Blood-brain barrier dysfunction in aging induces hyper-activation of TGF-beta signaling and chronic yet reversible neural dysfunction

Abstract

Aging involves a decline in neural function that contributes to cognitive impairment and disease. However, the mechanisms underlying the transition from a young-and-healthy to aged-anddysfunctional brain are not well understood. Here, we report breakdown of the vascular blood-brain barrier (BBB) in aging humans and rodents, which begins as early as middle age and progresses to the end of the lifespan. Gain-of-function and loss-of-function manipulations show that this BBB dysfunction triggers hyperactivation of transforming growth factor β (TGFβ) signaling in astrocytes, which is necessary and sufficient to cause neural dysfunction and age-related pathology. Specifically, infusion of the serum protein albumin into the young brain (mimicking BBB leakiness) induced astrocytic TGFβ signaling and an aged brain phenotype including aberrant electrocorticographic activity, vulnerability to seizures, and cognitive impairment. Furthermore, conditional genetic knockdown of astrocytic TGFβ receptors, or pharmacological inhibition of TGFβ signaling, reversed these symptomatic outcomes in aged mice. Finally, we found that this same signaling pathway is activated in aging human subjects with BBB dysfunction. Our study identifies dysfunction in the neurovascular unit as one of the earliest triggers of neurological aging, and demonstrates that the aging brain may retain considerable latent capacity which can be revitalized by therapeutic inhibition of TGFβ signaling. cm or less), and percentage of time at the novel object was quantified as (duration investigating novel object) / (total duration investigating all three objects). The set objects were chosen from common items such as lab bottles, pipette boxes, cups (placed open-side down), etc., that were of similar dimensions but varied in shape, color, and material. The sequence and position of objects used across trials was identical for all mice.

Development of Novel Therapeutics Targeting the Blood–Brain Barrier: From Barrier to Carrier

“…Pharmacological inhibition of TGF‐ β signaling reversed these symptomatic outcomes in aged mice. [ 217 ] Several lines of evidence from animal studies also support a role for IL‐1 β in BBB dysfunction during neuroinflammation. Treatment of IL‐1 β receptor antagonists or genetic deletion of the IL‐1 receptor attenuates BBB hyperpermeability induced by neuroinflammation in mice.…”

“…When inflammation is present, an altered BBB breaks the immune privilege of the brain, exposing neuronal antigens to the peripheral inflammatory molecules, which further stimulate the inflammatory response in the brain, leading to accelerated neurological disease development. [216][217][218][219] As such, communication between the immune system and the brain has become recognized as a central element of healthy brain function. [220] On one hand, targeting inflammation restores BBB integrity, which in turn benefits the treatment of neurological diseases associated with neuroinflammation.…”

Why is delirium more frequent in the elderly?

“…The CSF-to-plasma albumin ratio has usually been used to follow the increase in BBB permeability during aging [106]. A dynamic contrast-enhanced MRI study of 113 cognitively normal subjects aged 21-83 years by Senatorov et al [107] found that the increase begins in mid-life, and Chen et al [108] have calculated that, in comparison with young barriers that can stop proteins with a molecular weight of >91.9 kDa, elderly barriers can be crossed by heavier molecules of up to 120 kDa. Some capillaries are more vulnerable to permeability failure than others, thus suggesting where BBB dysfunction may start.…”

“…In addition, a senescent BBB may interfere with their ability to cross vessel walls, which normally occurs at venule level. Conversely, increased BBB permeability allows plasma albumin to enter astrocytes and overactivate neurotoxic cytokines [107], particularly in patients whose peripheral inflammation is responsible for further endothelial and perivascular cell involvement [154]. Perry and Holmes [155] have underlined the role of β-protein and misfolded proteins in microglial priming, whereas Safaiyan et al [156] have observed microglia that become senescent after accumulating membrane debris from myelin turnover.…”

Blood-brain barrier dysfunction promotes astrocyte senescence through albumin-induced TGFβ signaling activation

“…One potential physiological trigger of astrocyte senescence is age-associated BBBD and subsequent TGFβ signaling activation. BBBD enables blood-borne proteins such as serum albumin (Bar-Klein et al, 2014; Cacheaux et al, 2009; Senatorov et al, 2019; Weissberg et al, 2015) and fibrinogen (Schachtrup et al, 2010) to extravasate into the brain parenchyma, where they elicit a robust inflammatory response by activating canonical TGFβ signaling. In astrocytes, albumin binds to the type II TGFβR, which dimerizes and subsequently activates the type I TGFβR ALK5 before undergoing receptor-mediated endocytosis.…”