Neuroinflammatory process during pathogenesis of tauopathy in rTg4510 mice
Naruhiko Sahara, Jun Maeda, Takeharu Minamihisamatsu, Maiko Ono, Masafumi Shimojo, Hiroyuki Takuwa, Yuhei Takado, Taeko Kimura, Bin Ji, Tetsuya Suhara, Makoto Higuchi
National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan
Tauopathy is characterized by the filamentous tau aggregation in nerve cell and glial cells. To understand the causative mechanisms of tauopathy, neuroinflammation is now suggested to play important roles in disease progression. Since neuroinflammation is characterized predominantly by microglial activation, microglial functions and morphologies were widely investigated. However, it is still under debate whether microglial activation is a cause or a result of neurodegeneration. In this study, we examined the morphological changes of microglia using several microglial markers during tau pathology development. Ramified microglia labeled by P2Y12 antibody were significantly reduced at early stage of tauopathy, while unramified or amoeboid microglia continued to increase, followed by pathological tau accumulation in a mouse model of tauopathy. As previously reported, in vivo imaging (e.g., tau-PET, TSPO-PET and volumetric MRI) of tauopathy mice strongly supports the evidence of microglial activation along with both pathological tau accumulation and brain atrophy (1). Taken together, our results indicated that both early and late events of microglial phenotypic change were linked to the pathogenesis of tauopathy. Since the involvement of P2Y12 receptors at early stage of the microglial activation process has been clarified, P2Y12 receptor will present a promising target for mediating early microglial response in tauopathy. In addition, we will discuss novel approaches to the establishment of imaging biomarkers, thereby targeting the early diagnosis of tauopathy.
1. Ishikawa I, Tokunaga M, Maeda J, Minamihisamatsu T, Shimojo M, Takuwa H, Ono M, Ni R, Hirano S, Kuwahara S, Ji B, Zhang M-R, Aoki I, Suhara T, Higuchi M, Sahara N. In vivo visualization of tau accumulation, microglial activation and brain atrophy in a mouse model of tauopathy rTg4510 J. Alzheimer's Disease 2018 61(3): 1037-1052