The Role of NRF2 in Cerebrovascular Protection: Implications for Vascular Cognitive Impairment and Dementia (VCID)

doi:10.3390/ijms25073833

Review

. 2024 Mar 29;25(7):3833.

doi: 10.3390/ijms25073833.

The Role of NRF2 in Cerebrovascular Protection: Implications for Vascular Cognitive Impairment and Dementia (VCID)

Yizhou Hu^{1

2

3}, Feng Zhang^{1

2}, Milos Ikonomovic^{1

4

5}, Tuo Yang^{1

2

6}

Affiliations

¹ Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15216, USA.
² Pittsburgh Institute of Brain Disorders and Recovery, University of Pittsburgh, Pittsburgh, PA 15216, USA.
³ Department of Internal Medicine, University of Pittsburgh Medical Center (UPMC) McKeesport, McKeesport, PA 15132, USA.
⁴ Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15216, USA.
⁵ Geriatric Research Education and Clinical Center, VA Pittsburgh Healthcare System, Pittsburgh, PA 15240, USA.
⁶ Department of Internal Medicine, University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA 15216, USA.

PMID: 38612642
PMCID: PMC11012233
DOI: 10.3390/ijms25073833

Review

The Role of NRF2 in Cerebrovascular Protection: Implications for Vascular Cognitive Impairment and Dementia (VCID)

Yizhou Hu et al. Int J Mol Sci. 2024.

. 2024 Mar 29;25(7):3833.

doi: 10.3390/ijms25073833.

Authors

Yizhou Hu^{1

2

3}, Feng Zhang^{1

2}, Milos Ikonomovic^{1

4

5}, Tuo Yang^{1

2

6}

Affiliations

¹ Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15216, USA.
² Pittsburgh Institute of Brain Disorders and Recovery, University of Pittsburgh, Pittsburgh, PA 15216, USA.
³ Department of Internal Medicine, University of Pittsburgh Medical Center (UPMC) McKeesport, McKeesport, PA 15132, USA.
⁴ Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15216, USA.
⁵ Geriatric Research Education and Clinical Center, VA Pittsburgh Healthcare System, Pittsburgh, PA 15240, USA.
⁶ Department of Internal Medicine, University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA 15216, USA.

PMID: 38612642
PMCID: PMC11012233
DOI: 10.3390/ijms25073833

Abstract

Vascular cognitive impairment and dementia (VCID) represents a broad spectrum of cognitive decline secondary to cerebral vascular aging and injury. It is the second most common type of dementia, and the prevalence continues to increase. Nuclear factor erythroid 2-related factor 2 (NRF2) is enriched in the cerebral vasculature and has diverse roles in metabolic balance, mitochondrial stabilization, redox balance, and anti-inflammation. In this review, we first briefly introduce cerebrovascular aging in VCID and the NRF2 pathway. We then extensively discuss the effects of NRF2 activation in cerebrovascular components such as endothelial cells, vascular smooth muscle cells, pericytes, and perivascular macrophages. Finally, we summarize the clinical potential of NRF2 activators in VCID.

Keywords: aging; blood–brain barrier; lymphatic system; neuroinflammation; oxidative stress; perivascular macrophage.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

**Figure 1**
Schematic image showing cell types and structure of the arteriole and capillary/venule levels of the cerebral vasculature. In the lower panel, structural components of the blood–brain barrier are labeled in red. Abbreviations: AJ—adherens junction; BM—basement membrane; EC—endothelial cell; TJ—tight junction; PVM—perivascular macrophage; VSMC—vascular smooth muscle cell.

**Figure 2**
Simplified schematic image of the NRF2/Keap1 pathway.

**Figure 3**
Schematic image showing NRF2 effects in different cell types of the cerebral vasculature in VCID. BBB, blood–brain barrier; CAM, cell adhesion molecule; CSF, cerebrospinal fluid; EC, endothelial cell; PVM, perivascular macrophage; rCBF, regional cerebral blood flow; TJ, tight junction; VSMC, vascular smooth muscle cell. ↑: increase/upregulate. ↓: decrease/downregulate.

See this image and copyright information in PMC

Cited by

Characterization of Proteome Changes in Aged and Collagen VI-Deficient Human Pericyte Cultures.
Moriggi M, Torretta E, Cescon M, Russo L, Gregorio I, Braghetta P, Sabatelli P, Faldini C, Merlini L, Gargioli C, Bonaldo P, Gelfi C, Capitanio D. Moriggi M, et al. Int J Mol Sci. 2024 Jun 28;25(13):7118. doi: 10.3390/ijms25137118. Int J Mol Sci. 2024. PMID: 39000224 Free PMC article.

References

1. O’Brien J.T., Thomas A. Vascular dementia. Lancet. 2015;386:1698–1706. doi: 10.1016/S0140-6736(15)00463-8. - DOI - PubMed
1. Lobo A., Launer L.J., Fratiglioni L., Andersen K., Di Carlo A., Breteler M.M., Copeland J.R., Dartigues J.F., Jagger C., Martinez-Lage J., et al. Prevalence of dementia and major subtypes in Europe: A collaborative study of population-based cohorts. Neurologic Diseases in the Elderly Research Group. Neurology. 2000;54:S4–S9. - PubMed
1. Rizzi L., Rosset I., Roriz-Cruz M. Global Epidemiology of Dementia: Alzheimer’s and Vascular Types. BioMed. Res. Int. 2014;2014:908915. doi: 10.1155/2014/908915. - DOI - PMC - PubMed
1. Kalaria R.N., Maestre G.E., Arizaga R., Friedland R.P., Galasko D., Hall K., Luchsinger J.A., Ogunniyi A., Perry E.K., Potocnik F., et al. Alzheimer’s disease and vascular dementia in developing countries: Prevalence, management, and risk factors. Lancet Neurol. 2008;7:812–826. doi: 10.1016/S1474-4422(08)70169-8. - DOI - PMC - PubMed
1. Moon W., Han J.W., Bae J.B., Suh S.W., Kim T.H., Kwak K.P., Kim B.J., Kim S.G., Kim J.L., Moon S.W., et al. Disease Burdens of Alzheimer’s Disease, Vascular Dementia, and Mild Cognitive Impairment. J. Am. Med. Dir. Assoc. 2021;22:2093–2099.e3. doi: 10.1016/j.jamda.2021.05.040. - DOI - PubMed

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions

Substances

Actions

Grants and funding

R01 NS103810/NS/NINDS NIH HHS/United States

LinkOut - more resources

Full Text Sources

[1] O’Brien J.T., Thomas A. Vascular dementia. Lancet. 2015;386:1698–1706. doi: 10.1016/S0140-6736(15)00463-8. - DOI - PubMed

[2] O’Brien J.T., Thomas A. Vascular dementia. Lancet. 2015;386:1698–1706. doi: 10.1016/S0140-6736(15)00463-8. - DOI - PubMed

[3] Lobo A., Launer L.J., Fratiglioni L., Andersen K., Di Carlo A., Breteler M.M., Copeland J.R., Dartigues J.F., Jagger C., Martinez-Lage J., et al. Prevalence of dementia and major subtypes in Europe: A collaborative study of population-based cohorts. Neurologic Diseases in the Elderly Research Group. Neurology. 2000;54:S4–S9. - PubMed

[4] Lobo A., Launer L.J., Fratiglioni L., Andersen K., Di Carlo A., Breteler M.M., Copeland J.R., Dartigues J.F., Jagger C., Martinez-Lage J., et al. Prevalence of dementia and major subtypes in Europe: A collaborative study of population-based cohorts. Neurologic Diseases in the Elderly Research Group. Neurology. 2000;54:S4–S9. - PubMed

[5] Rizzi L., Rosset I., Roriz-Cruz M. Global Epidemiology of Dementia: Alzheimer’s and Vascular Types. BioMed. Res. Int. 2014;2014:908915. doi: 10.1155/2014/908915. - DOI - PMC - PubMed

[6] Rizzi L., Rosset I., Roriz-Cruz M. Global Epidemiology of Dementia: Alzheimer’s and Vascular Types. BioMed. Res. Int. 2014;2014:908915. doi: 10.1155/2014/908915. - DOI - PMC - PubMed

[7] Kalaria R.N., Maestre G.E., Arizaga R., Friedland R.P., Galasko D., Hall K., Luchsinger J.A., Ogunniyi A., Perry E.K., Potocnik F., et al. Alzheimer’s disease and vascular dementia in developing countries: Prevalence, management, and risk factors. Lancet Neurol. 2008;7:812–826. doi: 10.1016/S1474-4422(08)70169-8. - DOI - PMC - PubMed

[8] Kalaria R.N., Maestre G.E., Arizaga R., Friedland R.P., Galasko D., Hall K., Luchsinger J.A., Ogunniyi A., Perry E.K., Potocnik F., et al. Alzheimer’s disease and vascular dementia in developing countries: Prevalence, management, and risk factors. Lancet Neurol. 2008;7:812–826. doi: 10.1016/S1474-4422(08)70169-8. - DOI - PMC - PubMed

[9] Moon W., Han J.W., Bae J.B., Suh S.W., Kim T.H., Kwak K.P., Kim B.J., Kim S.G., Kim J.L., Moon S.W., et al. Disease Burdens of Alzheimer’s Disease, Vascular Dementia, and Mild Cognitive Impairment. J. Am. Med. Dir. Assoc. 2021;22:2093–2099.e3. doi: 10.1016/j.jamda.2021.05.040. - DOI - PubMed

[10] Moon W., Han J.W., Bae J.B., Suh S.W., Kim T.H., Kwak K.P., Kim B.J., Kim S.G., Kim J.L., Moon S.W., et al. Disease Burdens of Alzheimer’s Disease, Vascular Dementia, and Mild Cognitive Impairment. J. Am. Med. Dir. Assoc. 2021;22:2093–2099.e3. doi: 10.1016/j.jamda.2021.05.040. - DOI - PubMed

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

The Role of NRF2 in Cerebrovascular Protection: Implications for Vascular Cognitive Impairment and Dementia (VCID)

Affiliations

The Role of NRF2 in Cerebrovascular Protection: Implications for Vascular Cognitive Impairment and Dementia (VCID)

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Abstract

Conflict of interest statement

Figures

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Related information

Grants and funding

LinkOut - more resources

Full Text Sources