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The role of brain vasculature in neurodegenerative disorders

Abstract

Adequate supply of blood and structural and functional integrity of blood vessels are key to normal brain functioning. On the other hand, cerebral blood flow shortfalls and blood–brain barrier dysfunction are early findings in neurodegenerative disorders in humans and animal models. Here we first examine molecular definition of cerebral blood vessels, as well as pathways regulating cerebral blood flow and blood–brain barrier integrity. Then we examine the role of cerebral blood flow and blood–brain barrier in the pathogenesis of Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and multiple sclerosis. We focus on Alzheimer’s disease as a platform of our analysis because more is known about neurovascular dysfunction in this disease than in other neurodegenerative disorders. Finally, we propose a hypothetical model of Alzheimer’s disease biomarkers to include brain vasculature as a factor contributing to the disease onset and progression, and we suggest a common pathway linking brain vascular contributions to neurodegeneration in multiple neurodegenerative disorders.

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Fig. 1: Molecular definition of the BBB and cerebral blood vessels.
Fig. 2: Key cellular and molecular pathways regulating CBF.
Fig. 3: Key cellular and molecular pathways regulating BBB integrity.
Fig. 4: Hypothetical updated Jack model of AD biomarkers to include the role of brain vasculature.
Fig. 5: Commonality of an early involvement of brain vasculature in different neurodegenerative disorders.

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Acknowledgements

The work of B.V.Z. is supported by the National Institutes of Health grants R01AG023084, R01NS090904, R01NS034467, R01AG039452, 1R01NS100459, 5P01AG052350, and 5P50AG005142, in addition to the Alzheimer’s Association, 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 apologize to those authors whose excellent original papers we were not able to cite due to space limitations; instead, we sometimes cited recent reviews by leading authorities so that the reader can access all key primary papers in the field of our review.

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Sweeney, M.D., Kisler, K., Montagne, A. et al. The role of brain vasculature in neurodegenerative disorders. Nat Neurosci 21, 1318–1331 (2018). https://doi.org/10.1038/s41593-018-0234-x

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