Alzheimer Disease: The proposed role of tanycytes in the formation of tau tangles and amyloid beta plaques in human brain

Currently, the causes for Alzheimer Disease (AD) are thought to lie in the formation of abnormal protein deposits including tau tangles and Amyloid ß (Aß) plaques in the human cortex. These proteins are believed to accumulate in the brain due to impaired waste removal resulting in neurodegeneration. In an alternative hypothesis we have recently proposed the existence of an aquaporin-4 aqua channel (AQP4)-expressing tanycyte-derived canal network that likely internalizes waste for removal from the brain. We propose that both Aß and tau protein may play important structural roles in this canal system. In support of this hypothesis, we demonstrate the formation of waste-internalizing receptacles by AQP4-expressing myelinated tanycytes. Using RNA-scope in situ hybridization, immunohistochemistry, ultrastructural, and histological approaches, we demonstrate receptacle differentiation in tanycyte-derived ‘swell-bodies.’ We show that these receptacles are AQP4- and Aß-immunoreactive and that related gene expression is observed in ‘swell-bodies’ where receptacle differentiation is observed. Through correlative light- and electron-microscopy in human and mouse brain, we demonstrate that both Aß and tau protein are associated with these waste-internalizing structures and likely play important roles in the waste internalization process. Based on our findings, we postulate that the functional significance of Aß may be structural stabilization of waste-internalizing structures and canals to prevent their collapse during the uptake process. We propose that tau protein may govern the quantitatively appropriate release of waste-internalizing structures. We postulate that AD-related Aß-plaques and tau tangles likely show hypertrophic pathologies of this glial-canal-system and associated waste-internalizing receptacles.