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PreprintCited by 36Barrier Structure and Function StudiesTelomeres, Telomerase, and SenescenceGenetics, Aging, and Longevity in Model Organisms

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

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Preininger, Marcela K., Zaytseva, Dasha, Lin, Jessica May, Kaufer, Daniela·2022·Aging Cell
DOI 10.1101/2022.04.25.489438PMC PMC9924950

Preprint — published as 10.1111/acel.13747 · Paper page

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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 one week of albumin exposure significantly increased TGFβ1 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, one week of albumin infusion significantly increased TGFβ signaling activation and the burden of senescent astrocytes in hippocampal tissue. Pharmacological inhibition of TGFβR ALK5 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.

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Metadata

Authors
Preininger, M. K., Zaytseva, D., Lin, J. M., & Kaufer, D.
Affiliations
  • University of California, Berkeley (US)
  • San Francisco State University (US)
Corresponding author
Kaufer, Daniela
ORCID
Venue
Aging Cell
Publisher
openRxiv
Published
2022-04-28
Volume
22
Issue
2
Pages
e13747-e13747
ISSN
1474-9718 (ISSN-L)
DOI
10.1101/2022.04.25.489438
PMC
PMC9924950
OpenAlex
W4313640587
Cited by
36
References
1
Citations by year
2026: 12 · 2025: 10 · 2024: 7 · 2023: 6 · 2022: 1
FWCI
3.60
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Aging Cell (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Science Foundation
  • National Institutes of Health (T 32 fellowship, NIH T32)
  • National Science Foundation of Sri Lanka
  • National Institute of General Medical Sciences (T32GM098218)
Topics
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
Keywords
blood-brain barrier dysfunction, astrocyte senescence, serum albumin, TGF-beta signaling, ALK5, stress-induced premature senescence, hippocampus, brain aging, neuroinflammation, lateral ventricle infusion
MeSH terms
Animals, Astrocytes, Blood-Brain Barrier, Brain, Serum Albumin, Transforming Growth Factor beta, Cellular Senescence, Mice, Rats

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