Increased circulating TREM2⁺ microglial extracellular vesicles in aged APP/PS1 Alzheimer's disease rats

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.