Vessel permeability : a new target
Controlling vessel permeability as a new target against vascular ageing (WP3) N. Macrez, JL Morel, C Duplaa, J. Badaut, I Sibon (CNRS UMR 5293; CNRS UMR 5287; Inserm U1034 - Department of Neurology and Stroke Unit)
Vascular dysfunction is a critical element of brain aging and neurodegeneration, especially in Alzheimer disease (AD) (Iadecola, 2004, 2010; Nicolakakis and Hamel, 2011). Age-related brain Aβ peptide accumulation may depend on progressively impaired clearance mechanisms, as measured by in vivo kinetics of Aβ in cerebrospinal fluid of AD and control patients (Erickson and Banks, 2013; Mawuenyega et al., 2010). Accumulation of vasculotoxic and neurotoxic molecules within the brain parenchyma, could also result from vascular insults (stroke, trauma) and blood brain barrier (BBB) leakage thereby initiating and/or contributing to neuronal degeneration (Zlokovic, 2011).
At the BBB, the brain microvasculature develops unique properties to assure a tight control of permeability between blood and the nervous system. To this end, endothelial cells express many proteins involved in the adherens junctions and in building tight junctions between cells (Paolinelli et al., 2011). Canonic Wnt signaling is a major player in modulating early and late brain specific differentiation of EC necessary for BBB induction and maintenance (Liebner et al 2008). In addition, endothelial cells also express transporters involved in the bidirectional flow of substances : P-glycoprotein (P-gp) and low-density lipoprotein-related receptor protein 1 (LRP1) are responsible for brain-to-blood efflux, and the receptor for “advanced glycation end products” (RAGE) import blood-to-brain molecules (Ueno et al., 2010). Decreased P-gp or LRP1 on endothelial cells are linked to increased Aβ and neurodegeneration in human brain aging, AD, and aging rodents (Cirrito et al., 2005; Silverberg et al., 2010).
The present working program is aimed at determining how BBB alteration could be involved in neuronal dysfunction in various physiological and pathological situations.
- Increased BBB permeability in ageing vessel : MRI study
- Increased BBB leakage accelerates the progression of Alzheimer's disease
- Decrease BBB permeability reduces stroke size