Shedding light on innate immune dysfunction in a mouse model of Alzheimer's disease using a novel myeloid cell‐targeted PET imaging strategy.

Background: Non‐invasive assessment of maladaptive innate immune responses in the brains of Alzheimer's disease (AD) patients is a critical unmet need; such techniques have the potential to not only improve diagnosis and disease monitoring, but also serve as endpoints in clinical trials of novel therapeutics. Positron emission tomography (PET) imaging of the translocator protein 18 kDa (TSPO) is a widely used experimental approach for assessing inflammation in vivo but is limited by its lack of cell specificity and inability to discriminate between beneficial and adverse immune responses. We developed the first PET probe targeting triggering receptor expressed on myeloid cells 1 (TREM1) and demonstrated its ability to specifically detect CNS‐infiltrating pathogenic peripheral myeloid cells (e.g., macrophages, monocytes, neutrophils) in the context of neurological disease. Herein, we assess the utility of TREM1‐PET compared to TSPO‐PET for detecting innate immune responses in the 5XFAD mouse model of AD. Method: 5XFAD and wild‐type (WT) 6–7‐month‐old mice underwent 10 min static TREM1‐ and TSPO‐PET/CT imaging. TSPO‐PET was performed 50–60 minutes post‐intravenous injection of [18F]GE‐180 (175.1±13.8 μCi). TREM1‐PET was performed 20 hours following intravenous injection of [64Cu]TREM1‐mAb (94.75±4.96 μCi). Tracer binding was quantified in the cortex, hippocampus, thalamus, and whole brain using a semi‐automated brain atlas‐based approach. CD68 immunostaining of brain tissue was performed to assess microglia/macrophage activation. Result: TREM1‐PET quantification revealed significantly increased [64Cu]TREM1‐mAb binding in the hippocampus (1.37‐vs‐1.14 %ID/g, p=0.02) and thalamus (1.00‐vs‐0.76 %ID/g, p=0.04) of 6–7‐month‐old 5XFAD compared to WT mice (Fig 1A). Elevated TREM1‐PET binding was observed in the cortex (1.77‐vs‐1.62 %ID/g, p=0.14) and whole brain (1.64‐vs‐1.46 %ID/g, p=0.08) but did not reach significance. TSPO‐PET imaging demonstrated significantly increased [18F]GE‐180 binding in all regions (cortex: 2.36‐vs‐1.48 %ID/g; p=0.0003, hippocampus: 2.59‐vs‐1.52 %ID/g, p<0.0001, thalamus: 2.18‐vs‐1.20 %ID/g, p<0.0001, whole brain: 2.55‐vs‐1.66 %ID/g, p=0.0003, Fig. 1B). CD68 staining confirmed increased microglia/macrophage activation in cortical, hippocampal, and thalamic regions (Fig 2). Conclusion: Differential regional binding patterns were observed with TREM1‐ and TSPO‐PET imaging. Notably, increased TREM1‐PET signal in 5XFAD animals suggests a role for peripheral myeloid cells in AD. Longitudinal whole‐body TREM1‐ and TSPO‐PET imaging in this model is currently underway. [ABSTRACT FROM AUTHOR]