In vivo visualization of tau accumulation, microglial activation, and brain atrophy in a mouse model of tauopathy rTg4510

Background: Tau imaging using PET is a promising tool for the diagnosis and evaluation of tau-related neurodegenerative disorders, but the relationship among PET-detectable tau, neuroinflammation, and neurodegeneration is not yet fully understood. Objective: We aimed to elucidate sequential changes in tau accumulation, neuroinflammation, and brain atrophy by PET and MRI in a tauopathy mouse model. Methods: rTg4510 transgenic (tg) mice expressing P301L mutated tau and non-tg mice were examined with brain MRI and PET imaging (analyzed numbers: tg = 17, non-tg = 13; age 2.5∼14 months). As PET probes, [¹¹C]PBB3 (Pyridinyl-Butadienyl-Benzothiazole 3) and [¹¹C]AC-5216 were used to visualize tau pathology and 18-kDa translocator protein (TSPO) neuroinflammation. Tau pathology and microglia activation were subsequently analyzed by histochemistry. Results: PET studies revealed age-dependent increases in [¹¹C]PBB3 and [¹¹C]AC-5216 signals, which were correlated with age-dependent volume reduction in the forebrain on MRI. However, the increase in [¹¹C]PBB3 signals reached a plateau at age 7 months, and therefore its significant correlation with [¹¹C]AC-5216 disappeared after age 7 months. In contrast, [¹¹C]AC-5216 showed a strong correlation with both age and volume reduction until age 14 months. Histochemical analyses confirmed the relevance of pathological tau accumulation and elevated TSPO immunoreactivity in putative microglia. Conclusion: Our results showed that tau accumulation is associated with neuroinflammation and brain atrophy in a tauopathy mouse model. The time-course of the [¹¹C]PBB3-and TSPO-PET finding suggests that tau deposition triggers progressive neuroinflammation, and the sequential changes can be evaluated in vivo in mouse brains.