Modifications of physical and functional integrity of the blood-brain barrier in an inducible mouse model of neurodegeneration. (15th June 2021)

• Record Type: Journal Article
• Authors: Taccola, Camille; Barneoud, Pascal; Cartot-Cotton, Sylvaine; Valente, Delphine; Schussler, Nathalie; Saubaméa, Bruno; Chasseigneaux, Stéphanie; Cochois, Véronique; Mignon, Virginie; Curis, Emmanuel; Lochus, Murielle; Nicolic, Sophie; Dodacki, Agnès; Cisternino, Salvatore; Declèves, Xavier; Bourasset, Fanchon
• Is Part Of: Neuropharmacology. Volume 191(2021)
• Publication Date: 2021-06-15
• Subjects: Alzheimer's disease -- Neurodegeneration -- p25 mice -- Blood-brain barrier -- In situ brain perfusion -- Vascular density; AD Alzheimer's disease -- BBB blood-brain barrier -- BCECs brain capillary endothelial cells -- Clup brain uptake clearance -- Vvasc brain vascular volume -- ND neurodegeneration -- CNS central nervous system -- Aβ amyloid-beta peptide -- NFTs neurofibrillary tangles -- SLC solute carriers -- ABC ATP-binding cassette transporters -- APP amyloid precursor protein -- Cdk5 cyclin-dependent kinase 5; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2021.108588
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: The inducible p25 overexpression mouse model recapitulate many hallmark features of Alzheimer's disase including progressive neuronal loss, elevated Aβ, 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. Highlights: The physical integrity of the blood-brain barrier is not altered after 6 weeks of induction of the p25 transgene (6 weeks ON). The cerebrovascular volume is decreased after 6 weeks ON. The basement membrane thickness is increased after 6 weeks ON. Unlike phenylalanine transport, d -glucose cerebral uptake is reduced after 6 weeks ON.