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Role of the MEOX2 homeobox gene in neurovascular dysfunction in Alzheimer disease

Nature Medicine volume 11, pages 959–965 (2005)Cite this article

Abstract

Neurovascular dysfunction substantially contributes to Alzheimer disease. Here, we show that transcriptional profiling of human brain endothelial cells (BECs) defines a subset of genes whose expression is age-independent but is considerably altered in Alzheimer disease, including the homeobox gene MEOX2 (also known as GAX), a regulator of vascular differentiation, whose expression is low in Alzheimer disease. By using viral-mediated MEOX2 gene silencing and transfer, we show that restoring expression of the protein it encodes, GAX, in BECs from individuals with Alzheimer disease stimulates angiogenesis, transcriptionally suppresses AFX1 forkhead transcription factor–mediated apoptosis and increases the levels of a major amyloid-β peptide (Aβ) clearance receptor, the low-density lipoprotein receptor–related protein 1 (LRP), at the blood-brain barrier. In mice, deletion of Meox2 (also known as Gax) results in reductions in brain capillary density and resting cerebral blood flow, loss of the angiogenic response to hypoxia in the brain and an impaired Aβ efflux from brain caused by reduced LRP levels. The link of MEOX2 to neurovascular dysfunction in Alzheimer disease provides new mechanistic and therapeutic insights into this illness.

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Figure 1: Gene expression and function of Alzheimer disease neurovascular cells.
Figure 2: MEOX2 homeobox gene determines Alzheimer disease–like phenotype in neurovascular cells.
Figure 3: Meox2 gene deletion results in cerebrovascular incompetence in mice.
Figure 4: Meox2+/− mice show impaired Aβ clearance and LRP downregulation.
Figure 5: GAX-mediated regulation of LRP in primary human BECs.

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References

  1. Alzheimer, A. Uber eine eigenartig Erkrankung der Hirnrinde. Allg. Z. Psychiatrie Psych. Ger. Med 64, 146–148 (1907).

    Google Scholar 

  2. Zlokovic, B.V. Neurovascular mechanisms of Alzheimer's neurodegeneration. Trends Neurosci. 28, 202–208 (2005).

    Article  CAS  Google Scholar 

  3. de la Torre, J.C. Alzheimer's disease is a vasocognopathy: a new term to describe its nature. Neurol. Res. 26, 517–524 (2004).

    Article  Google Scholar 

  4. Gorelick, P.B. Risk factors for vascular dementia and Alzheimer's disease. Stroke 35, 2620–2622 (2004).

    Article  Google Scholar 

  5. Casserly, I. & Topol, E. Convergence of atherosclerosis and Alzheimer's disease: inflammation, cholesterol, and misfolded proteins. Lancet 363, 1139–1146 (2004).

    Article  CAS  Google Scholar 

  6. Roher, A.E. et al. Atherosclerosis of cerebral arteries in Alzheimer's disease. Stroke 35, 2623–2627 (2004).

    Article  Google Scholar 

  7. Greenberg, S.M. et al. Amyloid angiopathy-related vascular cognitive impairment. Stroke 35, 2616–2619 (2004).

    Article  Google Scholar 

  8. Bailey, T.L. et al. The nature and effects of cortical microvascular pathology in aging and Alzheimer's disease. Neurol. Res. 26, 573–578 (2004).

    Article  Google Scholar 

  9. Farkas, E. & Luiten, P.G. Cerebral microvascular pathology in aging and Alzheimer's disease. Prog. Neurobiol. 64, 575–611 (2001).

    Article  CAS  Google Scholar 

  10. Paris, D. et al. Impaired angiogenesis in a transgenic mouse model of cerebral amyloidosis. Neurosci. Lett. 366, 80–85 (2004).

    Article  CAS  Google Scholar 

  11. Paris, D. et al. Inhibition of angiogenesis by Aβ peptides. Angiogenesis 7, 75–78 (2004).

    Article  CAS  Google Scholar 

  12. Carmeliet, P. & Jain, R.K. Angiogenesis in cancer and other diseases. Nat. Med. 9, 653–660 (2003).

    Article  CAS  Google Scholar 

  13. Shibata, M. et al. Clearance of Alzheimer's amyloid-β 1–40 peptide from brain by LDL receptor related protein-1 at the blood-brain barrier. J. Clin. Invest. 106, 1489–1499 (2000).

    Article  CAS  Google Scholar 

  14. Deane, R. et al. LRP/amyloid β-peptide interaction mediates differential brain efflux of Aβ isoforms. Neuron 43, 333–344 (2004).

    Article  CAS  Google Scholar 

  15. Tanzi, R.E. et al. Clearance of Alzheimer's Aβ peptides: the many roads to perdition. Neuron 43, 605–608 (2004).

    CAS  PubMed  Google Scholar 

  16. Iadecola, C. Neurovascular regulation in the normal brain and in Alzheimer's disease. Nat. Rev. Neurosci. 5, 347–360 (2004).

    Article  CAS  Google Scholar 

  17. Iadecola, C. et al. SOD1 rescues cerebral endothelial dysfunction in mice overexpressing amyloid precursor protein. Nat. Neurosci. 2, 157–161 (1999).

    Article  CAS  Google Scholar 

  18. Gorski, D.H. et al. Molecular cloning of a diverged homeobox gene that is rapidly downregulated during the Go/G1 transition in vascular smooth muscle cells. Mol. Cell. Biol. 13, 3722–3733 (1993).

    Article  CAS  Google Scholar 

  19. Gorski, D.H. & Walsh, K. Control of vascular cell differentiation by homeobox transcription factors. Trends Cardiovasc. Med. 13, 213–220 (2003).

    Article  CAS  Google Scholar 

  20. Tang, T.T. et al. The Forkhead transcription factor AFX activates apoptosis by induction of the BCL-6 transcriptional repressor. J. Biol. Chem. 277, 14255–14265 (2002).

    Article  CAS  Google Scholar 

  21. Bu, G. & Marzolo, M.P. Role of RAP in the biogenesis of lipoprotein receptors. Trends Cardiovasc. Med. 10, 148–155 (2000).

    Article  CAS  Google Scholar 

  22. Mankoo, B.S. et al. Mox2 is a component of the genetic hierarchy controlling limb muscle development. Nature 400, 69–73 (1999).

    Article  CAS  Google Scholar 

  23. Braak, H. & Braak, E. Neuropathological staging of Alzheimer-related changes. Acta Neuropathol. (Berl.) 82, 239–259 (1991).

    Article  CAS  Google Scholar 

  24. Hyman, B.T. & Trojanowski, J.Q. Consensus recommendations for the postmortem diagnosis of Alzheimer disease from the National Institute on Aging and the Regan Institute Working Group on diagnostic criteria for the neuropathological assessment of Alzheimer disease. J. Neuropathol. Exp. Neurol. 56, 1095–1097 (1997).

    Article  CAS  Google Scholar 

  25. Baldi, P. & Long, A.D. A Bayesian framework for the analysis of microarray expression data: regularized t-test and statistical inferences of gene changes. Bioinformatics 17, 509–519 (2001).

    Article  CAS  Google Scholar 

  26. Liu, D., Jia, H., Holmes, D.I., Stannard, A. & Zachary, I. Vascular endothelial growth factor regulated gene expression in endothelial cells: KDR-mediated induction of Egr3 and the related nuclear receptors Nur77, Nurr1, and Nor1. Arterioscler. Thromb. Vasc. Biol. 23, 2002–2007 (2003).

    Article  CAS  Google Scholar 

  27. Citron, B.A., Suo, Z., SantaCruz, K. & Davies, P.J.A. Protein crosslinking, tissue transglutaminase, alternative splicing and neurodegeneration. Neurochem. Intl. 40, 69–78 (2002).

    Article  CAS  Google Scholar 

  28. Kozak, M. Initiation of translation in prokaryotes and eukaryotes. Gene 234, 187–208 (1999).

    Article  CAS  Google Scholar 

  29. Davis, G.E., Pintar, Allen, K.A., Salazar, R. & Maxwell, S.A. Matrix metalloproteinase-1 and -9 activation by plasmin regulates a novel endothelial cell-mediated mechanism of collagen gel contraction and capillary tube regression in three-dimensional collagen matrices. J. Cell Sci. 114, 917–930 (2001).

    CAS  PubMed  Google Scholar 

  30. Gorski, D.H. & Leal, A.J. Inhibition of endothelial cell activation by the homeobox gene Gax . J. Surg. Res. 111, 91–99 (2003).

    Article  CAS  Google Scholar 

  31. Patel, S., Leal, A.D. & Gorski, D.H. The homeobox gene Gax inhibits angiogenesis through inhibition of nuclear factor-kB-dependent endothelial cell gene expression. Cancer Res. 65, 1414–1424 (2005).

    Article  CAS  Google Scholar 

  32. Perlman, H. et al. Bax-mediated cell death by the Gax homeoprotein requires mitogen activation but is independent of cell cycle activity. EMBO J. 17, 3576–3586 (1998).

    Article  CAS  Google Scholar 

  33. LaRue, B. et al. Method for measurement of the blood-brain barrier permeability in the perfused mouse brain: application to amyloid β-peptide in wild type and Alzheimer's Tg2576 mice. J. Neurosci. Methods 138, 233–242 (2004).

    Article  CAS  Google Scholar 

  34. LaManna, J.C., Chavez, J.C. & Pichiule, P. Structural and functional adaptation to hypoxia in the rat brain. J. Exp. Biol. 207, 3163–3169 (2004).

    Article  CAS  Google Scholar 

  35. Kawarabayashi, T. et al. Age dependent changes in brain, CSF, and plasma amyloid-β in the Tg2576 transgenic mouse model of Alzheimer's disease. J. Neurosci. 21, 372–381 (2001).

    Article  CAS  Google Scholar 

  36. Fryer, J.D. et al. Apoliprotein E markedly facilitates age-dependent cerebral amyloid angiopathy an spontaneous hemorrhage in amyloid precursor protein transgenic mice. J. Neurosci. 23, 7889–7896 (2003).

    Article  CAS  Google Scholar 

  37. Herz, J. & Marschang, P. Coaxing the LDL receptor family into the blood. Cell 112, 289–292 (2003).

    Article  CAS  Google Scholar 

  38. Lahvis, G.P. et al. Portosystemic shunting and persistent fetal vascular structures in aryl hydrocarbon receptor-deficient mice. Proc. Natl. Acad. Sci. USA 97, 10442–10447 (2000).

    Article  CAS  Google Scholar 

  39. Li, Y., Lul, W., Marazolo, M.P. & Bu, G. Differential functions of members of the low density lipoprotein receptor family suggested by their distinct endoytosis rates. J. Biol. Chem. 276, 18000–18006 (2001).

    Article  CAS  Google Scholar 

  40. Andres, V., Fisher, S., Wearsch, P. & Walsh, K. Regulation of Gax homeobox gene transcription by a combination of positive factors including myocyte-specific enhancer factor 2. Mol. Cell. Biol. 15, 4272–4281 (1995).

    Article  CAS  Google Scholar 

  41. Saito, T. et al. Angiotensin II suppresses growth arrest specific homeobox (Gax) expression via redox-sensitive mitogen-activated protein kinase (MAPK). Reg. Peptides 127, 159–167 (2005).

    Article  CAS  Google Scholar 

  42. Atwood, C.S. et al. Amyloid-β: a chameleon walking in two worlds: a review of the trophic and toxic properties of amyloid-beta. Brain Res. Rev. 43, 1–16 (2003).

    Article  CAS  Google Scholar 

  43. Hermann, D.M. et al. Relationship between metabolic dysfunctions, gene responses and delayed cell death after mild focal cerebral ischemia in mice. Neuroscience 104, 947–955 (2001).

    Article  CAS  Google Scholar 

  44. Iscove, N.N. et al. Representation is faithfully preserved in global cDNA amplified exponentially from sub-picogram quantities of mRNA. Nat. Biotechnol. 20, 940–943 (2002).

    Article  CAS  Google Scholar 

  45. Holland, P.M., Abramson, R.D., Watson, R. & Gelfand, D.H. Detection of specific polymerase chain reaction product by utilizing the 5′,3′ exonuclease activity of Thermus aquaticus DNA polymerase. Proc. Natl. Acad. Sci. USA 88, 7276–7280 (1991).

    Article  CAS  Google Scholar 

  46. Mackic, J.B. et al. Human blood-brain barrier receptors for Alzheimer's amyloid-β. J. Clin. Invest. 102, 734–743 (1998).

    Article  CAS  Google Scholar 

  47. Russell, W.C. et al. Update on adenovirus and its vectors. J. Gen.Virol. 81, 2573–2604 (2000).

    Article  CAS  Google Scholar 

  48. Wu, Z., Hofman, F.M. & Zlokovic, B.V. A simple method for isolation and characterization of mouse brain microvascular endothelial cells. J. Neurosci. Methods 130, 53–63 (2003).

    Article  CAS  Google Scholar 

  49. Witzenbichler, B. et al. Regulation of smooth muscle cell migration and integrin expression by the Gax transcription factor. J. Clin. Invest. 104, 1469–1480 (1999).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by US National Institutes of Health (NIH) R37 AG023084 and a Socratech research grant to B.V.Z., NIH grants R43 AG24002 to J.S. and R43 AG23993 to N.C.

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Author notes

  1. Zhenhua Wu, Huang Guo, Nienwen Chow and Jan Sallstrom: These authors contributed equally to this work.

Authors and Affiliations

  1. Frank P. Smith Laboratories for Neuroscience and Neurosurgical Research, University of Rochester Medical Center, Arthur Kornberg Medical Research Building, 601 Elmwood Avenue, Box 670, Rochester, 14642, New York, USA

    Zhenhua Wu, Huang Guo, Rashid Deane, Abhay Sagare, Dong Liu, Xiaomei Song & Berislav V Zlokovic

  2. Socratech Research Laboratories, 625 Elmwood Avenue, Rochester, 14620, New York, USA

    Huang Guo, Nienwen Chow, Jan Sallstrom, Robert D Bell, Suhasini Kanagala, Anna Rubio, Fang Li, Don Armstrong, Raphael Zidovetzki, Florence Hofman & Berislav V Zlokovic

  3. Genomics Center, University of Rochester Medical Center, 575 Elmwood Avenue, Box EHSC, Rochester, 14642, New York, USA

    Andrew I Brooks

  4. Department of Cell Biology and Neuroscience, University of California Riverside, 1208 Spieth Hall, Riverside, 92521, California, USA

    Don Armstrong & Raphael Zidovetzki

  5. Department of Environmental Medicine, University of Rochester School of Medicine & Dentistry, Box EHSC, 575 Elmwood Avenue, Rochester, 14642, New York, USA

    Thomas Gasiewicz

  6. Department of Pathology, Keck School of Medicine, University of Southern California, Hoffman Medical Research Center 209, 2011 Zonal Avenue, Los Angeles, 90089-9092, California, USA

    Florence Hofman

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Correspondence to Berislav V Zlokovic.

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Competing interests

J. Sallstrom, N. Chow and R. Bell are Socratech employees, and B.V. Zlokovic, F. Hofman and R. Zidovetzki serve as Socratech consultants. Socratech LLS sponsored transcriptional profiling study and building of the BioBank with primary neurovascular cells. Socratech has an interest in developing new theories for Alzheimer's disease.

Supplementary information

Supplementary Fig. 1

TUNEL-positive and AFX1-positive microvessels in Alzheimer disease and age-matched control brains. (PDF 8635 kb)

Supplementary Fig. 2

Vascular reactivity in Gax+/+ and Gax+/− mice. (PDF 533 kb)

Supplementary Fig. 3

Brain capillary length and LRP levels in Ahr−/− mice. (PDF 1021 kb)

Supplementary Fig. 4

Internalization of α2M in BECs with suppressed MEOX2 expression. (PDF 327 kb)

Supplementary Fig. 5

Proteasomal proteolytic activity, transferrin levels and RAP in human BECs. (PDF 422 kb)

Supplementary Fig. 6

Expression of MEF2, ankyrin G, plectin 1 and TINUR in human BECs. (PDF 513 kb)

Supplementary Fig. 7

Aβ does not affect GAX expression in human BECs (PDF 491 kb)

Supplementary Table 1 (PDF 61 kb)

Supplementary Table 2 (PDF 94 kb)

Supplementary Methods (PDF 64 kb)

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Wu, Z., Guo, H., Chow, N. et al. Role of the MEOX2 homeobox gene in neurovascular dysfunction in Alzheimer disease. Nat Med 11, 959–965 (2005). https://doi.org/10.1038/nm1287

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