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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. Intravenous injection of green fluorescent protein (GFP) gene-loaded CAP-exosomes in mice transferred the GFP gene throughout the CNS as measured by monitoring brain sections for GFP expression with confocal microscopy. GFP gene transfer efficiency was at least 20-fold greater than that of the control Lamp2b-exosomes, and GFP gene transduction to mouse liver was low.
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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. To do this, we analyzed 2D and 3D images of hippocampal vasculature and hippocampal transcriptomic profiles of mice exposed to ALAN. ALAN reduced vascular density in the CA1 and CA2/3 of female mice and the dentate gyrus of male mice. Network structure and connectivity were also impaired in the CA2/3 of female mice. These results demonstrate the rapid and potent effects of ALAN on cerebrovascular networks, highlighting the importance of ALAN mitigation in the context of health and cerebrovascular disease.
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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. Several miRNAs, which include miR-146a, are elevated in the brain, CSF, and plasma of AD patients. miR-146a participates in pathways that regulate immune activation and has several mRNA targets which encode for proteins involved in cellular energy metabolism. An additional role for extracellular vesicles (EVs) has also emerged in the progression AD, as EVs can transfer functionally active proteins and RNAs from diseased to healthy cells. In the current study, we exposed various cell types present within the CNS to immunomodulatory molecules and observed significant upregulation of miR-146a expression, both within cells and within their secreted EVs. Further, we assessed the effects of miR-146a overexpression on bioenergetic function in primary rat glial cells and found significant reductions in oxidative phosphorylation and glycolysis. Lastly, we correlated miR-146a expression levels within various regions of the AD brain to disease staging and found significant, positive correlations. These novel results demonstrate that the modulation of miR-146a in response to neuroinflammatory stimuli may mediate the loss of mitochondrial integrity and function in cells, thereby contributing to the progression of beta-amyloid and tau pathology in the AD brain. Multiple inflammatory stimuli can upregulate miRNA-146a expression within neurons, mixed glial cells, and brain endothelial cells, which is either retained within these cells or released from them as extracellular vesicle cargo. The upregulation of miR-146a disrupts cellular bioenergetics in mixed glial cells. This mechanism may play a critical role in the neuroinflammatory response observed during Alzheimer's disease.
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Doença de Alzheimer , MicroRNAs , Animais , Ratos , Doença de Alzheimer/genética , Células Endoteliais , Imunomodulação , Metabolismo Energético , MicroRNAs/genéticaRESUMO
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. We used cerebrovascular corrosion cast and µCT imaging to evaluate the geometry, topology, and complexity of the angioarchitecture in the brain of wild type and 3xTg AD mice. We hypothesized that changes to the microvasculature occur early during the disease, and these early identifiable aberrations would be more prominent in the brain subregions implicated in the cognitive decline of AD. Whole-brain analysis of the angioarchitecture indicated early morphological abnormalities and degeneration of microvascular networks in 3xTg AD mice. Our analysis of the hippocampus and cortical subregions revealed microvascular degeneration with onset and progression that was subregion dependent.
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Envelhecimento/metabolismo , Envelhecimento/patologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Encéfalo/irrigação sanguínea , Microvasos/patologia , Placa Amiloide/metabolismo , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/psicologia , Animais , Encéfalo/diagnóstico por imagem , Cognição , Modelos Animais de Doenças , Progressão da Doença , Masculino , Camundongos Mutantes , Camundongos Transgênicos , Microvasos/diagnóstico por imagem , Microtomografia por Raio-XRESUMO
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. We have previously shown that administration of lipopolysaccharide (LPS) 30-minutes prior to stroke increases in infarct volume. In the current study, we found that animals intermittently exposed to LPS have larger cortical infarcts when compared to saline controls. To elucidate the mechanism behind this phenomenon, several avenues were investigated. We observed significant upregulation of tumor necrosis factor-alpha (TNF-α) mRNA, especially in the ipsilateral hemisphere of both saline and LPS exposed groups compared to sham surgery animals. We also observed significant reductions in expression of genes involved in autophagy in the ipsilateral hemisphere of LPS stroke animals. In addition, we assessed DNA methylation of autophagy genes and observed a significant increase in the ipsilateral hemisphere of LPS stroke animals. Intermittent exposure to LPS increases cortical infarct volume, downregulates autophagy genes, and induces hypermethylation of the corresponding CpG islands. These data suggest that intermittent immune activation may deregulate epigenetic mechanisms and promote neuropathological outcomes after stroke.
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Lipopolissacarídeos , Fator de Necrose Tumoral alfa , Animais , Autofagia , Infarto , Lipopolissacarídeos/toxicidade , RNA MensageiroRESUMO
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. In particular, a hierarchical three-dimensional nanostructure has been designed to create "hot spots", which can significantly amplify the SERS sensing signal, leading to high sensitivity. As a result, this PLFS has demonstrated a limit of detection (LOD) of 5.0 pg mL-1 toward detection of S-100ß, a traumatic brain injury (TBI) protein biomarker in blood plasma. The PLFS has been successfully used for rapid measurement of S-100ß in clinical TBI patient samples taken in the emergency department. Availability of PLFS for blood testing would shift the paradigm of TBI patient management and clinical outcome in emergency departments. It is expected that this type of PLFS can be adapted for rapid detection of various human diseases due to its capability of measuring a low level of protein blood biomarkers in complex human fluids.
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Técnicas Biossensoriais , Lesões Encefálicas Traumáticas , Biomarcadores , Humanos , Plasma , Subunidade beta da Proteína Ligante de Cálcio S100 , Análise Espectral RamanRESUMO
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. Electrochemiluminescence detection demonstrates that BR therapy reduces cytokine storm in plasma and ELISA demonstrates reduced levels of matrix metalloproteinase-9 (MMP-9) in the plasma and brains at different time points post-stroke. Further, we have demonstrated that the addition of MMP-9 to the blood diminishes the protective effect of the BR therapy. Our study is the first to show that BR therapy leads to profoundly improved stroke outcomes in mice and that the improved outcomes are mediated via MMP-9. These results offer new insights into the mechanisms of stroke damage.
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Substitutos Sanguíneos/uso terapêutico , Isquemia Encefálica/tratamento farmacológico , Encéfalo/metabolismo , Animais , Encéfalo/patologia , Infarto Encefálico/tratamento farmacológico , Isquemia Encefálica/patologia , Morte Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/complicações , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/metabolismo , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/patologiaRESUMO
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. Additionally, the dysregulation of MMPs has been implicated in the pathology of Alzheimer's disease (AD), where inhibiting the secretion of MMP-9 from astroglia reduces the proteolytic degradation of amyloid-beta. Thus, we hypothesize that exposure to MPA disrupts proteolytic degradation of amyloid-beta through the downregulation of MMP-9 expression and subsequent secretion. To assess the effect of progestins on MMP-9 and amyloid-beta, in vitro, C6 rat glial cells were exposed to MPA for 48 h and then the enzymatic, secretory, and amyloid-beta degrading capacity of MMP-9 was assessed from the conditioned culture medium. We found that MPA treatment inhibited transcription of MMP-9, which resulted in a subsequent decrease in the production and secretion of MMP-9 protein, in part through the glucocorticoid receptor. Additionally, we investigated the consequences of amyloid beta-degrading activity and found that MPA treatment decreased proteolytic degradation of amyloid-beta. Our results suggest MPA suppresses amyloid-beta degradation in an MMP-9-dependent manner, in vitro, and potentially compromises the clearance of amyloid-beta in vivo.
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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-ß 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. We present a mechanism for mitochondrial degeneration caused by the production of mitochondrial superoxide, which is driven by increased mitochondrial Ca2+ uptake. We found that persistent superoxide production injures mitochondria and disrupts electron transport in cerebrovascular endothelial cells. These observations provide a mechanism for the mitochondrial deficits that contribute to cerebrovascular dysfunction in patients with AD.
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Peptídeos beta-Amiloides/farmacologia , Cálcio/metabolismo , Células Endoteliais/metabolismo , Mitocôndrias/metabolismo , Fragmentos de Peptídeos/farmacologia , Superóxidos/metabolismo , Regulação para Cima/efeitos dos fármacos , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Linhagem Celular , Células Endoteliais/efeitos dos fármacos , Camundongos , Mitocôndrias/efeitos dos fármacos , Fosforilação Oxidativa , Espécies Reativas de Oxigênio/metabolismoRESUMO
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. After a stroke, a cascade of pathophysiological events results in the opening of the blood-brain barrier (BBB) through which further complications, disabilities, and mortality are likely to threaten the patient's health. Strikingly, tPA administration in eligible patients might cause hemorrhagic transformation and sustained damage to BBB integrity. One must, therefore, delineate upon stroke onset which cellular and molecular factors mediate BBB permeability as well as what key roles BBB rupture plays in the pathophysiology of stroke. In this review article, given our past findings of mechanisms underlying BBB opening in stroke animal models, we elucidate cellular, subcellular, and molecular factors involved in BBB permeability after ischemic stroke. The contribution of each factor to stroke severity and outcome is further discussed. Determinant factors in BBB permeability and stroke include mitochondria, miRNAs, matrix metalloproteinases (MMPs), immune cells, cytokines, chemokines, and adhesion proteins. Once these factors are interrogated and their roles in the pathophysiology of stroke are determined, novel targets for drug discovery and development can be uncovered in addition to novel therapeutic avenues for human stroke management.
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Barreira Hematoencefálica/metabolismo , Isquemia Encefálica/metabolismo , Permeabilidade Capilar/fisiologia , AVC Isquêmico/metabolismo , Animais , Barreira Hematoencefálica/diagnóstico por imagem , Barreira Hematoencefálica/imunologia , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/imunologia , Humanos , AVC Isquêmico/diagnóstico por imagem , AVC Isquêmico/imunologiaRESUMO
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. To investigate the role of miR-34a in a stroke, we purified primary cerebrovascular endothelial cells (pCECs) from mouse brains following 1 h transient middle cerebral artery occlusion (tMCAO) and measured real-time PCR to detect miR-34a levels. We demonstrate that the miR-34a levels are elevated in pCECs from tMCAO mice at the time point of BBB opening following 1 h tMCAO and reperfusion. Interestingly, knockout of miR-34a significantly reduces BBB permeability, alleviates disruption of tight junctions, and improves stroke outcomes compared to wild-type (WT) controls. CYC is decreased in the ischemic hemispheres and pCECs from WT but not in miR-34a-/- mice following stroke reperfusion. We further confirmed CYC is a target of miR-34a by a dural luciferase reporter gene assay in vitro. Our study provides the first description of miR-34a affecting stroke outcomes and may lead to discovery of new mechanisms and treatments for cerebrovascular and neurodegenerative diseases such as stroke.
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Citocromos c/metabolismo , MicroRNAs/metabolismo , Acidente Vascular Cerebral/genética , Animais , Barreira Hematoencefálica/patologia , Isquemia Encefálica/genética , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Junções Íntimas/metabolismo , Resultado do TratamentoRESUMO
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-ß oligomers. The present study characterized mitochondrial movement, number, and structure in 3xTg-AD primary cortical neurons and non-transgenic (nonTg) controls. We found a significant reduction in mitochondrial number and movement in 3xTg-AD primary cortical neurons with modest structural changes. Additionally, application of the sigma-1 receptor agonist, (+)SKF-10,047, markedly increased mitochondrial movement in both 3xTg-AD and nonTg primary cortical cultures after one hour of treatment. (+)SKF-10,047 also led to a trend of increased mitochondrial number in 3xTg-AD cultures. Embryonic mitochondrial movement and number deficits could be among the key steps in the early pathogenesis of AD that compromise cognitive or metabolic reserve, and amelioration of these deficits could be a promising area for further preclinical and clinical study.
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Doença de Alzheimer/metabolismo , Córtex Cerebral/metabolismo , Mitocôndrias/metabolismo , Neurônios/metabolismo , Doença de Alzheimer/patologia , Animais , Córtex Cerebral/patologia , Modelos Animais de Doenças , Camundongos , Camundongos Transgênicos , Mitocôndrias/patologia , Dinâmica Mitocondrial/fisiologia , Neurônios/patologiaRESUMO
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. In addition, several of these hallmarks are increasingly being associated with acute brain injury conditions. In this review, we consider the genes and their functional pathways involved in brain aging as a means of developing new strategies for therapies targeted to the neuropathological processes themselves, but also as targets for many age-related brain diseases. A single microRNA (miR), which is a short, non-coding RNA species, has the potential for targeting many genes simultaneously and, like practically all other cellular processes, genes associated with many features of brain aging and injury are regulated by miRs. We highlight how certain miRs can mediate deregulation of genes involved in neuroinflammation, acute neuronal injury and chronic neurodegenerative diseases. Finally, we review the recent progress in the development of effective strategies to block specific miR functions and discuss future approaches with the prediction that anti-miR drugs may soon be used in the clinic.
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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 ß (Aß) plaques, neurofibrillary tangles, and widespread cell death], AD is characterized by chronic neuroinflammation and mitochondrial dysfunction. In the current study, we sought to better understand the role of tumor necrosis factor-alpha (TNF-α), known to be involved in inflammation, in mediating alterations in mitochondrial function and EV secretion. Using an immortalized hippocampal cell line, we observed significant reductions in several parameters of mitochondrial oxygen consumption after a 24-h exposure period to TNF-α. In addition, after TNF-α exposure we also observed significant upregulation of two microRNAs (miRNAs; miR-34a and miR-146a) associated with mitochondrial dysfunction in secreted EVs. Despite this, when naïve cells are exposed to EVs isolated from TNF-α treated cells, mitochondrial respiration, proton leak, and reactive oxygen species (ROS) production are all significantly increased. Collectively these data indicate that a potent proinflammatory cytokine, TNF-α, induces significant mitochondrial dysfunction in a neuronal cell type, in part via the secretion of EVs, which significantly alter mitochondrial activity in recipient cells.
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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. However, the cell-extrinsic role of the UPR under physiological and pathological states in the CNS remains to be elucidated. To begin to address this, we evaluated if transferring conditioned media between ER-stressed astrocytes and neurons could modulate their functional characteristics. Our results indicate that ER-stressed astrocytes and neurons secrete a molecule(s) with lipid characteristics which regulates both inflammatory and ER stress responses in other astrocytes, neurons, and microglia in vitro. Initial exposure to this stress factor(s) confers resistance against subsequent ER stress to neurons. However, persistent exposure to this unidentified mediator(s) suppresses the initial protective effect and becomes cytotoxic. Overall, these findings provide insight into the cell non-autonomous influence of ER stress on cells of the central nervous system. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.
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Astrócitos/fisiologia , Encéfalo/fisiologia , Comunicação Celular/fisiologia , Estresse do Retículo Endoplasmático/fisiologia , Neurônios/fisiologia , Animais , Astrócitos/efeitos dos fármacos , Células Cultivadas , Meios de Cultivo Condicionados/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Resposta a Proteínas não Dobradas/fisiologiaRESUMO
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. We hypothesize that during metabolic distress in astrocytes; mitochondrial networks undergo a shift in fission-fusion dynamics that results in a change in the morphometric state of the entire mitochondrial network. This mitochondrial network shift may be protective during metabolic distress by priming mitochondrial size and facilitating mitophagy. We demonstrated that hypoxia and post-hypoxia reoxygenation of rat primary astrocytes results in a redistribution of mitochondria to smaller sizes evoked by increased mitochondrial fission. Excessive mitochondrial fission corresponded to Drp-1 dephosphorylation at Ser 637, which preceded mitophagy of relatively small mitochondria. Reoxygenation of astrocytes marked the initiation of elevated mitophagic activity primarily reserved to the perinuclear region where a large number of the smallest mitochondria occurred. Although, during hypoxia astrocytic ATP content was severely reduced, after reoxygenation ATP content returned to near normoxic values and these changes mirrored mitochondrial superoxide production. Concomitant with these changes in astrocytic mitochondria, the number of astrocytic extensions declined only after 10-hours post-hypoxic reoxygenation. Overall, we posit a drastic mitochondrial network change that is triggered by a metabolic crisis during hypoxia; these changes are followed by mitochondrial degradation and retraction of astrocytic extensions during reoxygenation.
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Astrócitos/metabolismo , Mitocôndrias/metabolismo , Dinâmica Mitocondrial , Mitofagia , Oxigênio/metabolismo , Animais , Astrócitos/patologia , Hipóxia Celular , Células Cultivadas , Dinaminas/metabolismo , Mitocôndrias/patologia , Proteínas Mitocondriais/metabolismo , Oxigênio/farmacologia , RatosRESUMO
Metabolic syndrome is a cluster of cardiovascular risk factors associated with a prothrombotic, proinflammatory and hypofibrinolysis state. Although resistance to tissue plasminogen activator (tPA) in metabolic syndrome patients has been associated with a defective fibrinolytic system, the factors and mechanisms underlining such resistance is unclear. While there is a great debate on proposed mechanisms, fundamental questions regarding resistance to tPA in metabolic syndrome patients with ischemic stroke remain unanswered. This article reviews articles and documents published between 2001 and 2017, and provides an overview of metabolic syndrome, factors associated with tPA resistance in metabolic syndrome, conflicting evidence of insufficient dosing of tPA in overweight/obese patients and future directions for research.
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Resistência a Medicamentos/fisiologia , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/fisiopatologia , Terapia Trombolítica , Ativador de Plasminogênio Tecidual/uso terapêutico , Resistência a Medicamentos/efeitos dos fármacos , Fibrinolíticos/uso terapêutico , Humanos , Síndrome Metabólica/complicações , Obesidade/complicações , Sobrepeso/complicações , Ativador de Plasminogênio Tecidual/administração & dosagemRESUMO
Aging of the nervous system, and the occurrence of age-related brain diseases such as stroke, are associated with changes to a variety of cellular processes controlled by many distinct genes. MicroRNAs (miRNAs), short non-coding functional RNAs that can induce translational repression or site-specific cleavage of numerous target mRNAs, have recently emerged as important regulators of cellular senescence, aging, and the response to neurological insult. Here, we focused on the assessment of the role of miR-34a in stroke. We noted increases in miR-34a expression in the blood of stroke patients as well as in blood and brain of mice subjected to experimental stroke. Our methodical genetic manipulation of miR-34a expression substantially impacted stroke-associated preclinical outcomes and we have in vitro evidence that these changes may be driven at least in part by disruptions to blood brain barrier integrity and mitochondrial oxidative phosphorylation in endothelial cells. Finally, aging, independent of brain injury, appears to be associated with shifts in circulating miRNA profiles. Taken together, these data support a role for miRNAs, and specifically miR-34a, in brain aging and the physiological response to age-related neurological insult, and lay the groundwork for future investigation of this novel therapeutic target.