Modifications of physical and functional integrity of the blood-brain barrier in an inducible mouse model of neurodegeneration.

The inducible p25 overexpression mouse model recapitulate many hallmark features of Alzheimer's disase including progressive neuronal loss, elevated Aß, tau pathology, cognitive dysfunction, and impaired synaptic plasticity. We chose p25 mice to evaluate the physical and functional integrity of the blood-brain barrier (BBB) in a context of Tau pathology (pTau) and severe neurodegeneration, at an early (3 weeks ON) and a late (6 weeks ON) stage of the pathology. Using in situ brain perfusion and confocal imaging, we found that the brain vascular surface area and the physical integrity of the BBB were unaltered in p25 mice. However, there was a significant 14% decrease in cerebrovascular volume in 6 weeks ON mice, possibly explained by a significant 27% increase of collagen IV in the basement membrane of brain capillaries. The function of the BBB transporters GLUT1 and LAT1 was evaluated by measuring brain uptake of d-glucose and phenylalanine, respectively. In 6 weeks ON p25 mice, d-glucose brain uptake was significantly reduced by about 17% compared with WT, without any change in the levels of GLUT1 protein or mRNA in brain capillaries. The brain uptake of phenylalanine was not significantly reduced in p25 mice compared with WT. Lack of BBB integrity, impaired BBB d-glucose transport have been observed in several mouse models of AD. In contrast, reduced cerebrovascular volume and an increased basement membrane thickness may be more specifically associated with pTau in mouse models of neurodegeneration.

Correction: Correlation between cognition and plasma noradrenaline level in Alzheimer's disease: a potential new blood marker of disease evolution.

A Correction to this paper has been published: https://doi.org/10.1038/s41398-020-01102-y.

Correlation between cognition and plasma noradrenaline level in Alzheimer's disease: a potential new blood marker of disease evolution.

Recent evidence showing degeneration of the noradrenergic system in the locus coeruleus (LC) in Alzheimer's disease (AD) has motivated great interest in noradrenaline (NA) as a potential brain hallmark of the disease. Despite the current exploration of blood markers for AD, the deregulation of the plasma NA concentration ([NA]plasma) in AD is currently not well understood. This retrospective study includes a cohort of 71 patients (32 AD patients, 22 with other dementia and 17 without dementia) who were given consultations for memory complaints in the Cognitive Neurology Center of Lariboisière (Paris) between 2009 and 2014. As previously described in brain tissue, we show for the first time a linear correlation between [NA]plasma and Mini Mental State Examination (MMSE) score in AD patients. We observed that high [NA]plasma in AD patients was associated with higher [Aß1-42]CSF than in other AD patients with [NA]plasma similar to NC patients. In parallel, we observed a lower (p-Tau/Tau)CSF in AD patients with low [NA]plasma than in non-AD patients with [NA]plasma similar to [NA]plasma in NC patients. Our data suggest that [NA]plasma could be a potential biomarker of disease evolution in the context of AD and could possibly improve early diagnosis.

High brain distribution of a new central nervous system drug candidate despite its P-glycoprotein-mediated efflux at the mouse blood-brain barrier.

Efficacy of drugs aimed at treating central nervous system (CNS) disorders rely partly on their ability to cross the cerebral endothelium, also called the blood-brain barrier (BBB), which constitutes the main interface modulating exchanges of compounds between the brain and blood. In this work, we used both, conventional pharmacokinetics (PK) approach and in situ brain perfusion technique to study the blood and brain PK of PKRinh, an inhibitor of the double-stranded RNA-dependent protein kinase (PKR) activation, in mice. PKRinh showed a supra dose-proportional blood exposure that was not observed in the brain, and a brain to blood AUC ratio of unbound drug smaller than 1 at all tested doses. These data suggested the implication of an active efflux at the BBB. Using in situ brain perfusion technique, we showed that PKRinh has a very high brain uptake clearance which saturates with increasing concentrations. Fitting the data to a Michaelis-Menten equation revealed that PKRinh transport through the BBB is composed of a passive unsaturable flux and an active saturable protein-mediated efflux with a km of ≅ 3 µM. We were able to show that the ATP-binding cassette (ABC) transporter P-gp (Abcb1), but not Bcrp (Abcg2), was involved in the brain to blood efflux of PKRinh. At the circulating PKRinh concentrations of this study, the P-gp was not saturated, in accordance with the linear brain PKRinh PK. Finally, PKRinh had high brain uptake clearance (14 µl/g/s) despite it is a good P-gp substrate (P-gp Efflux ratio ≅ 3.6), and reached similar values than the cerebral blood flow reference, diazepam, in P-gp saturation conditions. With its very unique brain transport properties, PKRinh improves our knowledge about P-gp-mediated efflux across the BBB for the development of new CNS directed drugs.