Aquaporin 4 is associated with cerebral amyloid‐beta and tau deposits in mouse models

Abstract

AbstractBackgroundEmerging evidence indicates that the glymphatic system plays an important role in Alzheimer’s disease. Aquaporin 4 (AQP4) constitutes a critical part of the glymphatic system in the clearance of accumulated amyloid‐beta and tau from the brain. Here, we aimed to establish the association between AQP4 and tau as well as amyloid‐beta (Aβ).MethodPerfusion and susceptibility weighted imaging (SWI) magnetic resonance imaging (MRI, at 7 or 9.4 T) were performed in arcAβ mouse model of amyloidosis (aged 16‐18 months), P301L mouse model of 4‐repeat tau (pR5 line) and respective nontransgenic littermates (aged 10‐12 months). Immunofluorescence staining was performed using antibodies against AQP4, CD31, astrogliosis (GFAP, s100β), microgliosis (Iba1, CD68), Aβ (6E10), and tau (AT‐8 and AT‐100) in brain tissue slices from transgenic arcAβ mice and wild‐type littermates.ResultCerebral microbleeds were detected in the cortex and subcortical regions in arcAβ mice. Cerebral blood flow was reduced in the cortex and hippocampus of arcAβ compared to nontransgenic mice but preserved in P301L mice. Increased AQP4 levels were observed surrounding tau deposits in the forebrain of P301L mice and parenchymal amyloid plaques/cerebral amyloid angiopathy in the cortex and hippocampus of arcAβ mice. Depolarization of AQP4 was detected in both arcAβ and P301L mice compared to their respective nontransgenic littermates. Increased s100b‐GFAP and CD68‐Iba1 fluorescence intensities indicative of atrogliosis and microgliosis were detected around tau deposits in P301L mice and amyloid plaques in arcAβ mice.ConclusionWe observed impaired perfusion in arcAβ mice but not in P301L mice, and a spatial association of AQP4 with both tau and Aβ in the brain.