Abstract
Blood-brain barrier (BBB) modeling in vitro is a huge area of research covering study of intercellular communications and development of BBB, establishment of specific properties that provide controlled permeability of the barrier. Current approaches in designing new BBB models include development of new (bio) scaffolds supporting barriergenesis/angiogenesis and BBB integrity; use of methods enabling modulation of BBB permeability; application of modern analytical techniques for screening the transfer of metabolites, bio-macromolecules, selected drug candidates and drug delivery systems; establishment of 3D models; application of microfluidic technologies; reconstruction of microphysiological systems with the barrier constituents. Acceptance of idea that BBB in vitro models should resemble real functional activity of the barrier in different periods of ontogenesis and in different (patho) physiological conditions leads to proposal that establishment of BBB in vitro model with alterations specific for aging brain is one of current challenges in neurosciences and bioengineering. Vascular dysfunction in the aging brain often associates with leaky BBB, alterations in perivascular microenvironment, neuroinflammation, perturbed neuronal and astroglial activity within the neurovascular unit, impairments in neurogenic niches where microvascular scaffold plays a key regulatory role. The review article is focused on aging-related alterations in BBB and current approaches to development of “aging” BBB models in vitro.
Highlights
Brain aging is one of the most intriguing issues in modern neurobiology, physiology and cell biology
As it is clearly seen from above data, the following approaches could be applied in order to induce senescent phenotype in Blood-brain barrier (BBB) cells in vitro: (1) induction of senescence-associated secretory phenotype (SASP) and inflammasome activation; (2) induction of insulin resistance (IR); (3) manipulating NAD+ levels; (4) induction of DNA-damage response (DDR) associated with γ-H2AX accumulation; and (5) promotion of mitochondrial biogenesis, glycolytic changes and aberrant production of lactate
It is clear that application of ‘‘standard’’ BBB in vitro models to study barrier alterations in the aging brain could be possible if cellular components of the BBB are obtained from the brain of aged animals or animal strains with accelerated aging, i.e., possessing genetically encoded impairments in the signaling of growth hormone/IGF-1, mTOR, sirtuins, suffering from weak antioxidant defense, prone to metabolic alterations, demonstrating prominent inflammatory response or alterations in DNA repair mechanisms, as excellently reviewed in Liao and Kennedy (2014)
Summary
Brain aging is one of the most intriguing issues in modern neurobiology, physiology and cell biology. It could be proposed that senescence of non-neuronal cells in the aging brain could contribute to progressive impairment of BBB (aging endothelial cells), insufficient myelination (aging oligodendrocytes), reduced neurogenesis (aging neural stem cells) and development of sterile neuroinflammation (aging astroglial and microglial cells) Another function of SASP induction might be found in the promotion of cell plasticity and stemness as it was shown in the skin: keratinocytes exposed to the SASP initially elevate expression of stem cell markers and regenerative capacity in vivo followed by the cell cycle arrest (Ritschka et al, 2017). Sub-telomeres are less responsive to external DNA damage than to endogenous stress (Seo et al, 2012)
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