Brain-Wide Transgene Expression in Mice by Systemic Injection of Genetically Engineered Exosomes: CAP-Exosomes.

The bottleneck in drug discovery for central nervous system diseases is the absence of effective systemic drug delivery technology for delivering therapeutic drugs into the brain. Despite the advances in the technology used in drug discovery, such as Adeno-Associated Virus (AAV) vectors, the development of drugs for central nervous system diseases remains challenging. In this manuscript, we describe, for the first time, the development of a workflow to generate a novel brain-targeted drug delivery system that involves the generation of genetically engineered exosomes by first selecting various functional AAV capsid-specific peptides (collectively called CAPs) known to be involved in brain-targeted high-expression gene delivery, and then expressing the CAPs in frame with lysosome-associated membrane glycoprotein (Lamp2b) followed by expressing CAP-Lamp2b fusion protein on the surface of mesenchymal stem cell-derived exosomes, thus generating CAP-exosomes.

Acute exposure to artificial light at night alters hippocampal vascular structure in mice.

The structure and function of the cardiovascular system are modulated across the day by circadian rhythms, making this system susceptible to circadian rhythm disruption. Recent evidence demonstrated that short-term exposure to a pervasive circadian rhythm disruptor, artificial light at night (ALAN), increased inflammation and altered angiogenic transcripts in the hippocampi of mice. Here, we examined the effects of four nights of ALAN exposure on mouse hippocampal vascular networks.

Intermittent systemic exposure to lipopolysaccharide-induced inflammation disrupts hippocampal long-term potentiation and impairs cognition in aging male mice.

Age-related cognitive decline, a common component of the brain aging process, is associated with significant impairment in daily functioning and quality of life among geriatric adults. While the complexity of mechanisms underlying cognitive aging are still being elucidated, microbial exposure and the multifactorial inflammatory cascades associated with systemic infections are emerging as potential drivers of neurological senescence. The negative cognitive and neurobiological consequences of a single pathogen-associated inflammatory experience, such as that modeled through treatment with lipopolysaccharide (LPS), are well documented.

Spatiotemporal Correlation Analysis of Hydraulic Fracturing and Stroke in the United States.

Hydraulic fracturing or fracking has led to a rapid growth of oil and gas production in the United States, but the impact of fracking on public health is an important but underresearched topic. We designed a methodology to study spatiotemporal correlations between the risk of fracking and stroke mortality. An annualized loss expectancy (ALE) model is applied to quantify the risk of fracking.

Extended Interval Aminoglycoside Treatment for Endocarditis in an Extremely Low Birth Weight Neonate.

Infective endocarditis (IE) in neonates is associated with high mortality and incidence has been increasing over the past two decades. The majority of very low birth weight infants will be treated with at least one nephrotoxic medication during their hospital course. Over one-quarter of very low birth weight neonates exposed to gentamicin may develop acute kidney injury (AKI); this is particularly worrisome as AKI is an independent factor associated with increased neonatal mortality and increased length of stay.

Microvascular degeneration occurs before plaque onset and progresses with age in 3xTg AD mice.

Heart disease and vascular disease positively correlate with the incidence of Alzheimer's disease (AD). Although there is ostensible involvement of dysfunctional cerebrovasculature in AD pathophysiology, the characterization of the specific changes and development of vascular injury during AD remains unclear. In the present study, we established a time-course for the structural changes and degeneration of the angioarchitecture in AD.

miR-146a Dysregulates Energy Metabolism During Neuroinflammation.

Alzheimer's disease (AD) and other neurodegenerative diseases are characterized by chronic neuroinflammation and a reduction in brain energy metabolism. An important role has emerged for small, non-coding RNA molecules known as microRNAs (miRNAs) in the pathophysiology of many neurodegenerative disorders. As epigenetic regulators, miRNAs possess the capacity to regulate and fine tune protein production by inhibiting translation.

The Mitochondrial mitoNEET Ligand NL-1 Is Protective in a Murine Model of Transient Cerebral Ischemic Stroke.

Purpose: Therapeutic strategies to treat ischemic stroke are limited due to the heterogeneity of cerebral ischemic injury and the mechanisms that contribute to the cell death. Since oxidative stress is one of the primary mechanisms that cause brain injury post-stroke, we hypothesized that therapeutic targets that modulate mitochondrial function could protect against reperfusion-injury after cerebral ischemia, with the focus here on a mitochondrial protein, mitoNEET, that modulates cellular bioenergetics.

Method: In this study, we evaluated the pharmacology of the mitoNEET ligand NL-1 in an in vivo therapeutic role for NL-1 in a C57Bl/6 murine model of ischemic stroke.

IL-1β Antibody Protects Brain from Neuropathology of Hypoperfusion.

Chronic brain hypoperfusion is the primary cause of vascular dementia and has been implicated in the development of white matter disease and lacunar infarcts. Cerebral hypoperfusion leads to a chronic state of brain inflammation with immune cell activation and production of pro-inflammatory cytokines, including IL-1β. In the present study, we induced chronic, progressive brain hypoperfusion in mice using ameroid constrictor, arterial stenosis (ACAS) surgery and tested the efficacy of an IL-1β antibody on the resulting brain damage.

Intermittent Lipopolysaccharide Exposure Significantly Increases Cortical Infarct Size and Impairs Autophagy.

Globally, stroke is a leading cause of death and disability. Traditional risk factors like hypertension, diabetes, and obesity do not fully account for all stroke cases. Recent infection is regarded as changes in systemic immune signaling, which can increase thrombosis formation and other stroke risk factors.

A "hot Spot"-Enhanced paper lateral flow assay for ultrasensitive detection of traumatic brain injury biomarker S-100β in blood plasma.

Currently colorimetric paper lateral flow strips (PLFS) encounter two major limitations, that is, low sensitivity and severe interference from complex sample matrices such as blood. These shortcomings limit their application in detection of low-concentration analytes in complex samples. To solve these problems, a PLFS has been developed by utilizing surface-enhanced Raman scattering (SERS) for sensing signal transduction.

Blood substitution therapy rescues the brain of mice from ischemic damage.

Acute stroke causes complex, pathological, and systemic responses that have not been treatable by any single medication. In this study, using a murine transient middle cerebral artery occlusion stroke model, a novel therapeutic strategy is proposed, where blood replacement (BR) robustly reduces infarctions and improves neurological deficits in mice. Our analyses of immune cell subsets suggest that BR therapy substantially decreases neutrophils in blood following a stroke.

Medroxyprogesterone Acetate Impairs Amyloid Beta Degradation in a Matrix Metalloproteinase-9 Dependent Manner.

Despite the extensive use of hormonal methods as either contraception or menopausal hormone therapy (HT), there is very little known about the potential effects of these compounds on the cellular processes of the brain. Medroxyprogesterone Acetate (MPA) is a progestogen used globally in the hormonal contraceptive, Depo Provera, by women in their reproductive prime and is a major compound found in HT formulations used by menopausal women. MPA promotes changes in the circulating levels of matrix metalloproteinases (MMPs), such as MMP-9, in the endometrium, yet limited literature studying the effects of MPA on neurons and astroglia cells has been conducted.

Mechanisms in blood-brain barrier opening and metabolism-challenged cerebrovascular ischemia with emphasis on ischemic stroke.

Stroke is the leading cause of disability among adults as well as the 2nd leading cause of death globally. Ischemic stroke accounts for about 85% of strokes, and currently, tissue plasminogen activator (tPA), whose therapeutic window is limited to up to 4.5 h for the appropriate population, is the only FDA approved drug in practice and medicine.

Amyloid-β Causes Mitochondrial Dysfunction via a Ca2+-Driven Upregulation of Oxidative Phosphorylation and Superoxide Production in Cerebrovascular Endothelial Cells.

Cerebrovascular pathology is pervasive in Alzheimer's disease (AD), yet it is unknown whether cerebrovascular dysfunction contributes to the progression or etiology of AD. In human subjects and in animal models of AD, cerebral hypoperfusion and hypometabolism are reported to manifest during the early stages of the disease and persist for its duration. Amyloid-β is known to cause cellular injury in both neurons and endothelial cells by inducing the production of reactive oxygen species and disrupting intracellular Ca2+ homeostasis.

MiR-34a Interacts with Cytochrome c and Shapes Stroke Outcomes.

Blood-brain barrier (BBB) dysfunction occurs in cerebrovascular diseases and neurodegenerative disorders such as stroke. Opening of the BBB during a stroke has a negative impact on acute outcomes. We have recently demonstrated that miR-34a regulates the BBB by targeting cytochrome c (CYC) in vitro.

The cerebral angiome: High resolution MicroCT imaging of the whole brain cerebrovasculature in female and male mice.

The cerebrovascular system provides crucial functions that maintain metabolic and homeostatic states of the brain. Despite its integral role of supporting cerebral viability, the topological organization of these networks remains largely uncharacterized. This void in our knowledge surmises entirely from current technological limitations that prevent the capturing of data through the entire depth of the brain.

Over-expression of miR-34a induces rapid cognitive impairment and Alzheimer's disease-like pathology.

Autosomal dominant Alzheimer disease (AD) is caused by rare mutations in one of three specific genes. This is in contrast to idiopathic, late-onset AD (LOAD), which has a more polygenetic risk profile and represents more than 95% of cases. Previously, we have demonstrated that increased expression of microRNA (miRNA)-34a (miR-34a) in AD brain targets genes linked to synaptic plasticity, energy metabolism, and resting state network activity.

Mitochondrial Movement and Number Deficits in Embryonic Cortical Neurons from 3xTg-AD Mice.

Mitochondrial dysfunction is often found in Alzheimer's disease (AD) patients and animal models. Clinical severity of AD is linked to early deficiencies in cognitive function and brain metabolism, indicating that pathological changes may begin early in life. Previous studies showed decreased mitochondrial function in primary hippocampal neurons from triple-transgenic Alzheimer's disease (3xTg-AD) mice and mitochondrial movement and structure deficits in primary neurons exposed to amyloid-β oligomers.

MicroRNAs and the Genetic Nexus of Brain Aging, Neuroinflammation, Neurodegeneration, and Brain Trauma.

Aging is a complex and integrated gradual deterioration of cellular activities in specific organs of the body, which is associated with increased mortality. This deterioration is the primary risk factor for major human pathologies, including cancer, diabetes, cardiovascular disorders, neurovascular disorders, and neurodegenerative diseases. There are nine tentative hallmarks of aging.

Extracellular Vesicles Secreted in Response to Cytokine Exposure Increase Mitochondrial Oxygen Consumption in Recipient Cells.

Extracellular vesicles (EVs) are small, membrane-bound nanoparticles released from most, if not all cells, and can carry functionally active cargo (proteins, nucleic acids) which can be taken up by neighboring cells and mediate physiologically relevant effects. In this capacity, EVs are being regarded as novel cell-to-cell communicators, which may play important roles in the progression of neurodegenerative diseases, like Alzheimer's disease (AD). Aside from the canonical physical hallmarks of this disease [amyloid β (Aβ) plaques, neurofibrillary tangles, and widespread cell death], AD is characterized by chronic neuroinflammation and mitochondrial dysfunction.

Hypoxia-reoxygenation of primary astrocytes results in a redistribution of mitochondrial size and mitophagy.

Astrocytes serve to maintain proper neuronal function and support neuronal viability, but remain largely understudied in research of cerebral ischemia. Astrocytic mitochondria are core participants in the metabolic activity of astrocytes. The objective of this study is to assess astrocyte mitochondrial competence during hypoxia and post-hypoxia reoxygenation and to determine cellular adaptive and pathological changes in the mitochondrial network.

Endoplasmic reticulum stress is transmissible in vitro between cells of the central nervous system.

Improper protein folding and trafficking are common pathological events in neurodegenerative diseases that result in the toxic accumulation of misfolded proteins within the lumen of the endoplasmic reticulum (ER). While low-level stimulation of the unfolded protein response (UPR) is protective, sustained UPR activation resulting from prolonged ER stress can promote neurotoxicity. The cell-autonomous mechanisms of the UPR have been extensively characterized.