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Increased circulating TREM2+ microglial extracellular vesicles in aged APP/PS1 Alzheimer's disease rats
Sarah J Myers1, Manoj Reddy Medapati1, Brian L Allman1
1Vulnerable Brain Lab, Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
Abstract:
TREM2 is a microglial marker important in Alzheimer's disease (AD) risk and pathogenesis, but current methods to detect microglial TREM2 expression in vivo are limited. Circulating extracellular vesicles (EVs) show promise as potential biomarkers for AD, and microglial EVs (MEVs) may offer valuable insight into brain TREM2 activity. Here, we investigated plasma-derived TREM2+ MEVs as a potential peripheral indicator of brain microglial TREM2 activity and cognition in a rat model of aging and AD. TMEM119+/TREM2+ EVs were fluorescently labelled and assessed using nanoscale flow cytometry directly in plasma collected from wildtype and APP/PS1 rats aged to 3-, 9-, and 15-months-old. Molecular and histological assays were used to assess microglial markers in rat brain tissue, and a radial arm water maze task was employed to evaluate spatial working and reference memory. We demonstrated that TMEM119+/TREM2+ EVs can be detected in the systemic circulation and were increased in 15-month APP/PS1 rats. Further, the amount of TMEM119+/TREM2+ EVs showed a modest association with the severity of cognitive impairment in aged rats, while TREM2 brain expression varied by anatomical region, age, transgene, and assay. Collectively, this study provides the first assessment of TMEM119+/TREM2+ EVs as a peripheral indicator of brain microglial expression and their relationship to cognitive impairment in a rat model of aging and AD.
Insights
Researchers identified TREM2-expressing microglial extracellular vesicles (EVs) in rat plasma. Increased levels of these EVs correlated with cognitive decline in an Alzheimer
Area of Science:
- Neuroscience
- Biomarkers
- Alzheimer's Disease Research
Background:
- TREM2 is a key microglial marker implicated in Alzheimer's disease (AD) pathogenesis.
- Detecting TREM2 expression *in vivo* is challenging, limiting understanding of its role.
- Extracellular vesicles (EVs), particularly microglial EVs (MEVs), are emerging as promising biomarkers.
Purpose of the Study:
- To investigate plasma-derived TREM2+ MEVs as peripheral indicators of brain microglial TREM2 activity.
- To assess the relationship between TREM2+ MEVs and cognitive function in a rat model of aging and AD.
- To establish TMEM119+/TREM2+ EVs as a potential peripheral biomarker for AD-related microglial changes.
Main Methods:
- Fluorescent labeling and nanoscale flow cytometry of TMEM119+/TREM2+ EVs in rat plasma.
- Analysis of plasma from wildtype and APP/PS1 rats at 3, 9, and 15 months of age.
- Assessment of brain microglial markers, TREM2 expression, and spatial memory using radial arm water maze.
Main Results:
- TMEM119+/TREM2+ EVs were successfully detected in systemic circulation.
- Elevated levels of TMEM119+/TREM2+ EVs were observed in aged APP/PS1 rats (15 months).
- A modest association was found between TMEM119+/TREM2+ EV levels and cognitive impairment severity.
Conclusions:
- Plasma-derived TMEM119+/TREM2+ EVs can serve as a peripheral indicator of brain microglial activity.
- These EVs show potential as a non-invasive biomarker for cognitive impairment in aging and AD.
- This study provides a novel method for assessing microglial function peripherally in AD models.
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