Soluble TREM1 contributes to aging-related neurodegeneration by binding to ROBO2 in hippocampal neurons and reducing synaptic protein expression via the ROBO2/ERK pathway, suggesting that inhibition of sTREM1-mediated signaling may represent a novel therapeutic strategy for aging-related cognitive decline.
Key Findings
Results
Serum sTREM1 levels were significantly increased during the aging process in senescence accelerated mouse prone 8 (SAMP8) mice, an animal model of accelerated aging.
SAMP8 mice were used as the animal model of accelerated aging to confirm age-related changes in sTREM1
The increase in serum sTREM1 was confirmed to occur during aging, consistent with prior findings of elevated sTREM1 in plasma or CSF of Alzheimer's disease patients
Prior research by the authors and others had shown elevated CSF sTREM1 was associated with more rapid hippocampal degeneration in cognitively impaired older adults
Results
Roundabout guidance receptor 2 (ROBO2) was identified as a receptor for sTREM1 in hippocampal neurons.
This is described as the first demonstration that ROBO2 functions as a receptor for sTREM1 in hippocampal neurons
ROBO2 expression was also found to be upregulated with aging
ROBO2 had not previously been identified as a functional receptor mediating sTREM1 signaling in neuronal cells
Results
Knockdown of neuronal ROBO2 mitigated aging-related hippocampal synaptic degeneration and cognitive impairments.
This represents the first evidence that neuronal ROBO2 knockdown can reduce aging-related hippocampal synaptic degeneration
Cognitive impairments associated with aging were also alleviated by ROBO2 knockdown
Experiments were conducted in the SAMP8 accelerated aging mouse model
Results
sTREM1 reduced the expression of synaptic proteins via the ROBO2/extracellular signal-regulated kinase (ERK) pathway.
This is described as the first evidence that the sTREM1-ROBO2 interaction signals through the ERK pathway to affect synaptic protein expression
Reduction in synaptic protein expression is a key mechanism linking sTREM1 to synaptic degeneration
The ROBO2/ERK pathway mediates the downstream effects of sTREM1 binding in hippocampal neurons
Background
Elevated CSF sTREM1 levels in prior studies were closely associated with a more rapid rate of hippocampal degeneration in cognitively impaired older adults.
This association was established by prior research from the authors' group and others, providing clinical context for the mechanistic findings
sTREM1 levels were measured in cerebrospinal fluid (CSF) of cognitively impaired older adults
The finding motivated investigation into the mechanistic pathways through which sTREM1 contributes to neurodegeneration
Conclusions
Inhibition of sTREM1-mediated signaling is proposed as a novel therapeutic strategy for neurodegeneration and cognitive decline induced by aging.
The findings collectively elucidate mechanisms through which sTREM1 contributes to aging-related neurodegeneration
The sTREM1/ROBO2/ERK signaling axis represents a potential therapeutic target
The authors suggest this approach may be applicable to treatment of both neurodegeneration and cognitive decline in the context of aging
What This Means
This research suggests that a protein called soluble TREM1 (sTREM1), which is a fragment shed from an immune receptor found on certain immune cells, plays an important role in the brain deterioration that comes with aging. The study found that blood levels of sTREM1 rise during aging in mice bred to age rapidly, and that this protein binds to another protein called ROBO2 on the surface of brain cells in the hippocampus — the part of the brain critical for memory. When sTREM1 attaches to ROBO2, it triggers a chain reaction inside neurons (via a signaling protein called ERK) that reduces the levels of proteins needed for healthy synaptic connections between brain cells, ultimately leading to memory and cognitive problems.
Importantly, the researchers found that when they reduced ROBO2 levels in hippocampal neurons, the aging-related loss of synaptic proteins and cognitive decline were lessened, suggesting that this pathway is functionally important — not just a bystander. These findings fill in a significant gap in understanding how inflammation-related molecules like sTREM1, which are elevated in the blood and spinal fluid of people with Alzheimer's disease, actually damage brain cells at a molecular level.
This research suggests that blocking the sTREM1-ROBO2 interaction or the downstream ERK signaling could be a new avenue for treating age-related cognitive decline and neurodegenerative diseases like Alzheimer's. Prior human studies had already shown that higher sTREM1 levels in cerebrospinal fluid were linked to faster hippocampal shrinkage in older adults with cognitive problems, giving this mechanistic work in mice added clinical relevance. Future research would be needed to determine whether targeting this pathway is safe and effective in humans.
Qi J, He X, Gu Y, Luo Z, Duan R, Zhang Y, et al.. (2026). Soluble TREM1 Contributes to Aging-Related Neurodegeneration via ROBO2/ERK Pathway.. Molecular neurobiology. https://doi.org/10.1007/s12035-026-05987-6