APOE4 accelerates advanced-stage vascular and neurodegenerative disorder in old Alzheimer's mice via cyclophilin A independently of amyloid-β. Montagne, A., Nikolakopoulou, A. M., Huuskonen, M. T., Sagare, A. P., Lawson, E. J., Lazic, D., Rege, S. V., Grond, A., Zuniga, E., Barnes, S. R., Prince, J., Sagare, M., Hsu, C., LaDu, M. J., Jacobs, R. E., & Zlokovic, B. V. Nature Aging, 1(6):506–520, June, 2021. doi abstract bibtex Apolipoprotein E4 (APOE4), the main susceptibility gene for Alzheimer's disease (AD), leads to vascular dysfunction, amyloid-β pathology, neurodegeneration and dementia. How these different pathologies contribute to advanced-stage AD remains unclear. Using aged APOE knock-in mice crossed with 5xFAD mice, we show that, compared to APOE3, APOE4 accelerates blood-brain barrier (BBB) breakdown, loss of cerebral blood flow, neuronal loss and behavioral deficits independently of amyloid-β. BBB breakdown was associated with activation of the cyclophilin A-matrix metalloproteinase-9 BBB-degrading pathway in pericytes. Suppression of this pathway improved BBB integrity and prevented further neuronal loss and behavioral deficits in APOE4;5FAD mice while having no effect on amyloid-β pathology. Thus, APOE4 accelerates advanced-stage BBB breakdown and neurodegeneration in Alzheimer's mice via the cyclophilin A pathway in pericytes independently of amyloid-β, which has implication for the pathogenesis and treatment of vascular and neurodegenerative disorder in AD.
@article{montagne_apoe4_2021,
title = {{APOE4} accelerates advanced-stage vascular and neurodegenerative disorder in old {Alzheimer}'s mice via cyclophilin {A} independently of amyloid-β},
volume = {1},
issn = {2662-8465},
doi = {10.1038/s43587-021-00073-z},
abstract = {Apolipoprotein E4 (APOE4), the main susceptibility gene for Alzheimer's disease (AD), leads to vascular dysfunction, amyloid-β pathology, neurodegeneration and dementia. How these different pathologies contribute to advanced-stage AD remains unclear. Using aged APOE knock-in mice crossed with 5xFAD mice, we show that, compared to APOE3, APOE4 accelerates blood-brain barrier (BBB) breakdown, loss of cerebral blood flow, neuronal loss and behavioral deficits independently of amyloid-β. BBB breakdown was associated with activation of the cyclophilin A-matrix metalloproteinase-9 BBB-degrading pathway in pericytes. Suppression of this pathway improved BBB integrity and prevented further neuronal loss and behavioral deficits in APOE4;5FAD mice while having no effect on amyloid-β pathology. Thus, APOE4 accelerates advanced-stage BBB breakdown and neurodegeneration in Alzheimer's mice via the cyclophilin A pathway in pericytes independently of amyloid-β, which has implication for the pathogenesis and treatment of vascular and neurodegenerative disorder in AD.},
language = {eng},
number = {6},
journal = {Nature Aging},
author = {Montagne, Axel and Nikolakopoulou, Angeliki M. and Huuskonen, Mikko T. and Sagare, Abhay P. and Lawson, Erica J. and Lazic, Divna and Rege, Sanket V. and Grond, Alexandra and Zuniga, Edward and Barnes, Samuel R. and Prince, Jacob and Sagare, Meghana and Hsu, Ching-Ju and LaDu, Mary J. and Jacobs, Russell E. and Zlokovic, Berislav V.},
month = jun,
year = {2021},
pmid = {35291561},
pmcid = {PMC8920485},
pages = {506--520},
}
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How these different pathologies contribute to advanced-stage AD remains unclear. Using aged APOE knock-in mice crossed with 5xFAD mice, we show that, compared to APOE3, APOE4 accelerates blood-brain barrier (BBB) breakdown, loss of cerebral blood flow, neuronal loss and behavioral deficits independently of amyloid-β. BBB breakdown was associated with activation of the cyclophilin A-matrix metalloproteinase-9 BBB-degrading pathway in pericytes. Suppression of this pathway improved BBB integrity and prevented further neuronal loss and behavioral deficits in APOE4;5FAD mice while having no effect on amyloid-β pathology. Thus, APOE4 accelerates advanced-stage BBB breakdown and neurodegeneration in Alzheimer's mice via the cyclophilin A pathway in pericytes independently of amyloid-β, which has implication for the pathogenesis and treatment of vascular and neurodegenerative disorder in AD.","language":"eng","number":"6","journal":"Nature Aging","author":[{"propositions":[],"lastnames":["Montagne"],"firstnames":["Axel"],"suffixes":[]},{"propositions":[],"lastnames":["Nikolakopoulou"],"firstnames":["Angeliki","M."],"suffixes":[]},{"propositions":[],"lastnames":["Huuskonen"],"firstnames":["Mikko","T."],"suffixes":[]},{"propositions":[],"lastnames":["Sagare"],"firstnames":["Abhay","P."],"suffixes":[]},{"propositions":[],"lastnames":["Lawson"],"firstnames":["Erica","J."],"suffixes":[]},{"propositions":[],"lastnames":["Lazic"],"firstnames":["Divna"],"suffixes":[]},{"propositions":[],"lastnames":["Rege"],"firstnames":["Sanket","V."],"suffixes":[]},{"propositions":[],"lastnames":["Grond"],"firstnames":["Alexandra"],"suffixes":[]},{"propositions":[],"lastnames":["Zuniga"],"firstnames":["Edward"],"suffixes":[]},{"propositions":[],"lastnames":["Barnes"],"firstnames":["Samuel","R."],"suffixes":[]},{"propositions":[],"lastnames":["Prince"],"firstnames":["Jacob"],"suffixes":[]},{"propositions":[],"lastnames":["Sagare"],"firstnames":["Meghana"],"suffixes":[]},{"propositions":[],"lastnames":["Hsu"],"firstnames":["Ching-Ju"],"suffixes":[]},{"propositions":[],"lastnames":["LaDu"],"firstnames":["Mary","J."],"suffixes":[]},{"propositions":[],"lastnames":["Jacobs"],"firstnames":["Russell","E."],"suffixes":[]},{"propositions":[],"lastnames":["Zlokovic"],"firstnames":["Berislav","V."],"suffixes":[]}],"month":"June","year":"2021","pmid":"35291561","pmcid":"PMC8920485","pages":"506–520","bibtex":"@article{montagne_apoe4_2021,\n\ttitle = {{APOE4} accelerates advanced-stage vascular and neurodegenerative disorder in old {Alzheimer}'s mice via cyclophilin {A} independently of amyloid-β},\n\tvolume = {1},\n\tissn = {2662-8465},\n\tdoi = {10.1038/s43587-021-00073-z},\n\tabstract = {Apolipoprotein E4 (APOE4), the main susceptibility gene for Alzheimer's disease (AD), leads to vascular dysfunction, amyloid-β pathology, neurodegeneration and dementia. How these different pathologies contribute to advanced-stage AD remains unclear. Using aged APOE knock-in mice crossed with 5xFAD mice, we show that, compared to APOE3, APOE4 accelerates blood-brain barrier (BBB) breakdown, loss of cerebral blood flow, neuronal loss and behavioral deficits independently of amyloid-β. BBB breakdown was associated with activation of the cyclophilin A-matrix metalloproteinase-9 BBB-degrading pathway in pericytes. Suppression of this pathway improved BBB integrity and prevented further neuronal loss and behavioral deficits in APOE4;5FAD mice while having no effect on amyloid-β pathology. 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