Decreased parenchymal arteriolar tone uncouples vessel-to-neuronal communication in a mouse model of vascular cognitive impairment

AbstractChronic hypoperfusion is a key contributor to cognitive decline and neurodegenerative conditions, but the cellular mechanisms remain ill-defined. Using a multidisciplinary approach, we sought to elucidate chronic hypoperfusion-evoked functional changes at the neurovascular unit. We used bilateral common carotid artery stenosis (BCAS), a well-established model of vascular cognitive impairment, combined with an ex vivo preparation that allows pressurization of parenchymal arterioles in a brain slice. Our results demonstrate that mild (~ 30%), chronic hypoperfusion significantly altered the functional integrity of the cortical neurovascular unit. Although pial cerebral perfusion recovered over time, parenchymal arterioles progressively lost tone, exhibiting significant reductions by day 28 post-surgery. We provide supportive evidence for reduced adenosine 1 receptor-mediated vasoconstriction as a potential mechanism in the adaptive response underlying the reduced baseline tone in parenchymal arterioles. In addition, we show that in response to the neuromodulator adenosine, the action potential frequency of cortical pyramidal neurons was significantly reduced in all groups. However, a significant decrease in adenosine-induced hyperpolarization was observed in BCAS 14 days. At the microvascular level, constriction-induced inhibition of pyramidal neurons was significantly compromised in BCAS mice. Collectively, these results suggest that BCAS uncouples vessel-to-neuron communication—vasculo-neuronal coupling—a potential early event in cognitive decline.

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Mild Cognitive Impairment in Clinical Practice: A Review Article

American Journal of Alzheimer s Disease & Other Dementias® ◽

10.1177/1533317518791401 ◽

2018 ◽

Vol 33 (8) ◽

pp. 500-507 ◽

Cited By ~ 15

Author(s):

Sukanya Jongsiriyanyong ◽

Panita Limpawattana

Keyword(s):

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Cognitive Decline ◽

Preventive Intervention ◽

Lifestyle Modification ◽

The Elderly ◽

Vascular Cognitive Impairment ◽

Review Article ◽

Subjective Cognitive Impairment ◽

Rate Of Progression

The spectrum of cognitive decline in the elderly ranges from what can be classified as normal cognitive decline with aging to subjective cognitive impairment to mild cognitive impairment (MCI) to dementia. This article reviewed the up-to-date evidence of MCI including the diagnostic criteria of MCI due to Alzheimer’s disease, vascular cognitive impairment and MCI due to Parkinson disease, management and preventive intervention of MCI. There are various etiologies of MCI, and a large number of studies have been conducted to ascertain the practical modalities of preserving cognition in predementia stages. Lifestyle modification, such as aerobic exercise, is an approved modality to preserve cognitive ability and decrease the rate of progression to dementia, as well as being recommended for frailty prevention.

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Abstract P604: Astrocyte-dependent Regulation of Vascular Tone: Role in Hypertension

Hypertension ◽

10.1161/hyp.68.suppl_1.p604 ◽

2016 ◽

Vol 68 (suppl_1) ◽

Author(s):

Juan Manuel Ramiro-Diaz ◽

Ki Jung Kim ◽

Jessica A Filosa

Keyword(s):

Vascular Tone ◽

Structural Changes ◽

Neurovascular Unit ◽

Brain Slices ◽

Vascular Cognitive Impairment ◽

Vascular Density ◽

Aqp4 Expression ◽

Functional Changes ◽

Functional Studies ◽

Underlying Mechanisms

Clinical studies support that untreated hypertension (HT) accelerates the development of vascular cognitive impairment (VCI). Yet, the underlying mechanisms for VCI are not known. In a recent study we demonstrated the role of astrocytes in the regulation of parenchymal arteriole (PA) steady-state vascular tone. Here we hypothesized hypertension results in structural and functional changes to the neurovascular unit resulting in enhanced astrocytic TRPV4 channel-dependent Ca 2+ increases contributing to augmented pressure-induced PA constriction . Functional studies were conducted in brain slices from angiotensin II (AngII) treated mice (600 ng/Kg/min, 28 days). PA arterioles within brain slices were perfused and pressurized and myogenic-evoked diameter changes measured using video microscopy. In addition, using the GLAST-CreERT2 ; R26-lsl-GCaMP3 mice we measure myogenic-evoked Ca 2+ changes in perivascular astrocytes. We demonstrate that HT increases pressure-induced PA tone by 11.14% at 30 mmHg and 12.97% at 60 mmHg (10.88 to 22.02 and 15.46 to 28.43% of tone, P<0.05 and P<0.01, respectively). In ANG II-treated mice, PA myogenic-evoked responses significantly increased astrocytic Ca 2+ oscillations frequency (119.4%, 0.0366 to 0.0803 Hz, P<0.0001). A significant increase in astrocytic Ca 2+ oscillation frequency was also observed after 2 min of AngII (500 nM) bath application (44.8%, 0.0366 to 0.053 Hz, P<0.01) in brain slices from AngII treated mice. Furthermore, using the model of spontaneous hypertensive rat (SHR) we observed that HT differentially increases vascular density and the number of vascular pericytes in cortical layers with highest neuronal densities (L III-V). Finally, while aquaporin 4 (AQP4) expression pattern was not different in the gray matter of SHR compared with WKY rats, a significant increase in unpolarized AQP4 expression was observed in the white matter of SHR. Taken together, this evidence indicates that HT induces functional and structural changes to the neurovascular unit favoring the development of regional brain hypoperfusion likely contributing to the development of VCI.

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The role of high-mobility group box protein 1 in chronic cerebral hypoperfusion-induced vascular cognitive impairment animals

10.21203/rs.2.17046/v1 ◽

2019 ◽

Author(s):

Amelia Nur Vidyanti ◽

Jia-Yu Hsieh ◽

Kun-Ju Lin ◽

Yao-Ching Fang ◽

Ismail Setyopranoto ◽

...

Keyword(s):

Cognitive Impairment ◽

Cognitive Decline ◽

High Mobility ◽

Vascular Cognitive Impairment ◽

High Mobility Group ◽

Cerebral Hypoperfusion ◽

Hippocampal Atrophy ◽

Amyloid Pet ◽

Knock Out

Abstract Background: The molecular mechanisms of vascular cognitive impairment (VCI) are diverse and still in puzzle. VCI could be attributed to chronic cerebral hypoperfusion (CCH). CCH may cause a cascade of reactions involved in ischemia and neuro-inflammation which plays important roles in the pathophysiology of VCI. High-mobility group box protein 1 (HMGB1) is a non-histone protein that serves as a damage-associated molecular signal leading to cascades of inflammation. Increased level of HMGB1 has been established in the acute phase of CCH. However, the role of HMGB1 at the chronic phase of CCH remains elucidated. Methods: We performed modified bilateral common carotid artery occlusion (BCCAO) in C57BL/6 mice to induce CCH. We examined the cerebral blood flow (CBF) reduction by laser doppler flowmetry, the protein expression of HMGB1 and its pro-inflammatory cytokines (TNF-a, IL-1b, and IL-6) by western blotting and immunohistochemistry. The brain pathology was assessed by 7T-animal MRI and amyloid-b accumulation was assessed by amyloid-PET scanning. We further evaluated the effect of HMGB1 suppression by injecting CRISPR/Cas9 knock-out plasmid intra-hippocampus bilaterally. Results: There were reduction of CBF up to 50% which persisted three months after CCH. The modified-BCCAO animals developed significant cognitive decline. The 7T-MRI image showed hippocampal atrophy, although the amyloid-PET showed no significant amyloid-beta accumulation. Increased protein levels of HMGB1, TNF-a and IL-1b were found three months after BCCAO. HMGB1 suppression by CRISPR/Cas9 knock-out plasmid restored the CBF, IL-1B, TNF-alpha, IL-6, and attenuated hippocampal atrophy and cognitive decline. Conclusion: HMGB1 plays a pivotal role in the pathophysiology of the animal model of CCH and it might be a candidate as therapeutic targets of VCI.

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Neurovascular unit dysregulation, white matter disease, and executive dysfunction: the shared triad of vascular cognitive impairment and Alzheimer disease

GeroScience ◽

10.1007/s11357-020-00164-6 ◽

2020 ◽

Vol 42 (2) ◽

pp. 445-465 ◽

Cited By ~ 4

Author(s):

Alexander Levit ◽

Vladimir Hachinski ◽

Shawn N. Whitehead

Keyword(s):

Cognitive Impairment ◽

White Matter ◽

Alzheimer Disease ◽

Neurovascular Unit ◽

Executive Dysfunction ◽

Vascular Cognitive Impairment ◽

White Matter Disease

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Role of HMGB1 in an Animal Model of Vascular Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion

International Journal of Molecular Sciences ◽

10.3390/ijms21062176 ◽

2020 ◽

Vol 21 (6) ◽

pp. 2176 ◽

Cited By ~ 1

Author(s):

Amelia Nur Vidyanti ◽

Jia-Yu Hsieh ◽

Kun-Ju Lin ◽

Yao-Ching Fang ◽

Ismail Setyopranoto ◽

...

Keyword(s):

Animal Model ◽

Cognitive Impairment ◽

Cognitive Decline ◽

Chronic Phase ◽

Vascular Cognitive Impairment ◽

Chronic Cerebral Hypoperfusion ◽

Cerebral Hypoperfusion ◽

Hippocampal Atrophy ◽

Tnf Α

The pathophysiology of vascular cognitive impairment (VCI) is associated with chronic cerebral hypoperfusion (CCH). Increased high-mobility group box protein 1 (HMGB1), a nonhistone protein involved in injury and inflammation, has been established in the acute phase of CCH. However, the role of HMGB1 in the chronic phase of CCH remains unclear. We developed a novel animal model of CCH with a modified bilateral common carotid artery occlusion (BCCAO) in C57BL/6 mice. Cerebral blood flow (CBF) reduction, the expression of HMGB1 and its proinflammatory cytokines (tumor necrosis factor-alpha [TNF-α], interleukin [IL]-1β, and IL-6), and brain pathology were assessed. Furthermore, we evaluated the effect of HMGB1 suppression through bilateral intrahippocampus injection with the CRISPR/Cas9 knockout plasmid. Three months after CCH induction, CBF decreased to 30–50% with significant cognitive decline in BCCAO mice. The 7T-aMRI showed hippocampal atrophy, but amyloid positron imaging tomography showed nonsignificant amyloid-beta accumulation. Increased levels of HMGB1, TNF-α, IL-1β, and IL-6 were observed 3 months after BCCAO. HMGB1 suppression with CRISPR/Cas9 knockout plasmid restored TNF-α, IL-1β, and IL-6 and attenuated hippocampal atrophy and cognitive decline. We believe that HMGB1 plays a pivotal role in CCH-induced VCI pathophysiology and can be a potential therapeutic target of VCI.

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Biomarkers Related to Endothelial Dysfunction and Vascular Cognitive Impairment: A Systematic Review

Dementia and Geriatric Cognitive Disorders ◽

10.1159/000510053 ◽

2020 ◽

pp. 1-10

Author(s):

Rui Kleber Martins-Filho ◽

Maria Clara Zotin ◽

Guilherme Rodrigues ◽

Octavio Pontes-Neto

Keyword(s):

Cognitive Impairment ◽

Endothelial Dysfunction ◽

Selection Criteria ◽

Data Extraction ◽

Neurovascular Unit ◽

Vascular Cognitive Impairment ◽

Original Research ◽

Clinical Approach ◽

Qualitative Synthesis ◽

The Past

Introduction: The damage in the endothelium and the neurovascular unit appears to play a key role in the pathogenesis of vascular cognitive impairment (VCI). Although there have been many advances in understanding the physiopathology of this disease, several questions remain unanswered. The association with other degenerative diseases and the heterogeneity of its clinical spectrum establish a diagnostic problem, compromising a better comprehension of the pathology and halting the development of effective treatments. The investigation of biomarkers is an important movement to the development of novel explicative models and treatment targets involved in VCI. Methods: We searched MEDLINE considering the original research based on VCI biomarkers in the past 20 years, following prespecified selection criteria, data extraction, and qualitative synthesis. Results: We reviewed 42 articles: 16 investigated plasma markers, 17 analyzed neuropathological markers, 4 studied CSF markers, 4 evaluated neuroimaging markers (ultrasound and MRI), and 1 used peripheral Doppler perfusion imaging. Conclusions: The biomarkers in these studies suggest an intrinsic relationship between endothelial dysfunction and VCI. Nonetheless, there is still a need for identification of a distinctive set of markers that can integrate the clinical approach of VCI, improve diagnostic accuracy, and support the discovery of alternative therapies.

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[P3-258]: TRAJECTORIES OF COGNITIVE DECLINE IN SUBCORTICAL VASCULAR COGNITIVE IMPAIRMENT

Alzheimer s & Dementia ◽

10.1016/j.jalz.2017.06.1472 ◽

2017 ◽

Vol 13 (7S_Part_21) ◽

pp. P1042-P1042

Author(s):

Hee Jin Kim ◽

Seong-Kyung Cho ◽

Young Kyoung Jang ◽

Jin San Lee ◽

Hyemin Jang ◽

...

Keyword(s):

Cognitive Impairment ◽

Cognitive Decline ◽

Vascular Cognitive Impairment ◽

Subcortical Vascular Cognitive Impairment

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Therapeutic Potential of Remote Ischemic Conditioning in Vascular Cognitive Impairment

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.706759 ◽

2021 ◽

Vol 15 ◽

Author(s):

Rui Xu ◽

Qianyan He ◽

Yan Wang ◽

Yi Yang ◽

Zhen-Ni Guo

Keyword(s):

Cognitive Impairment ◽

Cognitive Processing ◽

Therapeutic Potential ◽

Recurrent Stroke ◽

Neurovascular Unit ◽

Vascular Cognitive Impairment ◽

Cerebrovascular Diseases ◽

Remote Ischemic Conditioning ◽

Ischemic Conditioning ◽

Social Burden

Vascular cognitive impairment (VCI) is a heterogeneous disease caused by a variety of cerebrovascular diseases. Patients with VCI often present with slower cognitive processing speed and poor executive function, which affects their independence in daily life, thus increasing social burden. Remote ischemic conditioning (RIC) is a non-invasive and efficient intervention that triggers endogenous protective mechanisms to generate neuroprotection. Over the past decades, evidence from basic and clinical research has shown that RIC is promising for the treatment of VCI. To further our understanding of RIC and improve the management of VCI, we summarize the evidence on the therapeutic potential of RIC in relation to the risk factors and pathobiologies of VCI, including reducing the risk of recurrent stroke, decreasing high blood pressure, improving cerebral blood flow, restoring white matter integrity, protecting the neurovascular unit, attenuating oxidative stress, and inhibiting the inflammatory response.

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The role of inflammasomes in vascular cognitive impairment

Molecular Neurodegeneration ◽

10.1186/s13024-021-00506-8 ◽

2022 ◽

Vol 17 (1) ◽

Author(s):

Luting Poh ◽

Wei Liang Sim ◽

Dong-Gyu Jo ◽

Quynh Nhu Dinh ◽

Grant R. Drummond ◽

...

Keyword(s):

Cognitive Impairment ◽

Critical Role ◽

Disease Onset ◽

The Elderly ◽

Vascular Cognitive Impairment ◽

Cerebral Hypoperfusion ◽

Early Event ◽

Cellular Mechanisms ◽

Structural Brain Damage

AbstractThere is an increasing prevalence of Vascular Cognitive Impairment (VCI) worldwide, and several studies have suggested that Chronic Cerebral Hypoperfusion (CCH) plays a critical role in disease onset and progression. However, there is a limited understanding of the underlying pathophysiology of VCI, especially in relation to CCH. Neuroinflammation is a significant contributor in the progression of VCI as increased systemic levels of the proinflammatory cytokine interleukin-1β (IL-1β) has been extensively reported in VCI patients. Recently it has been established that CCH can activate the inflammasome signaling pathways, involving NLRP3 and AIM2 inflammasomes that critically regulate IL-1β production. Given that neuroinflammation is an early event in VCI, it is important that we understand its molecular and cellular mechanisms to enable development of disease-modifying treatments to reduce the structural brain damage and cognitive deficits that are observed clinically in the elderly. Hence, this review aims to provide a comprehensive insight into the molecular and cellular mechanisms involved in the pathogenesis of CCH-induced inflammasome signaling in VCI.

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