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Soluble TREM1 Contributes to Aging-Related Neurodegeneration via ROBO2/ERK Pathway.
Jing-Wen Qi1, Xin-Yu He1, Yu-Cheng Gu2
1Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
Molecular Neurobiology
|June 3, 2026
Summary
Soluble triggering receptor expressed on myeloid cells 1 (sTREM1) drives aging-related neurodegeneration by binding to ROBO2 on neurons, causing synaptic damage and cognitive decline. Inhibiting this pathway may offer a new therapeutic strategy.
Area of Science:
- Neuroscience
- Immunology
- Aging Research
Background:
- Aging is the primary risk factor for neurodegenerative diseases.
- Inflammation, regulated by triggering receptor expressed on myeloid cells 1 (TREM1), is implicated in aging-related neurodegeneration.
- Elevated soluble TREM1 (sTREM1) levels are observed in Alzheimer's disease patients and correlate with hippocampal degeneration.
Purpose of the Study:
- To elucidate the mechanisms by which sTREM1 contributes to aging-related neurodegeneration.
- To identify the receptor for sTREM1 in the brain.
- To investigate the therapeutic potential of targeting the sTREM1 pathway.
Main Methods:
- Utilized senescence accelerated mouse prone 8 (SAMP8) mice as a model of accelerated aging.
- Assessed serum sTREM1 levels and roundabout guidance receptor 2 (ROBO2) expression in aging mice.
- Performed knockdown of neuronal ROBO2 to evaluate its role in synaptic degeneration and cognitive function.
- Investigated the signaling pathway downstream of sTREM1/ROBO2 interaction.
Main Results:
- Serum sTREM1 levels were significantly increased in aging mice.
- ROBO2 was identified as the receptor for sTREM1 in hippocampal neurons and its expression increased with aging.
- Knockdown of neuronal ROBO2 ameliorated aging-related hippocampal synaptic degeneration and cognitive impairments.
- sTREM1 was shown to reduce synaptic protein expression via the ROBO2/extracellular signal-regulated kinase (ERK) pathway.
Conclusions:
- sTREM1 contributes to aging-related neurodegeneration by targeting ROBO2 in hippocampal neurons.
- The sTREM1-ROBO2-ERK pathway mediates synaptic damage and cognitive decline during aging.
- Inhibiting sTREM1 signaling presents a potential therapeutic strategy for age-related cognitive decline and neurodegeneration.
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