TSPO and P2X7 discriminate between amyloid‐ and tau‐induced glial responses

Abstract

AbstractBackgroundCurrent clinical PET imaging relies on translocator protein (TSPO) to detect neuroinflammation in brain disorders including degenerative conditions such as AD, however this marker lacks cell type‐specificity and offers no information on what type of insult is causing the reaction. An ideal PET tracer would detect both the rise in pro‐inflammatory and loss of anti‐inflammatory glial responses and would discriminate cellular responses to amyloid‐beta from tau. We investigated whether a pair of glial purinergic receptors would provide a better measure of inflammatory status in mouse models of AD than the current standard TSPO.MethodWe studied the expression of P2X7, P2Y12, and TSPO in 5xFAD and PS19 transgenic mice at early and late stages of pathology using quantitative immunohistochemistry. Co‐staining with microglial (Iba1) and astroglial (GFAP) markers was used to identify cell types expressing each receptor.ResultExpression of P2Y12 decreased significantly with the onset of both Aβ and tau pathology. TSPO increased in 5xFAD mice with amyloid pathology, but not in PS19 mice with tau pathology. We observed the opposite pattern in P2X7 signal, which increased in PS19 mice with tau pathology, but less in 5xFAD mice with amyloid plaques.ConclusionOur findings suggest there may be distinct neuroinflammatory responses to Aβ and tau with increased TSPO around amyloid but not tau, and a reciprocal increase in P2X7 around tau but not amyloid. We found that P2Y12 and P2X7 serve as complementary markers reflecting the loss of homeostatic microglia and the rise of a reactive phenotype. Our results support continued investigation of P2Y12 and P2X7 as potential biomarkers of distinct neuroinflammatory responses which may be used in conjunction with TSPO to distinguish AD pathologies in clinical settings.