Abstract Background: Neuroinflammation and myelin loss are hallmark features of Alzheimer’s disease (AD) associated with cognitive decline. Emerging evidence highlights the significant role of glial cell activation, particularly microglia, in driving neuroinflammation and disease progression. While translocator protein (TSPO) PET imaging is commonly used to detect neuroinflammation, limitations have prompted investigation into alternative targets such as the P2X7 receptor (P2X7R), which is upregulated during pathological conditions. Additionally, myelin loss has gained recognition as an important pathological feature in AD, potentially linked to chronic neuroinflammation. However, the temporal dynamics and interplay between neuroinflammation and myelin loss remain poorly understood in the context of AD. Methods: We conducted a longitudinal PET study from 4 to 22 months of age in TgF344-AD rats and wild-type controls to assess neuroinflammation with 18FJNJ-64413739 (P2X7R) and 18FDPA-714 (TSPO), alongside myelin content using 18FFlorbetaben. Diffusion tensor imaging (DTI) was used to study variations on myelin structure in old AD and WT rats. In vitro studies, including autoradiography, immunoflusorescence and staining were used to support the in vivo results. Results: 18FJNJ-64413739 PET showed increased P2X7 receptor expression in AD and control animals over time, while 18FDPA-714 PET showed significant differences between groups at 22 months. 18FFlorbetaben PET showed different uptake in white matter rich areas between groups with observed demyelination in AD rats at 20 months in the brain stem, supported by diffusional MRI findings. Conclusions: In our study, P2X7R overexpression was attributed to aging rather than genotype effects, and no link was found to the observed demyelination in AD rats. Conversely, increased TSPO neuroinflammation in TgF344-AD rats correlated with myelin loss and the reported cognitive decline in this model. Our results support the use of the TgF344-AD model to study early AD pathology, focusing on neuroinflammation and white matter integrity.
Moreno et al. (Wed,) studied this question.