The role of ATP and P2X purinoreceptor 7 in the pathogenesis of cerebral tau

Abstract

The tauopathies are a group of neurodegenerative diseases characterized by abnormal deposition of hyperphosphorylated-tau. The pathogenesis of these changes remains uncertain. In chronic traumatic encephalopathy, tauopathy is hypothesized to occur after repeated mild traumatic brain injury (TBI). Post-traumatic extracellular ATP release and signalling via the P2X purinoceptor 7 (P2RX7) has been shown to be important in mediating pathological changes in TBI. We hypothesized that ATP-P2RX7 is involved in the development of tauopathy.

We injected ATP analogue bzATP or vehicle intraventricularly into C57BL/6 mice, pre-treated with either intraperitoneal P2RX7 antagonist Brilliant Blue G (BBG) or vehicle. At 2 weeks and 3 months, behavioural change was assessed with the tail suspension test, accelerating rotatrod, and fear conditioning; mice were then sacrificed for immunohistochemistry and western blot.

We observed increased immobile time in the tail suspension test for mice treated with bzATP at 3 months. Similarly, for rotarod, mice treated with bzATP showed poorer performance at 3 months. These effects were diminished by BBG pre-treatment. Fear conditioning, however, did not demonstrate a significant difference between groups. Immunohistochemical staining for GFAP showed increased intensity at both 2 weeks and 3 months for bzATP-treated mice compared to those pre-treated with BBG. Levels of phosphorylated tau (AT8) were increased in bzATP-treated mice compared to controls.

In summary, ATP-P2RX7-mediated mechanisms may play a role in the development of behavioural deficits and tauopathy.