Nicotinamide mononucleotide (NMN) treatment attenuates oxidative stress and rescues angiogenic capacity in aged cerebromicrovascular endothelial cells: a potential mechanism for the prevention of vascular cognitive impairment.

Oxidative stress- (OS-) related endothelial damage is involved in the occurrence and progression of several disorders, such as vascular depression and dementia. It has been reported that moderate, aerobic, physical exercise could reduce OS and inflammation, thus limiting the cardiovascular risk factors while improving endothelial homeostasis, mood, and cognition. In this review, we will discuss about the role of OS and OS-related endothelial damage in vascular depression and vascular cognitive impairment. Then, we will comment on the effects of physical exercise on both disorders.

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Hyperhomocysteinemia-Induced Gene Expression Changes in the Cell Types of the Brain

ASN NEURO ◽

10.1177/1759091417742296 ◽

2017 ◽

Vol 9 (6) ◽

pp. 175909141774229 ◽

Cited By ~ 14

Author(s):

Erica M. Weekman ◽

Abigail E. Woolums ◽

Tiffany L. Sudduth ◽

Donna M. Wilcock

Keyword(s):

Gene Expression ◽

Endothelial Cells ◽

Cognitive Impairment ◽

Matrix Metalloproteinase ◽

Inflammatory Marker ◽

Neuronal Cells ◽

Specific Effect ◽

Vascular Cognitive Impairment ◽

Matrix Metalloproteinase 9 ◽

Metalloproteinase 9

High plasma levels of homocysteine, termed hyperhomocysteinemia, are a risk factor for vascular cognitive impairment and dementia, which is the second leading cause of dementia. While hyperhomocysteinemia induces microhemorrhages and cognitive decline in mice, the specific effect of hyperhomocysteinemia on each cell type remains unknown. We took separate cultures of astrocytes, microglia, endothelial cells, and neuronal cells and treated each with moderate levels of homocysteine for 24, 48, 72, and 96 hr. We then determined the gene expression changes for cell-specific markers and neuroinflammatory markers including the matrix metalloproteinase 9 system. Astrocytes had decreased levels of several astrocytic end feet genes, such as aquaporin 4 and an adenosine triphosphate (ATP)-sensitive inward rectifier potassium channel at 72 hr, as well as an increase in matrix metalloproteinase 9 at 48 hr. Gene changes in microglia indicated a peak in proinflammatory markers at 48 hr followed by a peak in the anti-inflammatory marker, interleukin 1 receptor antagonist, at 72 hr. Endothelial cells had reduced occludin expression at 72 hr, while kinases and phosphatases known to alter tau phosphorylation states were increased in neuronal cells. This suggests that hyperhomocysteinemia induces early proinflammatory changes in microglia and astrocytic changes relevant to their interaction with the vasculature. Overall, the data show how hyperhomocysteinemia could impact Alzheimer’s disease and vascular cognitive impairment and dementia.

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Oxidative stress mediates the effect of apathy on executive function in those at risk of vascular cognitive impairment

Alzheimer s & Dementia ◽

10.1002/alz.055307 ◽

2021 ◽

Vol 17 (S6) ◽

Author(s):

Krista L. Lanctôt

Keyword(s):

Oxidative Stress ◽

At Risk ◽

Cognitive Impairment ◽

Executive Function ◽

Vascular Cognitive Impairment

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Glutathione Peroxidase Activity is Altered in Vascular Cognitive Impairment-No Dementia and Is a Potential Marker for Verbal Memory Performance

Journal of Alzheimer s Disease ◽

10.3233/jad-200754 ◽

2021 ◽

pp. 1-12

Author(s):

Mehnaz Ahmed ◽

Nathan Herrmann ◽

Jinghan Jenny Chen ◽

Mahwesh Saleem ◽

Paul I. Oh ◽

...

Keyword(s):

Oxidative Stress ◽

Cognitive Impairment ◽

Glutathione Peroxidase ◽

Peroxidase Activity ◽

Verbal Memory ◽

Vascular Cognitive Impairment ◽

Glutathione Peroxidase Activity ◽

Compensatory Response ◽

Potential Marker ◽

Cognitive Impairment No Dementia

Background: Coronary artery disease (CAD) increases risk for vascular cognitive impairment-no dementia (VCIND), a precursor to dementia, potentially through persistent oxidative stress. Objective: This study assessed peripheral glutathione peroxidase activity (GPX), which is protective against oxidative stress, in VCIND versus cognitively normal CAD controls (CN). GPX activity was also evaluated as a biomarker of cognition, particularly verbal memory. Methods: 120 CAD patients with VCIND (1SD below norms on executive function or verbal memory (VM)) or without (CN) participated in exercise rehabilitation for 24 weeks. Neurocognitive and cardiopulmonary fitness (VO2 peak) assessments and plasma were collected at baseline and 24-weeks. Results: GPX was higher in VCIND compared to CN (F1,119 = 3.996, p = 0.048). Higher GPX was associated with poorer baseline VM (β= –0.182, p = 0.048), and longitudinally with VM decline controlling for sex, body mass index, VO2 peak, and education (b[SE] = –0.02[0.01], p = 0.004). Only CN participants showed improved VM performance with increased fitness (b[SE] = 1.30[0.15], p < 0.005). Conclusion: GPX was elevated in VCIND consistent with a compensatory response to persistent oxidative stress. Increased GPX predicted poorer cognitive outcomes (verbal memory) in VCIND patients despite improved fitness.

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Targeting Transcription Factor Nrf2 (Nuclear Factor Erythroid 2-Related Factor 2) for the Intervention of Vascular Cognitive Impairment and Dementia

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.120.314804 ◽

2020 ◽

Author(s):

Tuo Yang ◽

Feng Zhang

Keyword(s):

Oxidative Stress ◽

Cognitive Impairment ◽

White Matter ◽

Blood Brain Barrier ◽

Vascular Cognitive Impairment ◽

Brain Barrier ◽

Brain Diseases ◽

Related Factor ◽

Nuclear Factor ◽

Blood Brain

Vascular cognitive impairment and dementia (VCID) is an age-related, mild to severe mental disability due to a broad panel of cerebrovascular disorders. Its pathobiology involves neurovascular dysfunction, blood-brain barrier disruption, white matter damage, microRNAs, oxidative stress, neuroinflammation, and gut microbiota alterations, etc. Nrf2 (Nuclear factor erythroid 2-related factor 2) is the master regulator of redox status and controls the transcription of a panel of antioxidative and anti-inflammatory genes. By interacting with NF-κB (nuclear factor-κB), Nrf2 also fine-tunes the cellular oxidative and inflammatory balance. Aging is associated with Nrf2 dysfunction, and increasing evidence has proved the role of Nrf2 in mitigating the VCID process. Based on VCID pathobiologies and Nrf2 studies from VCID and other brain diseases, we point out several hypothetical Nrf2 targets for VCID management, including restoration of endothelial function and neurovascular coupling, preservation of blood-brain barrier integrity, reduction of amyloidopathy, promoting white matter integrity, and mitigating oxidative stress and neuroinflammation. Collectively, the Nrf2 pathway could be a promising direction for future VCID research. Targeting Nrf2 would shed light on VCID managing strategies.

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Nicotinamide Mononucleotide Supplementation

10.14232/phd.10743 ◽

2021 ◽

Author(s):

Tamás Kiss

Keyword(s):

Gene Expression ◽

Endothelial Cells ◽

Molecular Mechanisms ◽

Bioinformatic Analysis ◽

Vascular Cognitive Impairment ◽

Vascular Aging ◽

Nad Metabolism ◽

Nicotinamide Mononucleotide

Vascular cognitive impairment (VCI) is a major cause of dementia among elderly individuals. Understanding molecular mechanisms behind vascular aging is essential to develop novel interventional strategies for the treatment and prevention of VCI. Recent studies have provided critical evidence that vascular aging is characterized by cellular NAD+ depletion. In our studies we systematically investigated the effects of boosting cellular NAD+ levels by the use of nicotinamide mononucleotide (NMN), an intermediate of NAD+ metabolism. First, we conducted in vitro examination of cultured cerebromicrovascular endothelial cells (CMVES) isolated from young and aged F344xBN rats. We have shown that NMN treatment attenuates oxidative stress and rescues angiogenic capacity in aged CMVES. Next, in vivo aged C57BL/6 mice were treated daily with NMN for 14 days. NMN treatment rescued cognitive performance, motor function and neurovascular coupling in aged animals. To understand the fundamental gene regulation underlying the beneficial effects of NMN treatment, we generated a miRNA profile from the aorta and a gene expression profile from isolated brain endothelial cells. Bioinformatic analysis revealed that the effects of NMN treatment were mediated by the sirtuin pathway and induced gene expression changes associated with mitochondrial rejuvenation, anti-inflammatory and anti- apoptotic pathways.

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