Brain Endothelial Cells Synthesize Neurotoxic Thrombin in Alzheimer’s Disease
Open accessAbstract
Alzheimer's disease (AD) is characterized by neuronal death; thus, identifying neurotoxic proteins and their source is central to understanding and treating AD. The multifunctional protease thrombin is neurotoxic and found in AD senile plaques. The objective of this study was to determine whether brain endothelial cells can synthesize thrombin and thus be a source of this neurotoxin in AD brains. Microvessels were isolated from AD patient brains and from age-matched controls. Reverse transcription-PCR demonstrated that thrombin message was highly expressed in microvessels from AD brains but was not detectable in control vessels. Similarly, Western blot analysis of microvessels showed that the thrombin protein was highly expressed in AD- but not control-derived microvessels. In addition, high levels of thrombin were detected in cerebrospinal fluid obtained from AD but not control patients, and sections from AD brains showed reactivity to thrombin antibody in blood vessel walls but not in vessels from controls. Finally, we examined the ability of brain endothelial cells in culture to synthesize thrombin and showed that oxidative stress or cell signaling perturbations led to increased expression of thrombin mRNA in these cells. The results demonstrate, for the first time, that brain endothelial cells can synthesize thrombin, and suggest that novel therapeutics targeting vascular stabilization that prevent or decrease release of thrombin could prove useful in treating this neurodegenerative disease.
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Intracranial injection of thrombin activates microglia, leading to production of NO and TNFα via JAK2-STAT3 signaling pathway, which induce BBB disruption.
“Furthermore, it was shown that intracranial injection of thrombin activates microglia, leading to the production of NO and TNFα via JAK2-STAT3 signaling pathway, which induce BBB disruption.”
From The impact of microglial activation on blood-brain barrier in brain diseases (2014) · cites this paper as Yin et al., 2010
Thrombin causes disruption of the BBB indirectly by activation of microglia.
“Thus, it appears that thrombin causes a disruption of BBB indirectly by activation of microglia (Huang et al., 2008a,b; Yin et al., 2010; Grammas, 2011).”
From The impact of microglial activation on blood-brain barrier in brain diseases (2014) · cites this paper as Yin et al., 2010
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- Authors
- Yin, X., Wright, J., Wall, T., & Grammas, P.
- Affiliations
- Texas Tech University (US)
- Corresponding author
- Grammas, Paula
- ORCID
- Grammas, Paula
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2010-04
- Volume
- 176
- Issue
- 4
- Pages
- 1600-1606
- ISSN
- 0002-9440 (ISSN-L)
- PMC
- PMC2843451
- OpenAlex
- W2105503070
- Cited by
- 104
- References
- 72
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 6 · 2023: 6 · 2022: 5 · 2021: 7 · 2020: 8 · 2019: 10 · 2018: 3 · 2017: 3 · 2016: 9 · 2015: 6 · 2014: 10 · 2013: 8 · 2012: 3
- FWCI
- 5.41
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- American Journal Of Pathology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (AG 15964, AG-020569, AG028367, R01AG028367, R01AG020569, R01AG015964)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, thrombin, brain endothelial cells, neurotoxicity, cerebral microvasculature, amyloid plaques, cerebrospinal fluid, oxidative stress, vascular stabilization, neurodegeneration
- MeSH terms
- Aged, Alzheimer Disease, Animals, Brain, Disease Models, Animal, Humans, Microcirculation, Middle Aged, Neurotoxins, Thrombin, Signal Transduction, Neurodegenerative Diseases, Reverse Transcriptase Polymerase Chain Reaction, Endothelial Cells, Rats, Plaque, Amyloid
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