Abstract
241584
Introduction: The TgF344-AD rats express human mutant amyloid precursor protein (APPsw) and presenilin-1 (PS1ΔE9) and manifest cerebral amyloidosis, tauopathy, gliosis, apoptotic loss of neurons, and cognitive deficiency(1). [18F]FDDNP, the first PET tracer to visualize both amyloid plaques and tau tangles in living humans (2), exhibits uptake in the frontal cortices of 15-month-old TgF344-AD rats (1). Preliminary studies in humans and healthy mice using [18F]MK6240, the second-generation tau radiotracer demonstrated promising results with improved target specificity (3). So far, [18F]MK6240 has not been tested in AD animal models. In the present study, we explored the ability of [18F]MK6240 PET imaging to visualize tau tangles in the TgF344-AD rats.
Methods: TgF344-AD breeder rats were originally obtained from RRRC (University of Missouri) and mated in Yale Animal Resource Center to provide littermates for designated studies. [18F]MK6240 was produced in Yale PET center with a radiochemical purity of >99%. Female littermates (WT, n=4; AD, n=5) of 19 months old were scanned for 90 min using the FOCUS-220 scanner after [18F]MK6240 injection via the tail vein. Standard uptake value (SUV) curves were generated for brain regions (brain stem, hippocampus, limbic insular cortex, motor sensory cortex, striatum, cerebellum) and the whole brain. The striatum was used as the reference region to calculate SUV30-90 min and DVR using the simplified reference tissue model 2 (SRTM2). Immunohistochemical staining (IHC) was carried out in AD rat brain sections using rabbit anti-SV2A (1:1000) and mouse anti-Phospho-Tau (Ser202, Thr205; 1:200) antibody (Invitrogen) with ImmPRESS® Duet Double Staining Kit (Vector Lab). In vitro autoradiography (ARG) was carried out by incubating TgF344-AD brain slices (n=2 males; n=1 female; 20 um thickness/section) in 1x HEPES buffer (0.1% BSA) solution of [18F]MK6240 at room temperature for 30 min, followed by exposure to phosphor imaging plates. The plates were scanned, and images retrieved on the Typhoon 5 scanner. Data are presented as mean ± standard deviation (SD). Student t test was used to compare the differences.
Results: The average body weight of AD rats at ~19-month-old was ~ 16% heavier than the WT littermates (AD: 348.8±12.7 g; WT: 301.3±28.6 g). The average dosage/rat injected for AD and WT were 17.5±5.4 MBq and 14.2±2.7 MBq, respectively. There was no difference in administered activity dose between AD and WT groups (AD: 0.050 ±0.016 MBq/g; WT: 0.047±0.007 MBq/g; p=0.7). The tracer uptake peaked at ~ 3 min post tracer injection, quickly washed out within 20 min, and remained at the same level until the end of scan (Fig. 1A). Among the brain regions examined, cerebellum was found to have the increased SUV30-90 min (15%, p<0.05) and DVR (19%, p<0.05) in AD compared to WT rats (Fig. 1B, C; Table 1). SUV30-90 min correlated to DVR with an R2 of 0.83 (Fig. 1D). In addition, except for the hippocampus DVR (8%, p<0.05), all the other examined regions show a trend of increase in both SUV30-90 min and DVR values but didn’t reach the statistically significant difference. Importantly, in vitro ARG showed higher specific tracer uptake in the neocortex, cerebellum, and mid brain, but lower in the medulla, pons, and striatum of AD brains (Fig. 2A, B). Further, Tau IHC staining results confirmed the findings from both the PET imaging and in vitro ARG (Fig. 2C).
Conclusions: Conclusion: Our data suggest that at age of 19-month-old, the female TgF344-AD rats have widespread expression of phospho-Tau proteins in their brains. Our result supports the use of [18F]MK6240 for tau imaging in TgF344-AD rats in future studies.
References
1. Cohen RM, et al. J Neurosci. 2013;33:6245-6256.
2. Shin J, et al. J Alzheimers Dis. 2011;26 Suppl 3:135-145.
3. Bao W, et al. Front Aging Neurosci. 2021;13:624330.
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