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

Abstract

Blood–brain barrier dysfunction (BBBD) and accumulation of senescent astrocytes occur during brain aging and contribute to neuroinflammation and disease. Here, we explored the relationship between these two age‐related events, hypothesizing that chronic hippocampal exposure to the blood‐borne protein serum albumin could induce stress‐induced premature senescence (SIPS) in astrocytes via transforming growth factor beta 1 (TGFβ) signaling. We found that 1 week of albumin exposure significantly increased TGFβ signaling and senescence marker expression in cultured rat hippocampal astrocytes. These changes were preventable by pharmacological inhibition of the type I TGFβ receptor (TGFβR) ALK5. To study these effects in vivo, we utilized an animal model of BBBD in which albumin was continuously infused into the lateral ventricles of adult mice. Consistent with our in vitro results, 1 week of albumin infusion significantly increased TGFβ signaling activation and the burden of senescent astrocytes in hippocampal tissue. Pharmacological inhibition of ALK5 TGFβR or conditional genetic knockdown of astrocytic TGFβR prior to albumin infusion was sufficient to prevent albumin‐induced astrocyte senescence. Together, these results establish a link between TGFβ signaling activation and astrocyte senescence and suggest that prolonged exposure to serum albumin due to BBBD can trigger these phenotypic changes.

A Functional Single Nucleotide Polymorphism in the 3′ Untranslated Region of the Porcine JARID2 Gene Is Associated with Aggressive Behavior of Weaned Pigs after Mixing

“…Astrocytes and microglia are known to be involved in the regulation of inflammation in the central nervous system and are also closely associated with Parkinson’s and Alzheimer’s diseases [ 40 ]. Astrocytes play irreplaceable roles in maintaining the blood-brain barrier, regulating synaptic activity, balancing neurotransmitters, and controlling neurotrophin secretion [ 41 , 42 ]. Previous studies found that bipolar patients have normal numbers and densities of oligodendrocytes but an increase in oligodendrocyte numbers compared to healthy controls [ 43 ].…”

Role of Senescent Astrocytes in Health and Disease

“…During aging, the conditions already mentioned start conversion towards senescence and CNS neurodegenerative diseases of early astrocytes [11][12][13][14][26][27][28]. Additionally, in re-sponse to dysfunctions of the BBB [29], early astrocytes stop their proliferation and increase their apoptosis resistance. Moreover, senescent astrocytes accumulate progressively in the brain tissue.…”

“…Concomitantly, aging astrocytes decrease their secretion of IL-10 and growth factors, such as BDNF [13]. After their changed expression in the brain, some of these factors' levels also become appreciable in the blood [21,29]. Additional genes downregulated in senescent astrocytes participate in neuronal development and other governing responses based on major histocompatibility complex class II and glial fibrillary acidic protein.…”

Alterations of the blood-brain barrier during aging

“…25 When astrocytes interface with the BBB destruction, TGFβ has been found to be over-activated accompanied by up-regulation of inflammatory factors, resulting in impaired synaptic connection within both surrounding cells and astrocytes. 26 There is evidence that TGFβ is also involved in the up-regulation of astrocyte inflammatory cytokines through microglial activation. 70 In A1-like astrocytes, several complements, such as C3 and C4B, are over-activated and play an important role in neurotoxicity and microglial stimulation.…”