Research

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21 pages, 4159 KiB

Open AccessEditor’s ChoiceArticle

A Soluble Platelet-Derived Growth Factor Receptor-β Originates via Pre-mRNA Splicing in the Healthy Brain and Is Upregulated during Hypoxia and Aging

by Laura Beth Payne, Hanaa Abdelazim, Maruf Hoque, Audra Barnes, Zuzana Mironovova, Caroline E. Willi, Jordan Darden, Clifton Houk, Meghan W. Sedovy, Scott R. Johnstone and John C. Chappell

Biomolecules 2023, 13(4), 711; https://doi.org/10.3390/biom13040711 - 21 Apr 2023

Cited by 1 | Viewed by 2403

Abstract

The platelet-derived growth factor-BB (PDGF-BB) pathway provides critical regulation of cerebrovascular pericytes, orchestrating their investment and retention within the brain microcirculation. Dysregulated PDGF Receptor-beta (PDGFRβ) signaling can lead to pericyte defects that compromise blood-brain barrier (BBB) integrity and cerebral perfusion, impairing neuronal activity [...] Read more.

The platelet-derived growth factor-BB (PDGF-BB) pathway provides critical regulation of cerebrovascular pericytes, orchestrating their investment and retention within the brain microcirculation. Dysregulated PDGF Receptor-beta (PDGFRβ) signaling can lead to pericyte defects that compromise blood-brain barrier (BBB) integrity and cerebral perfusion, impairing neuronal activity and viability, which fuels cognitive and memory deficits. Receptor tyrosine kinases such as PDGF-BB and vascular endothelial growth factor-A (VEGF-A) are often modulated by soluble isoforms of cognate receptors that establish signaling activity within a physiological range. Soluble PDGFRβ (sPDGFRβ) isoforms have been reported to form by enzymatic cleavage from cerebrovascular mural cells, and pericytes in particular, largely under pathological conditions. However, pre-mRNA alternative splicing has not been widely explored as a possible mechanism for generating sPDGFRβ variants, and specifically during tissue homeostasis. Here, we found sPDGFRβ protein in the murine brain and other tissues under normal, physiological conditions. Utilizing brain samples for follow-on analysis, we identified mRNA sequences corresponding to sPDGFRβ isoforms, which facilitated construction of predicted protein structures and related amino acid sequences. Human cell lines yielded comparable sequences and protein model predictions. Retention of ligand binding capacity was confirmed for sPDGFRβ by co-immunoprecipitation. Visualizing fluorescently labeled sPDGFRβ transcripts revealed a spatial distribution corresponding to murine brain pericytes alongside cerebrovascular endothelium. Soluble PDGFRβ protein was detected throughout the brain parenchyma in distinct regions, such as along the lateral ventricles, with signals also found more broadly adjacent to cerebral microvessels consistent with pericyte labeling. To better understand how sPDGFRβ variants might be regulated, we found elevated transcript and protein levels in the murine brain with age, and acute hypoxia increased sPDGFRβ variant transcripts in a cell-based model of intact vessels. Our findings indicate that soluble isoforms of PDGFRβ likely arise from pre-mRNA alternative splicing, in addition to enzymatic cleavage mechanisms, and these variants exist under normal physiological conditions. Follow-on studies will be needed to establish potential roles for sPDGFRβ in regulating PDGF-BB signaling to maintain pericyte quiescence, BBB integrity, and cerebral perfusion—critical processes underlying neuronal health and function, and in turn, memory and cognition. Full article

(This article belongs to the Special Issue The Role of Vascular Dysfunction in Neuronal Degeneration and Cognitive Impairment)

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12 pages, 1461 KiB

Open AccessFeature PaperArticle

Elevated Soluble TNF-Receptor 1 in the Serum of Predementia Subjects with Cerebral Small Vessel Disease

by Kaung H. T. Salai, Liu-Yun Wu, Joyce R. Chong, Yuek Ling Chai, Bibek Gyanwali, Caroline Robert, Saima Hilal, Narayanaswamy Venketasubramanian, Gavin S. Dawe, Christopher P. Chen and Mitchell K. P. Lai

Biomolecules 2023, 13(3), 525; https://doi.org/10.3390/biom13030525 - 13 Mar 2023

Cited by 4 | Viewed by 1817

Abstract

Tumor necrosis factor-receptor 1 (TNF-R1)-mediated signaling is critical to the regulation of inflammatory responses. TNF-R1 can be proteolytically released into systemic blood circulation in a soluble form (sTNF-R1), where it binds to circulating TNF and functions to attenuate TNF-mediated inflammation. Increases of peripheral [...] Read more.

Tumor necrosis factor-receptor 1 (TNF-R1)-mediated signaling is critical to the regulation of inflammatory responses. TNF-R1 can be proteolytically released into systemic blood circulation in a soluble form (sTNF-R1), where it binds to circulating TNF and functions to attenuate TNF-mediated inflammation. Increases of peripheral sTNF-R1 have been reported in both Alzheimer’s disease (AD) dementia and vascular dementia (VaD). However, the status of sTNF-R1 in predementia subjects (cognitive impairment, no dementia, CIND) is unknown, and putative associations with cerebral small vessel disease (CSVD), as well as with longitudinal changes in cognitive functions are unclear. We measured baseline serum sTNF-R1 in a longitudinally assessed cohort of 93 controls and 103 CIND, along with neuropsychological evaluations and neuroimaging assessments. Serum sTNF-R1 levels were increased in CIND compared with controls (p < 0.001). Higher baseline sTNF-R1 levels were specifically associated with lacunar infarcts (rate ratio = 6.91, 95% CI 3.19–14.96, p < 0.001), as well as lower rates of cognitive decline in the CIND subgroup. Our data suggest that sTNF-R1 interacts with vascular cognitive impairment in a complex manner at predementia stages, with elevated levels associated with more severe CSVD at baseline, but which may subsequently be protective against cognitive decline. Full article

(This article belongs to the Special Issue The Role of Vascular Dysfunction in Neuronal Degeneration and Cognitive Impairment)

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12 pages, 1882 KiB

Open AccessArticle

The Role of Nuclear Factor-Kappa B in Fibrinogen-Induced Inflammatory Responses in Cultured Primary Neurons

by Nurul Sulimai, Jason Brown and David Lominadze

Biomolecules 2022, 12(12), 1741; https://doi.org/10.3390/biom12121741 - 23 Nov 2022

Cited by 4 | Viewed by 1392

Abstract

Traumatic brain injury (TBI) is an inflammatory disease associated with a compromised blood–brain barrier (BBB) and neurodegeneration. One of the consequences of inflammation is an elevated blood level of fibrinogen (Fg), a protein that is mainly produced in the liver. The inflammation-induced changes [...] Read more.

Traumatic brain injury (TBI) is an inflammatory disease associated with a compromised blood–brain barrier (BBB) and neurodegeneration. One of the consequences of inflammation is an elevated blood level of fibrinogen (Fg), a protein that is mainly produced in the liver. The inflammation-induced changes in the BBB result in Fg extravasation into the brain parenchyma, creating the possibility of its contact with neurons. We have previously shown that interactions of Fg with the neuronal intercellular adhesion molecule-1 and cellular prion protein induced the upregulation of pro-inflammatory cytokines, oxidative damage, increased apoptosis, and cell death. However, the transcription pathway involved in this process was not defined. The association of Fg with the activation of the nuclear factor-κB (NF-κB) and the resultant expression of interleukin-6 (IL-6) and C–C chemokine ligand-2 (CCL2) were studied in cultured primary mouse brain cortex neurons. Fg-induced gene expression of CCL2 and IL-6 and the expression of NF-κB protein were increased in response to a specific interaction of Fg with neurons. These data suggest that TBI-induced neurodegeneration can involve the direct interaction of extravasated Fg with neurons, resulting in the overexpression of pro-inflammatory cytokines through the activation of transcription factor NF-κB. This may be a mechanism involved in vascular cognitive impairment during neuroinflammatory diseases. Full article

(This article belongs to the Special Issue The Role of Vascular Dysfunction in Neuronal Degeneration and Cognitive Impairment)

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15 pages, 3350 KiB

Open AccessCommunication

PHLPP Inhibitor NSC74429 Is Neuroprotective in Rodent Models of Cardiac Arrest and Traumatic Brain Injury

by Travis C. Jackson, Cameron Dezfulian, Vincent A. Vagni, Jason Stezoski, Keri Janesko-Feldman and Patrick M. Kochanek

Biomolecules 2022, 12(10), 1352; https://doi.org/10.3390/biom12101352 - 23 Sep 2022

Cited by 1 | Viewed by 1835

Abstract

Pleckstrin homology domain and leucine rich repeat protein phosphatase (PHLPP) knockout mice have improved outcomes after a stroke, traumatic brain injury (TBI), and decreased maladaptive vascular remodeling following vascular injury. Thus, small-molecule PHLPP inhibitors have the potential to improve neurological outcomes in a [...] Read more.

Pleckstrin homology domain and leucine rich repeat protein phosphatase (PHLPP) knockout mice have improved outcomes after a stroke, traumatic brain injury (TBI), and decreased maladaptive vascular remodeling following vascular injury. Thus, small-molecule PHLPP inhibitors have the potential to improve neurological outcomes in a variety of conditions. There is a paucity of data on the efficacy of the known experimental PHLPP inhibitors, and not all may be suited for targeting acute brain injury. Here, we assessed several PHLPP inhibitors not previously explored for neuroprotection (NSC13378, NSC25247, and NSC74429) that had favorable predicted chemistries for targeting the central nervous system (CNS). Neuronal culture studies in staurosporine (apoptosis), glutamate (excitotoxicity), and hydrogen peroxide (necrosis/oxidative stress) revealed that NSC74429 at micromolar concentrations was the most neuroprotective. Subsequent testing in a rat model of asphyxial cardiac arrest, and in a mouse model of severe TBI, showed that serial dosing of 1 mg/kg of NSC74429 over 3 days improved hippocampal survival in both models. Taken together, NSC74429 is neuroprotective across multiple insult mechanisms. Future pharmacokinetic and pharmacodynamic (PK/PD) studies are warranted to optimize dosing, and mechanistic studies are needed to determine the percentage of neuroprotection mediated by PHLPP1/2 inhibition, or potentially from the modulation of PHLPP-independent targets. Full article

(This article belongs to the Special Issue The Role of Vascular Dysfunction in Neuronal Degeneration and Cognitive Impairment)

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Review

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12 pages, 1992 KiB

Open AccessReview

Atrial Fibrillation and Dementia: Pathophysiological Mechanisms and Clinical Implications

by Dimitrios Varrias, Tinatin Saralidze, Pawel Borkowski, Sumant Pargaonkar, Michail Spanos, George Bazoukis and Damianos Kokkinidis

Biomolecules 2024, 14(4), 455; https://doi.org/10.3390/biom14040455 - 08 Apr 2024

Viewed by 397

Abstract

Numerous longitudinal studies suggest a strong association between cardiovascular risk factors and cognitive impairment. Individuals with atrial fibrillation are at higher risk of dementia and cognitive dysfunction, as atrial fibrillation increases the risk of cerebral hypoperfusion, inflammation, and stroke. The lack of comprehensive [...] Read more.

Numerous longitudinal studies suggest a strong association between cardiovascular risk factors and cognitive impairment. Individuals with atrial fibrillation are at higher risk of dementia and cognitive dysfunction, as atrial fibrillation increases the risk of cerebral hypoperfusion, inflammation, and stroke. The lack of comprehensive understanding of the observed association and the complex relationship between these two diseases makes it very hard to provide robust guidelines on therapeutic indications. With this review, we attempt to shed some light on how atrial fibrillation is related to dementia, what we know regarding preventive interventions, and how we could move forward in managing those very frequently overlapping conditions. Full article

(This article belongs to the Special Issue The Role of Vascular Dysfunction in Neuronal Degeneration and Cognitive Impairment)

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26 pages, 1574 KiB

Open AccessEditor’s ChoiceReview

Microvascular Contributions to Alzheimer Disease Pathogenesis: Is Alzheimer Disease Primarily an Endotheliopathy?

by Rawan Tarawneh

Biomolecules 2023, 13(5), 830; https://doi.org/10.3390/biom13050830 - 13 May 2023

Cited by 1 | Viewed by 4336

Abstract

Alzheimer disease (AD) models are based on the notion that abnormal protein aggregation is the primary event in AD, which begins a decade or longer prior to symptom onset, and culminates in neurodegeneration; however, emerging evidence from animal and clinical studies suggests that [...] Read more.

Alzheimer disease (AD) models are based on the notion that abnormal protein aggregation is the primary event in AD, which begins a decade or longer prior to symptom onset, and culminates in neurodegeneration; however, emerging evidence from animal and clinical studies suggests that reduced blood flow due to capillary loss and endothelial dysfunction are early and primary events in AD pathogenesis, which may precede amyloid and tau aggregation, and contribute to neuronal and synaptic injury via direct and indirect mechanisms. Recent data from clinical studies suggests that endothelial dysfunction is closely associated with cognitive outcomes in AD and that therapeutic strategies which promote endothelial repair in early AD may offer a potential opportunity to prevent or slow disease progression. This review examines evidence from clinical, imaging, neuropathological, and animal studies supporting vascular contributions to the onset and progression of AD pathology. Together, these observations support the notion that the onset of AD may be primarily influenced by vascular, rather than neurodegenerative, mechanisms and emphasize the importance of further investigations into the vascular hypothesis of AD. Full article

(This article belongs to the Special Issue The Role of Vascular Dysfunction in Neuronal Degeneration and Cognitive Impairment)

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19 pages, 2254 KiB

Open AccessReview

A Brief Overview of Neutrophils in Neurological Diseases

by Supriya Chakraborty, Zeynab Tabrizi, Nairuti Nikhil Bhatt, Sofia Andrea Franciosa and Oliver Bracko

Biomolecules 2023, 13(5), 743; https://doi.org/10.3390/biom13050743 - 25 Apr 2023

Cited by 3 | Viewed by 3383

Abstract

Neutrophils are the most abundant leukocyte in circulation and are the first line of defense after an infection or injury. Neutrophils have a broad spectrum of functions, including phagocytosis of microorganisms, the release of pro-inflammatory cytokines and chemokines, oxidative burst, and the formation [...] Read more.

Neutrophils are the most abundant leukocyte in circulation and are the first line of defense after an infection or injury. Neutrophils have a broad spectrum of functions, including phagocytosis of microorganisms, the release of pro-inflammatory cytokines and chemokines, oxidative burst, and the formation of neutrophil extracellular traps. Traditionally, neutrophils were thought to be most important for acute inflammatory responses, with a short half-life and a more static response to infections and injury. However, this view has changed in recent years showing neutrophil heterogeneity and dynamics, indicating a much more regulated and flexible response. Here we will discuss the role of neutrophils in aging and neurological disorders; specifically, we focus on recent data indicating the impact of neutrophils in chronic inflammatory processes and their contribution to neurological diseases. Lastly, we aim to conclude that reactive neutrophils directly contribute to increased vascular inflammation and age-related diseases. Full article

(This article belongs to the Special Issue The Role of Vascular Dysfunction in Neuronal Degeneration and Cognitive Impairment)

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16 pages, 694 KiB

Open AccessReview

Vascular Effects on Cerebrovascular Permeability and Neurodegeneration

by Nurul Sulimai, Jason Brown and David Lominadze

Biomolecules 2023, 13(4), 648; https://doi.org/10.3390/biom13040648 - 04 Apr 2023

Cited by 6 | Viewed by 1565

Abstract

Neurons and glial cells in the brain are protected by the blood brain barrier (BBB). The local regulation of blood flow is determined by neurons and signal conducting cells called astrocytes. Although alterations in neurons and glial cells affect the function of neurons, [...] Read more.

Neurons and glial cells in the brain are protected by the blood brain barrier (BBB). The local regulation of blood flow is determined by neurons and signal conducting cells called astrocytes. Although alterations in neurons and glial cells affect the function of neurons, the majority of effects are coming from other cells and organs of the body. Although it seems obvious that effects beginning in brain vasculature would play an important role in the development of various neuroinflammatory and neurodegenerative pathologies, significant interest has only been directed to the possible mechanisms involved in the development of vascular cognitive impairment and dementia (VCID) for the last decade. Presently, the National Institute of Neurological Disorders and Stroke applies considerable attention toward research related to VCID and vascular impairments during Alzheimer’s disease. Thus, any changes in cerebral vessels, such as in blood flow, thrombogenesis, permeability, or others, which affect the proper vasculo-neuronal connection and interaction and result in neuronal degeneration that leads to memory decline should be considered as a subject of investigation under the VCID category. Out of several vascular effects that can trigger neurodegeneration, changes in cerebrovascular permeability seem to result in the most devastating effects. The present review emphasizes the importance of changes in the BBB and possible mechanisms primarily involving fibrinogen in the development and/or progression of neuroinflammatory and neurodegenerative diseases resulting in memory decline. Full article

(This article belongs to the Special Issue The Role of Vascular Dysfunction in Neuronal Degeneration and Cognitive Impairment)

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11 pages, 594 KiB

Open AccessReview

The Potential Role of Integrin Signaling in Memory and Cognitive Impairment

by Ifechukwude Joachim Biose, Saifudeen Ismael, Blake Ouvrier, Amanda Louise White and Gregory Jaye Bix

Biomolecules 2023, 13(1), 108; https://doi.org/10.3390/biom13010108 - 05 Jan 2023

Cited by 2 | Viewed by 1955

Abstract

Dementia currently has no cure and, due to the increased prevalence and associated economic and personal burden of this condition, current research efforts for the development of potential therapies have intensified. Recently, targeting integrins as a strategy to ameliorate dementia and other forms [...] Read more.

Dementia currently has no cure and, due to the increased prevalence and associated economic and personal burden of this condition, current research efforts for the development of potential therapies have intensified. Recently, targeting integrins as a strategy to ameliorate dementia and other forms of cognitive impairment has begun to gain traction. Integrins are major bidirectional signaling receptors in mammalian cells, mediating various physiological processes such as cell–cell interaction and cell adhesion, and are also known to bind to the extracellular matrix. In particular, integrins play a critical role in the synaptic transmission of signals, hence their potential contribution to memory formation and significance in cognitive impairment. In this review, we describe the physiological roles that integrins play in the blood–brain barrier (BBB) and in the formation of memories. We also provide a clear overview of how integrins are implicated in BBB disruption following cerebral pathology. Given that vascular contributions to cognitive impairment and dementia and Alzheimer’s’ disease are prominent forms of dementia that involve BBB disruption, as well as chronic inflammation, we present current approaches shown to improve dementia-like conditions with integrins as a central focus. We conclude that integrins are vital in memory formation and that their disruption could lead to various forms of cognitive impairment. While further research to understand the relationships between integrins and memory is needed, we propose that the translational relevance of research efforts in this area could be improved through the use of appropriately aged, comorbid, male and female animals. Full article

(This article belongs to the Special Issue The Role of Vascular Dysfunction in Neuronal Degeneration and Cognitive Impairment)

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