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APOE4 accelerates advanced-stage vascular and neurodegenerative disorder in old Alzheimer’s mice via cyclophilin A independently of amyloid-β

Nature Aging volume 1, pages 506–520 (2021)Cite this article

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An Author Correction to this article was published on 29 June 2021

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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.

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Fig. 1: Blood–brain barrier breakdown in old APOE4 and APOE4;5xFAD mice.
Fig. 2: Cerebral blood flow reductions in old APOE4 and APOE4;5xFAD mice.
Fig. 3: Increased levels of cyclophilin A and matrix metalloproteinase-9 in pericytes in old APOE4 and APOE4;5xFAD mice correlate with the loss of tight junction proteins.
Fig. 4: Aβ pathology in old APOE3;5xFAD and APOE4;5xFAD mice and Aβ-independent vascular changes.
Fig. 5: Neurodegenerative changes in old APOE4 and APOE4;5xFAD mice correlate with BBB breakdown but not with Aβ pathology.
Fig. 6: Behavioral deficits in old APOE4 and APOE4;5xFAD mice correlate with vascular dysfunction but not with Aβ pathology.
Fig. 7: Debio-025 inhibits the CypA-MMP9 pathway in pericytes and improves BBB integrity in APOE4;5xFAD mice.
Fig. 8: Debio-025 prevents further loss of neurons and improves cognitive function in APOE4;5xFAD mice without affecting Aβ42 or Aβ40 levels in the brain.

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Data availability

The data that support the findings of this study are available from the corresponding author upon request. We also provided a complete data source (Excel sheets for data panels of Figs. 1–8 and Extended Data Figs. 1–4) with corresponding statistical analysis.

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Acknowledgements

The work of B.V.Z. is supported by the National Institutes of Health grant nos. R01NS034467, R01AG023084, R01AG039452 and 1R01NS100459, in addition to Cure Alzheimer’s Fund and the Foundation Leducq Transatlantic Network of Excellence for the Study of Perivascular Spaces in Small Vessel Disease reference no. 16 CVD 05. We thank V. Li for technical assistance with some experiments.

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  1. These authors contributed equally: Axel Montagne, Angeliki M. Nikolakopoulou, Mikko T. Huuskonen, Abhay P. Sagare.

Authors and Affiliations

  1. Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Axel Montagne, Angeliki M. Nikolakopoulou, Mikko T. Huuskonen, Abhay P. Sagare, Erica J. Lawson, Divna Lazic, Sanket V. Rege, Alexandra Grond, Edward Zuniga, Jacob Prince, Meghana Sagare, Ching-Ju Hsu, Russell E. Jacobs & Berislav V. Zlokovic

  2. Department of Radiology, Loma Linda University, Loma Linda, CA, USA

    Samuel R. Barnes

  3. Department of Anatomy and Cell Biology, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA

    Mary J. LaDu

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Contributions

A.M., A.M.N., M.T.H., A.P.S. and B.V.Z. designed the research study and analyzed and interpreted the data. A.M. and M.T.H. performed MRI scans and MRI data analyses. M.S. helped with MRI data analyses. A.M.N., M.T.H. and A.P.S. performed brain tissue assays. A.P.S. performed amyloid assays. E.J.L., D.L. and S.V.R. performed behavioral tests. E.Z., A.G. and C.-J.H. performed tissue collection. A.M., S.R.B. and J.P. developed our in-house DSC-MRI program. M.J.L. provided human APOE mice crossed with 5xFAD line. M.J.L. and R.E.J. provided critical reading of the manuscript. A.M. contributed to manuscript writing and B.V.Z. supervised all data analysis and interpretation and wrote the manuscript.

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Correspondence to Berislav V. Zlokovic.

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Peer review information Nature Aging thanks Jan Klohs, and the other, anonymous reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 Additional characterization of blood-brain barrier breakdown in old APOE4 and APOE4;5xFAD male and female mice.

Blood-brain barrier (BBB) permeability Ktrans values in the cortex (Ctx) and hippocampus (Hipp) in male and female E3 (n = 12, 6 ♂ and 6 ♀; blue empty circles), E4 (n = 14, 7 ♂ and 7 ♀; blue filled circles), E3+FAD (n = 13, 8 ♂ and 5 ♀; red empty circles), and E4+FAD (n = 16, 11 ♂ and 5 ♀; red filled circles) mice generated from dynamic contrast-enhanced magnetic resonance scans. Mice (both genders) were 18–24-month old. Data are presented as truncated violin plots; continuous line, median; dotted line, interquartile range. Significance by one-way ANOVA followed by the Tukey post hoc test; ns, non-significant.

Source data

Extended Data Fig. 2 Additional characterization of cerebral blood flow reductions in old APOE4 and APOE4;5xFAD male and female mice.

Cerebral blood flow (CBF) values in the cortex (Ctx) and hippocampus (Hipp) in male and female E3 (n = 12, 6 ♂ and 6 ♀; blue empty circles), E4 (n = 14, 7 ♂ and 7 ♀; blue filled circles), E3+FAD (n = 13, 8 ♂ and 5 ♀; red empty circles), and E4+FAD (n = 16, 11 ♂ and 5 ♀; red filled circles) mice generated from dynamic susceptibility-contrast magnetic resonance scans. Mice (both genders) were 18–24-month old. Data are presented as truncated violin plots; continuous line, median; dotted line, interquartile range. Significance by one-way ANOVA followed by the Tukey post hoc test; ns, non-significant.

Source data

Extended Data Fig. 3 Additional characterization of Aβ pathology in old APOE3;5xFAD and APOE4;5xFAD male and female mice and Aβ-independent vascular changes.

a Aβ40 levels in the Ctx and Hipp in E3+FAD (n = 14) and E4+FAD (n = 17) mice. b, Aβ40 levels in the Ctx and Hipp in male and female E3+FAD (n = 13–14, 8–9 ♂ and 5 ♀) and E4+FAD (n = 17, 12 ♂ and 5 ♀) mice. Data are presented as truncated violin plots; continuous line, median; dotted line, interquartile range. c-f, Lack of correlation between the blood-brain barrier (BBB) permeability Ktrans values and Aβ40 levels in the Ctx and Hipp (c,d) and regional cerebral blood flow (CBF) values and Aβ40 levels in the Ctx and Hipp (e,f). Mice (both genders) were 18–24-month old (n = 28 individual points from both groups). In a, significance by unpaired two-tailed Student t-tests. In b, significance by one-way ANOVA followed by the Tukey post hoc test. In c-f, significance by two-tailed simple linear regression; r, Pearson correlation; ns, non-significant.

Source data

Extended Data Fig. 4 Effects of Debio-025 relative to vehicle on neuron counts, neuritic density and behavior in APOE4;5xFAD and APOE3;5xFAD mice (red circles, data taken from Fig. 8) compared to the littermate controls without 5XFAD transgenes (blue circles).

a–d, Quantification of NeuN+-neurons (a,b) and SMI312+-neuritic density (c,d) in the Ctx and Hipp in E3 (blue empty circles) and E4 (blue filled circles) untreated littermate controls without 5xFAD transgenes compared to age-matched E3+FAD (red empty circles) and E4+FAD (red filled circles) mice treated with vehicle or Debio-025; In a-d, n = 5 mice per group except in a. n = 4 in for E3 littermate controls without 5XFAD transgenes. e,f, Novel object location (NOL; e) and novel object recognition (NOR; f) in E3 (n = 8, blue empty circles) and E4 (n = 8, blue filled circles) untreated littermate controls without 5XFAD transgenes compared to age-matched E3+FAD vehicle-treated (n = 8; red empty circles), E3+FAD Debio-025-treated (n = 9; red empty circles), E4+FAD vehicle-treated (n = 7; red filled circles), and E4+FAD Debio-025-treated (n = 8; red filled circles) mice. Mice (both genders) were 10–12-month-old. In all graphs, data for E3+FAD and E4+FAD animals are the same as in Fig. 8 (red circles empty and filled); new data used for comparison are from their respective untreated littermate controls without 5XFAD transgenes (blue circles empty and filled). All data are presented as violin plots; continuous line, median; dotted line, interquartile range. Significance by one-way ANOVA followed by the Tukey post hoc test.

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Montagne, A., Nikolakopoulou, A.M., Huuskonen, M.T. et al. APOE4 accelerates advanced-stage vascular and neurodegenerative disorder in old Alzheimer’s mice via cyclophilin A independently of amyloid-β. Nat Aging 1, 506–520 (2021). https://doi.org/10.1038/s43587-021-00073-z

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