The Effects of Physical Activity on Experimental Models of Vascular Dementia: A Systematic Review and Meta-Analysis.

Background: Physical activity is associated with improved brain health and cognition in humans. However, the validity, range, and quality of evidence for the beneficial outcomes linked to exercise in experimental models of vascular dementia (VaD) have not been evaluated. We performed a systematic review and meta-analysis of studies that assessed the effect of exercise intervention on models of VaD to provide an unbiased and comprehensive determination of the cognitive function and brain morphology benefits of exercise.

Selective deletion of interleukin-1 alpha in microglia does not modify acute outcome but regulates neurorepair processes after experimental ischemic stroke.

Inflammation is a key contributor to stroke pathogenesis and exacerbates brain damage leading to poor outcome. Interleukin-1 (IL-1) is an important regulator of post-stroke inflammation, and blocking its actions is beneficial in pre-clinical stroke models and safe in the clinical setting. However, the distinct roles of the two major IL-1 receptor type 1 agonists, IL-1α and IL-1β, and the specific role of IL-1α in ischemic stroke remain largely unknown.

Senescence and SASP Are Potential Therapeutic Targets for Ischemic Stroke.

Aging is a known co-morbidity of ischemic stroke with its risk and severity increasing every year past 55+. While many of the current stroke therapies have shown success in reducing mortality, post-stroke morbidity has not seen the same substantial reduction. Recently, the involvement of cellular senescence and SASP in brain injury and neurological degeneration has been recognized.

Prevalence of MTHFR Polymorphisms in Patients With Hypermobile Ehlers-Danlos Syndrome and Hypermobile Spectrum Disorders in a US Hypermobility Clinic.

Objective: Hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD) are characterized by joint hypermobility, joint subluxations and dislocations, hyperextensible skin, and chronic and progressive multiorgan comorbidities. Diagnosing hEDS and HSD is difficult because of variable phenotypes and unknown genetic etiology. In our clinic, we observed many patients with hEDS and HSD with a high serum level of unmetabolized folate, which suggests that hypermobility may be linked to methylenetetrahydrofolate reductase (MTHFR)-mediated folate metabolism.

Respiratory Syncytial Virus Infects Peripheral and Spinal Nerves and Induces Chemokine-Mediated Neuropathy.

Respiratory syncytial virus (RSV) primarily infects the respiratory epithelium, but growing evidence suggests that it may also be responsible for neurologic sequelae. In 3-dimensional microphysiologic peripheral nerve cultures, RSV infected neurons, macrophages, and dendritic cells along 2 distinct trajectories depending on the initial viral load. Low-level infection was transient, primarily involved macrophages, and induced moderate chemokine release with transient neural hypersensitivity.

Molecular interactions between perlecan LG3 and the SARS-CoV-2 spike protein receptor binding domain.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused a global health crisis with significant clinical morbidity and mortality. While angiotensin-converting enzyme 2 (ACE2) is the primary receptor for viral entry, other cell surface and extracellular matrix proteins may also bind to the viral receptor binding domain (RBD) within the SARS-CoV-2 spike protein. Recent studies have implicated heparan sulfate proteoglycans, specifically perlecan LG3, in facilitating SARS-CoV-2 binding to ACE2.

Jedi-1/MEGF12-mediated phagocytosis controls the pro-neurogenic properties of microglia in the ventricular-subventricular zone.

Microglia are the primary phagocytes in the central nervous system and clear dead cells generated during development or disease. The phagocytic process shapes the microglia phenotype, which affects the local environment. A unique population of microglia resides in the ventricular-subventricular zone (V-SVZ) of neonatal mice, but how they influence the neurogenic niche is not well understood.

Perlecan: a review of its role in neurologic and musculoskeletal disease.

Perlecan is a 500 kDa proteoglycan residing in the extracellular matrix of endothelial basement membranes with five distinct protein domains and three heparan sulfate chains. The complex structure of perlecan and the interaction it has with its local environment accounts for its various cellular and tissue-related effects, to include cartilage, bone, neural and cardiac development, angiogenesis, and blood brain barrier stability. As perlecan is a key contributor to extracellular matrix health involved in many tissues and processes throughout the body, dysregulation of perlecan has the potential to contribute to various neurological and musculoskeletal diseases.

Corrigendum to "Folate-dependent hypermobility syndrome: A proposed mechanism and diagnosis" [Heliyon 9 (4), (April 2023) Article e15387].

[This corrects the article DOI: 10.1016/j.heliyon.

Co-administration of extracellular matrix-based biomaterials with neural stem cell transplantation for treatment of central nervous system injury.

Injuries and disorders of the central nervous system (CNS) present a particularly difficult challenge for modern medicine to address, given the complex nature of the tissues, obstacles in researching and implementing therapies, and barriers to translating efficacious treatments into human patients. Recent advancements in neural stem cell (NSC) transplantation, endogenous neurogenesis, and reprogramming of non-neural cells into the neuronal lineage represent multiple approaches to resolving CNS injury. However, we propose that one practice that must be incorporated universally in neuroregeneration studies is the use of extracellular matrix (ECM)-mimicking biomaterials to supply the architectural support and cellular microenvironment necessary for partial or complete restoration of function.

VEGFA Isoforms as Pro-Angiogenic Therapeutics for Cerebrovascular Diseases.

Therapeutic angiogenesis has long been considered a viable treatment for vasculature disruptions, including cerebral vasculature diseases. One widely-discussed treatment method to increase angiogenesis is vascular endothelial growth factor (VEGF) A. In animal models, treatment with VEGFA proved beneficial, resulting in increased angiogenesis, increased neuronal density, and improved outcome.

Folate-dependent hypermobility syndrome: A proposed mechanism and diagnosis.

Hypermobility involves excessive flexibility and systemic manifestations of connective tissue fragility. We propose a folate-dependent hypermobility syndrome model based on clinical observations, and through a review of existing literature, we raise the possibility that hypermobility presentation may be dependent on folate status. In our model, decreased methylenetetrahydrofolate reductase (MTHFR) activity disrupts the regulation of the ECM-specific proteinase matrix metalloproteinase 2 (MMP-2), leading to high levels of MMP-2 and elevated MMP-2-mediated cleavage of the proteoglycan decorin.

Mouse Adapted SARS-CoV-2 Model Induces "Long-COVID" Neuropathology in BALB/c Mice.

The novel coronavirus SARS-CoV-2 has caused significant global morbidity and mortality and continues to burden patients with persisting neurological dysfunction. COVID-19 survivors develop debilitating symptoms to include neuro-psychological dysfunction, termed "Long COVID", which can cause significant reduction of quality of life. Despite vigorous model development, the possible cause of these symptoms and the underlying pathophysiology of this devastating disease remains elusive.

Jedi-1/MEGF12-mediated phagocytosis controls the pro-neurogenic properties of microglia in the ventricular-subventricular zone.

Microglia are the primary phagocytes in the central nervous system and are responsible for clearing dead cells generated during development or disease. The phagocytic process shapes the phenotype of the microglia, which affects the local environment. A unique population of microglia reside in the ventricular-subventricular zone (V-SVZ) of neonatal mice, but how they influence this neurogenic niche is not well-understood.

Effect of acetic acid inactivation of SARS-CoV-2.

Effective measures are needed to prevent the spread and infectivity of SARS-CoV-2 that causes COVID-19. Chemical inactivation may help to prevent the spread and transmission of this and other viruses. Hence, we tested the SARS-CoV-2 antiviral activity of acetic acid, the main component of vinegar, in vitro.

Bilateral Carotid Artery Stenosis and Cerebral Blood Flow Outcomes.

Bilateral carotid artery stenosis (BCAS) is a valid approach for modeling vascular dementia (VaD) in mice as it induces cerebral hypoperfusion and produces white matter degeneration and cognitive impairment. VaD is one of the major causes of cognitive impairment and currently has no approved therapy; hence its preclinical modeling is warranted for investigating potential therapeutic compounds. BCAS enables the characterization of brain pathology and associated cognitive phenotype of VaD.

Mouse Adapted SARS-CoV-2 (MA10) Viral Infection Induces Neuroinflammation in Standard Laboratory Mice.

Increasing evidence suggests that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection impacts neurological function both acutely and chronically, even in the absence of pronounced respiratory distress. Developing clinically relevant laboratory mouse models of the neuropathogenesis of SARS-CoV-2 infection is an important step toward elucidating the underlying mechanisms of SARS-CoV-2-induced neurological dysfunction. Although various transgenic models and viral delivery methods have been used to study the infection potential of SARS-CoV-2 in mice, the use of commonly available laboratory mice would facilitate the study of SARS-CoV-2 neuropathology.

The Potential Role of Integrin Signaling in Memory and Cognitive Impairment.

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.

Gabapentin Disrupts Binding of Perlecan to the αδ Voltage Sensitive Calcium Channel Subunit and Impairs Skeletal Mechanosensation.

Our understanding of how osteocytes, the principal mechanosensors within bone, sense and perceive force remains unclear. Previous work identified "tethering elements" (TEs) spanning the pericellular space of osteocytes and transmitting mechanical information into biochemical signals. While we identified the heparan sulfate proteoglycan perlecan (PLN) as a component of these TEs, PLN must attach to the cell surface to induce biochemical responses.

Recombinant Human Perlecan DV and Its LG3 Subdomain Are Neuroprotective and Acutely Functionally Restorative in Severe Experimental Ischemic Stroke.

Despite recent therapeutic advancements, ischemic stroke remains a major cause of death and disability. It has been previously demonstrated that  ~ 85-kDa recombinant human perlecan domain V (rhPDV) binds to upregulated integrin receptors (α2β1 and α5β1) associated with neuroprotective and functional improvements in various animal models of acute ischemic stroke. Recombinant human perlecan laminin-like globular domain 3 (rhPDV), a 21-kDa C-terminal subdomain of rhPDV, has been demonstrated to more avidly bind to the α2β1 integrin receptor than its parent molecule and consequently was postulated to evoke significant neuroprotective and functional effects.

Promising Cerebral Blood Flow Enhancers in Acute Ischemic Stroke.

Ischemic stroke presents a major global economic and public health burden. Although recent advances in available endovascular therapies show improved functional outcome, a good number of stroke patients are either ineligible or do not have access to these treatments. Also, robust collateral flow during acute ischemic stroke independently predicts the success of endovascular therapies and the outcome of stroke.

Amyloid [Formula: see text] (1-42) peptide impairs mitochondrial respiration in primary human brain microvascular endothelial cells: impact of dysglycemia and pre-senescence.

Diabetes increases the risk of Alzheimer's disease (AD). We investigated the impact of glucose concentrations on the β-amyloid (Aβ)-induced alteration of mitochondrial/cellular energetics in primary human brain microvascular endothelial cells (HBMECs). HBMECs were grown and passaged in media containing 15 mmol/l glucose (normal) based on which the glucose levels in the media were designated as high (25 mmol/L) or low (5 mmol/L).

T-Lymphocyte Interactions with the Neurovascular Unit: Implications in Intracerebral Hemorrhage.

In the pathophysiology of hemorrhagic stroke, the perturbation of the neurovascular unit (NVU), a functional group of the microvascular and brain intrinsic cellular components, is implicated in the progression of secondary injury and partially informs the ultimate patient outcome. Given the broad NVU functions in maintaining healthy brain homeostasis through its maintenance of nutrients and energy substrates, partitioning central and peripheral immune components, and expulsion of protein and metabolic waste, intracerebral hemorrhage (ICH)-induced dysregulation of the NVU directly contributes to numerous destructive processes in the post-stroke sequelae. In ICH, the damaged NVU precipitates the emergence and evolution of perihematomal edema as well as the breakdown of the blood-brain barrier structural coherence and function, which are critical facets during secondary ICH injury.