Abstract
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Introduction: Neuroinflammation is a fundamental underlying hallmark of Alzheimer’s disease (AD), a debilitating neurodegenerative condition marked by accumulation of extracellular amyloid plaques and intracellular neurofibrillary tangles composed of aggregated amyloid β (Aβ) and hyperphosphorylated tau, respectively, leading to progressive cognitive impairment and dementia. Monoacylglycerol lipase (MAGL) is an enzyme belonging to the serine hydrolase superfamily metabolizing lipids, but its most striking role unveiled within this decade is in hydrolyzing the endogenous cannabinoid 2-arachidonoylglycerol (2-AG), resulting in the release of the free fatty acid arachidonic acid (AA), a precursor of eicosanoids, and glycerol. This is evidenced by the observations where inhibition of MAGL by a selective and potent inhibitor JZL184 dramatically elevates brain levels of 2-AG and decreases levels of AA and AA-derived prostaglandins, suggesting that MAGL is a promising therapeutic target for preventing and treating AD. Here we show that MAGL inhibition prevents and decreases synthesis and accumulation of Aβ and suppresses microglial and astrocytic activation and prevents neurodegeneration; and [18F]MAGL-2102 PET enabled imaging MAGL changes after JZL184 treatment in these.
Methods: We employed 5XFAD transgenic (TG) mice as AD model; JZL184 was dissolved in the vehicle containing Tween-80 (10%), DMSO (10%) and saline (80%). We treated TG mice with vehicle or JZL184 (12 mg/kg) three times per week by intraperitoneal (i.p.) starting at 2 months of age for 16 weeks or starting at 4 months of age for 8 weeks. Western blot assay was conducted to determine production of MAGL and expression of APP in the brain from WT and TG mice treated with vehicle or JZL184. Immunohistochemical analyses were performed to determine astrocytic (GFAP) and microglial (Iba-1) markers in coronal sectioned brain slices. We used an MAGL-specific PET to evaluate cerebral MAGL PET signal and uptake in the 5XFAD mouse models.
Results: We found that JZL184 reduced reactive astrocytic and microglial cells in the hippocampus of TG mice (Fig. 1), indicating that neuroinflammation was suppressed when MAGL is inhibited. Figure 2 represents summed transverse, coronal and sagittal cerebral PET/CT images (0-60 min) of normal WT mice, 5XFAD mice, WT + JZL184 mice and 5XFAD+ JZL184. The tracer uptake was gradually declined after JZL184 treatment in WT mice. Declined uptakes of [18F]MAGL-2102 were also found in 5XFAD mice+JZL184 compared with 5XFAD. Significantly lower levels of radioactivity were observed in WT+JZL184 and 5XFAD+JZL184. Time-activity curves (TACs) were analyzed by drawn interest area for [18F]MAGL-2102 in the brain between 0- and 60-min. TACs which radioactivity is expressed as %injected dose per gram (%ID/g). Brain APP was detected in TG mice. As shown in Figure 3 and figure 4, MAGL inhibition for 16 weeks robustly decreased total MAGL and APP in the hippocampus.
Conclusions: [18F]MAGL-2102 is a promising candidate for noninvasive imaging of target engagement of MAGL therapeutics for Alzheimer’s disease.
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