Analog of kynurenic acid decreases tau pathology by modulating astrogliosis in rat model for tauopathy.

Kynurenines have immunomodulatory and neuroactive properties and can influence the central nervous system. Previous studies showed the involvement of the kynurenines in the pathogenesis and progression of neurodegenerative disease. In neurodegenerative disorders, including tauopathies, the tryptophan metabolism is shifted toward neurotoxic agents and the reduction of neuroprotectant products. Astrocyte-derived kynurenic acid serves as a neuroprotectant. However, systemic administration of kynurenic acid is not effective because of low permeability across the blood-brain barrier (BBB). We used a kynurenic acid analog with similar biological activity but higher brain permeability to overcome BBB limitations. In the present study, we used amide derivate of kynurenic acid N-(2-N, N-dimethylaminoethyl)- 4-oxo-1 H-quinoline-2-carboxamid (KYNA-1). We administered KYNA-1 for three months to tau transgenic rats SHR-24 and analyzed the effect on tau pathology and activation of glial cells. Primary glial cell cultures were applied to identify the mechanism of the KYNA-1 effect. KYNA-1 was not toxic to rats after chronic three-month administration. When chronically administered, KYNA-1 reduced hyperphosphorylation of insoluble tau in the brain of transgenic rats. Noteworthily, the plasma total tau was also reduced. We determined that the effect of KYNA-1 on tau pathology was induced through the modulation of glial activation. KYNA-1 inhibited LPS induced activation of astrocytes and induced transformation of microglia to M2 phenotype. We identified that the administration of KYNA-1 reduced tau hyperphosphorylation and neuroinflammation. KYNA-1 may serve as a promising treatment for tauopathies.

Trafficking of immune cells across the blood-brain barrier is modulated by neurofibrillary pathology in tauopathies.

Tauopathies represent a heterogeneous group of neurodegenerative disorders characterized by abnormal deposition of the hyperphosphorylated microtubule-associated protein tau. Chronic neuroinflammation in tauopathies is driven by glial cells that potentially trigger the disruption of the blood-brain barrier (BBB). Pro-inflammatory signaling molecules such as cytokines, chemokines and adhesion molecules produced by glial cells, neurons and endothelial cells, in general, cooperate to determine the integrity of BBB by influencing vascular permeability, enhancing migration of immune cells and altering transport systems. We considered the effect of tau about vascular permeability of peripheral blood cells in vitro and in vivo using primary rat BBB model and transgenic rat model expressing misfolded truncated protein tau. Immunohistochemistry, electron microscopy and transcriptomic analysis were employed to characterize the structural and functional changes in BBB manifested by neurofibrillary pathology in a transgenic model. Our results show that misfolded protein tau ultimately modifies the endothelial properties of BBB, facilitating blood-to-brain cell transmigration. Our results suggest that the increased diapedesis of peripheral cells across the BBB, in response to tau protein, could be mediated by the increased expression of endothelial signaling molecules, namely ICAM-1, VCAM-1, and selectins. We suggest that the compensation of BBB in the diseased brain represents a crucial factor in neurodegeneration of human tauopathies.