Improvement of autophagy dysfunction as a potential mechanism for environmental enrichment to protect blood-brain barrier in rats with vascular cognitive impairment

The entry of blood-borne macromolecular substances into the brain parenchyma from cerebral vessels is blocked by the blood–brain barrier (BBB) function. Accordingly, increased permeability of the vessels induced by insult noted in patients suffering from vascular dementia likely contributes to the cognitive impairment. On the other hand, blood-borne substances can enter extracellular spaces of the brain via endothelial cells at specific sites without the BBB, and can move to brain parenchyma, such as the hippocampus and periventricular areas, adjacent to specific sites, indicating the contribution of increased permeability of vessels in the specific sites to brain function. It is necessary to consider influx and efflux of interstitial fluid (ISF) and cerebrospinal fluid (CSF) in considering effects of brain transfer of intravascular substances on brain function. Two pathways of ISF and CSF are recently being established. One is the intramural peri-arterial drainage (IPAD) pathway of ISF. The other is the glymphatic system of CSF. Dysfunction of the two pathways could also contribute to brain dysfunction. We review the effects of several kinds of insult on vascular permeability and the failure of fluid clearance on the brain function.

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Protection of blood-brain barrier as a potential mechanism for enriched environments to improve cognitive impairment caused by chronic cerebral hypoperfusion

Behavioural Brain Research ◽

10.1016/j.bbr.2019.112385 ◽

2020 ◽

Vol 379 ◽

pp. 112385

Author(s):

Changhua Qu ◽

Linling Xu ◽

Jun Shen ◽

Yaqing Li ◽

Chujie Qu ◽

...

Keyword(s):

Cognitive Impairment ◽

Blood Brain Barrier ◽

Chronic Cerebral Hypoperfusion ◽

Brain Barrier ◽

Cerebral Hypoperfusion ◽

Potential Mechanism ◽

Blood Brain ◽

Enriched Environments

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Abstract 44: Enlarged Perivascular Spaces Correlate With CSF Biomarkers for Abnormal Blood-brain Barrier Permeability and Neuroinflammation in Patients With Vascular Cognitive Impairment

Stroke ◽

10.1161/str.47.suppl_1.44 ◽

2016 ◽

Vol 47 (suppl_1) ◽

Author(s):

Laith Maali ◽

Branko Huisa ◽

Jillian Prestopnik ◽

Clifford Qualls ◽

Jeffrey Thompson ◽

...

Keyword(s):

Cognitive Impairment ◽

White Matter ◽

Blood Brain Barrier ◽

Vascular Cognitive Impairment ◽

Brain Barrier ◽

Csf Biomarkers ◽

Perivascular Spaces ◽

Albumin Ratio ◽

Blood Brain ◽

Bbb Permeability

Background: Enlarged perivascular spaces (PVS) in the brain are common but their etiology and specificity are unclear. Multiple studies have shown a correlation between enlarged PVS and white matter hyperintensities (WMHs), but the relationship with vascular disease is uncertain. We used albumin CSF to blood ratio as a method to measure permeability of the blood-brain barrier (BBB) in patients with vascular cognitive impairment (VCI). It is possible that the enlarged PVS are associated with an increase in BBB permeability, which could interfere with perivascular fluid flow. Therefore, we hypothesized that enlarged PVS correlate with CSF markers of increased BBB permeability and neuroinflammation. Methods: We prospectively recruited 107 VCI patients with white matter disease. At entry, they had brain MRIs with standardized ranking for enlarged PVS. Sixty-one had lumbar puncture to obtain CSF for analysis of albumin ratio, matrix metalloproteinases-2 (MMP-2) index, and amyloid-beta1-42 (Abeta42). The data was analyzed statistically with nonparametric correlation methods. Results: Enlarged PVS had a positive correlation with CSF albumin ratio, which is a biomarker for increased BBB permeability ( p <0.01), and a negative correlation with the neuroinflammatory biomarker, MMP2 index ( p <0.02), and with Abeta42 ( p <0.02), which is cleared by the PVS. Conclusion: Our results suggest an association between PVS, MMP-mediated increased BBB permeability, and clearance of Abeta42. The role of perivascular fluid movement and its relationship with CSF biomarkers will require further investigation.

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Role of microRNAs on Blood Brain Barrier Dysfunction in Vascular Cognitive Impairment

Current Drug Delivery ◽

10.2174/1567201813666160830124627 ◽

2017 ◽

Vol 14 (6) ◽

Cited By ~ 11

Author(s):

Kensuke Toyama ◽

Joshua Michael Spin ◽

Philip Shih Tsao

Keyword(s):

Cognitive Impairment ◽

Blood Brain Barrier ◽

Vascular Cognitive Impairment ◽

Brain Barrier ◽

Barrier Dysfunction ◽

Blood Brain

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Inhibition of mTOR protects the blood-brain barrier in models of Alzheimer’s disease and vascular cognitive impairment

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00570.2017 ◽

2018 ◽

Vol 314 (4) ◽

pp. H693-H703 ◽

Cited By ~ 31

Author(s):

Candice E. Van Skike ◽

Jordan B. Jahrling ◽

Angela B. Olson ◽

Naomi L. Sayre ◽

Stacy A. Hussong ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Blood Brain Barrier ◽

Vascular Cognitive Impairment ◽

Brain Barrier ◽

Target Of Rapamycin ◽

Mtor Inhibition ◽

Mechanistic Target Of Rapamycin ◽

Blood Brain

An intact blood-brain barrier (BBB) limits entry of proinflammatory and neurotoxic blood-derived factors into the brain parenchyma. The BBB is damaged in Alzheimer’s disease (AD), which contributes significantly to the progression of AD pathologies and cognitive decline. However, the mechanisms underlying BBB breakdown in AD remain elusive, and no interventions are available for treatment or prevention. We and others recently established that inhibition of the mammalian/mechanistic target of rapamycin (mTOR) pathway with rapamycin yields significant neuroprotective effects, improving cerebrovascular and cognitive function in mouse models of AD. To test whether mTOR inhibition protects the BBB in neurological diseases of aging, we treated hAPP(J20) mice modeling AD and low-density lipoprotein receptor-null (LDLR−/−) mice modeling vascular cognitive impairment with rapamycin. We found that inhibition of mTOR abrogates BBB breakdown in hAPP(J20) and LDLR−/− mice. Experiments using an in vitro BBB model indicated that mTOR attenuation preserves BBB integrity through upregulation of specific tight junction proteins and downregulation of matrix metalloproteinase-9 activity. Together, our data establish mTOR activity as a critical mediator of BBB breakdown in AD and, potentially, vascular cognitive impairment and suggest that rapamycin and/or rapalogs could be used for the restoration of BBB integrity. NEW & NOTEWORTHY This report establishes mammalian/mechanistic target of rapamycin as a critical mediator of blood-brain barrier breakdown in models of Alzheimer's disease and vascular cognitive impairment and suggests that drugs targeting the target of rapamycin pathway could be used for the restoration of blood-brain barrier integrity in disease states.

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MicroRNA-Mediated Therapy Modulating Blood–Brain Barrier Disruption Improves Vascular Cognitive Impairment

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.118.310822 ◽

2018 ◽

Vol 38 (6) ◽

pp. 1392-1406 ◽

Cited By ~ 25

Author(s):

Kensuke Toyama ◽

Joshua M. Spin ◽

Alicia C. Deng ◽

Ting-Ting Huang ◽

Ke Wei ◽

...

Keyword(s):

Cognitive Impairment ◽

Blood Brain Barrier ◽

Vascular Cognitive Impairment ◽

Brain Barrier ◽

Barrier Disruption ◽

Blood Brain Barrier Disruption ◽

Blood Brain ◽

Brain Barrier Disruption

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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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