

• The microglia-specific TREM2 p.R47H variant promotes neuronal dysfunction by increasing brain TNF-α levels, leading to enhanced glutamatergic transmission and suppressed LTP.
• This mechanism represents a potential early, Aβ-independent pathway contributing to dementia pathogenesis.
• This study directly links microglial dysfunction to neuronal impairment in the context of Alzheimer's disease risk.