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.

miRNAs as biofluid markers for diagnostics of Alzheimer's disease: recent status and perspectives.

After many decades of research in the field of neurodegeneration, we have no effective cure for Alzheimer's disease (AD), a major form of dementia. It is mainly due to the lack of early, reliable and sensitive biomarkers and incomplete understanding of disease mechanisms at molecular level. Several recently employed biomarkers, especially their combinations, can discriminate advanced stages of AD from other forms of dementia or neuropathy. They do not provide much information on molecular mechanisms of disease rather they reflect the amount of key histopathological markers in the diseased brain. This review is focussed on novel class of potentially very promising AD biomarkers: extracellular miRNAs in body liquids, such as cerebrospinal fluid and blood. They have a great potential not only to indicate the presence of AD, but more importantly, to reflect the molecular mechanisms playing a role early at the beginning of the pathogenic pathways consequently leading to AD. We believe this comprehensive review on deregulated miRNAs in AD can be a good source of information for thorough in silico analyses aiming to identification, development and validation of miRNAs as "diseases mechanism engaged" candidate biomarkers. Having such molecules could bring us closer to the goal - successful treatment of AD.

Stress-Induced Alterations of Immune Profile in Animals Suffering by Tau Protein-Driven Neurodegeneration.

Alzheimer's disease (AD) is a multifactorial disorder; neurofibrillary pathology composed of tau protein is found side by side with amyloid-ß deposits and extensive neuroinflammation. The immune system of the brain is considered as one of the factors that could influence the speed of the progression of AD neuropathology as a potential mediator of the damage induced by AD protein deposits. Alzheimer's disease pathology can be impacted by psychological stress; however, signalling pathways in background are not well known. We have explored possible avenues of how stress could influence the brain's immune system in a rat model of AD. Animals were subjected either to a single or multiple instances of immobilization stress. The analysis of a panel of immunity-related genes was used to evaluate the impact of stress on the immune response in the brain. We have identified 19 stress-responsive genes that are involved in neuroinflammation accompanying tau pathology: Nos2, Ptgs2, IL-8rb, C5, Mmp9, Cx3cr1, CD40lg, Adrb2, IL-6, IL-6r, IL-1r2, Ccl2, Ccl3, Ccl4, Ccl12, TNF-α, IL-1α, IL-1ß, IL-10. Most of them are deregulated under the stress conditions also in control animals; however, the magnitude of the response to either acute or chronic stress differs. This can lead to serious influence, most probably to acceleration of neurodegenerative phenotype in diseased animals. Several of the genes (IL-1ß, Casp1, Cx3cr1 and C5) are deregulated solely in tauopathic animals. The stress-induced changes in the inflammatory picture of the brain highlight the fact that the brain's immune response is highly responsive to environmental stimuli. The pattern of changes is indicative of an attempt to protect the brain in the short term, while being potentially detrimental to the response against a long-term pathological process such as neurofibrillary degeneration.