Search

While cardiovascular disease, cancer, and human immunodeficiency virus (HIV) mortality rates have decreased over the past 20 years, Alzheimer’s Disease (AD) deaths have risen by 145% since 2010. Despite significant research efforts, effective AD treatments remain elusive due to a poorly defined etiology and difficulty in targeting events that occur too downstream of disease onset. In hopes of elucidating alternative treatment pathways, now, AD is commonly being more broadly defined not only as a neurological disorder but also as a progression of a variety of cerebrovascular pathologies highlighted by the breakdown of the blood-brain barrier. The endothelial glycocalyx (GCX), which is an essential regulator of vascular physiology, plays a crucial role in the function of the neurovascular system, acting as an essential vascular mechanotransducer to facilitate ultimate blood-brain homeostasis. Shedding of the cerebrovascular GCX could be an early indication of neurovascular dysfunction and may subsequently progress neurodegenerative diseases like AD. Recent advances in in vitro modeling, gene/ protein silencing, and imaging techniques offer new avenues of scrutinizing the GCX’s effects on AD-related neurovascular pathology. Initial studies indicate GCX degradation in AD and other neurodegenerative diseases and have begun to demonstrate a possible link to GCX loss and cerebrovascular dysfunction. This review will scrutinize the GCX’s contribution to known vascular etiologies of AD and propose future work aimed at continuing to uncover the relationship between GCX dysfunction and eventual AD-associated neurological deterioration. [ABSTRACT FROM AUTHOR]

While cardiovascular disease, cancer, and human immunodeficiency virus (HIV) mortality rates have decreased over the past 20 years, Alzheimer’s Disease (AD) deaths have risen by 145% since 2010. Despite significant research efforts, effective AD treatments remain elusive due to a poorly defined etiology and difficulty in targeting events that occur too downstream of disease onset. In hopes of elucidating alternative treatment pathways, now, AD is commonly being more broadly defined not only as a neurological disorder but also as a progression of a variety of cerebrovascular pathologies highlighted by the breakdown of the blood-brain barrier. The endothelial glycocalyx (GCX), which is an essential regulator of vascular physiology, plays a crucial role in the function of the neurovascular system, acting as an essential vascular mechanotransducer to facilitate ultimate blood-brain homeostasis. Shedding of the cerebrovascular GCX could be an early indication of neurovascular dysfunction and may subsequently progress neurodegenerative diseases like AD. Recent advances in in vitro modeling, gene/protein silencing, and imaging techniques offer new avenues of scrutinizing the GCX’s effects on AD-related neurovascular pathology. Initial studies indicate GCX degradation in AD and other neurodegenerative diseases and have begun to demonstrate a possible link to GCX loss and cerebrovascular dysfunction. This review will scrutinize the GCX’s contribution to known vascular etiologies of AD and propose future work aimed at continuing to uncover the relationship between GCX dysfunction and eventual AD-associated neurological deterioration.

Acquired brain injury (ABI) is the most common disease of the nervous system, involving complex pathological processes, which often leads to a series of nervous system disorders. The structural destruction and dysfunction of the Neurovascular Unit (NVU) are prominent features of ABI. Therefore, understanding the molecular mechanism underlying NVU destruction and its reconstruction is the key to the treatment of ABI. SUMOylation is a protein post-translational modification (PTM), which can degrade and stabilize the substrate dynamically, thus playing an important role in regulating protein expression and biological signal transduction. Understanding the regulatory mechanism of SUMOylation can clarify the molecular mechanism of the occurrence and development of neurovascular dysfunction after ABI and is expected to provide a theoretical basis for the development of potential treatment strategies. This article reviews the role of SUMOylation in vascular events related to ABI, including NVU dysfunction and vascular remodeling, and puts forward therapeutic prospects. [ABSTRACT FROM AUTHOR]

Diabetes is a major risk factor for compromised visual health, leading to retinal vasculopathy and neuropathy, both of which are hallmarks of neurovascular unit dysfunction. Despite the critical impact of diabetic retinopathy, the precise mechanism underlying neurovascular coupling and effective strategies to suppress neurovascular dysfunction remain unclear. In this study, the up-regulation of a tRNA-derived stress-induced RNA, 5'tiRNA-His-GTG, in response to diabetic stress is revealed. 5'tiRNA-His-GTG directly regulates Müller glia action and indirectly alters endothelial angiogenic effects and retinal ganglion cell (RGC) survival in vitro. Downregulation of 5'tiRNA-His-GTG alleviates diabetes-induced retinal neurovascular dysfunction, characterized by reduced retinal vascular dysfunction, decreased retinal neurodegeneration, and improved visually-guided behaviors in vivo. Mechanistically, 5'tiRNA-His-GTG acts as a key regulator of retinal neurovascular dysfunction, primarily by modulating arachidonic acid (AA) metabolism via the CYPs pathway. The 5'tiRNA-His-GTG-CYP2E1-19(S)-HETE signaling axis is identified as a key driver of retinal neurovascular dysfunction. Thus, targeting 5'tiRNA-His-GTG presents a promising therapeutic strategy for treating vasculopathy and neuropathy associated with diabetes mellitus. Modulating this novel signaling pathway can open up new avenues for intervention in diabetic retinopathy and its related complications., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Border-associated macrophages (BAMs) constitute a highly heterogeneous group of central nervous system-resident macrophages at the brain boundaries. Despite their significance, BAMs have mainly been overlooked compared to microglia, resulting in a limited understanding of their functions. However, recent advancements in single-cell immunophenotyping and transcriptomic analyses of BAMs have revealed a previously unrecognized complexity in these cells, in addition to their critical roles under non-pathological conditions and diseases like Alzheimer's disease (AD), Parkinson's disease, glioma, and ischemic stroke. In this review, we discuss the origins, self-renewal capabilities, and extensive heterogeneity of BAMs, and clarify their important physiological functions such as immune monitoring, waste removal and vascular permeability regulation. We also summarize experimental evidence linking BAMs to the progression of AD. Finally, we review therapeutic strategies targeting brain innate immune cells mainly focusing on strategies aimed at modulating BAMs to treat AD and evaluate their potential in clinical applications. • High heterogeneity exists among distinct subsets of border-associated macrophages. • border-associated macrophages exert unique functions in border immunity. • Perivascular macrophages lead to neurovascular dysfunction in AD. • Therapies targeting border-associated macrophages hold great potential. [ABSTRACT FROM AUTHOR]

Chronic neuromicrovascular dysfunction and its induced multifaceted neuropathology involving the interaction of cellular differential pathogenic mechanisms pose challenges to the precise treatment of Alzheimer's disease (AD). Here we report the development of an ellagic acid-derived self-assembled micellar SIRT1 activator (REn) that enables cross-scale targeted remodeling of neurovascular and neurometabolic coupling in AD. Efficient transcytosis of the receptor for advanced glycation endproducts by modified peptides allows for programmed delivery of REn to cerebral microvessels and parenchymal neurons. The resulting SIRT1 cascade activation enhances endothelial nitric oxide signaling-mediated cerebral blood flow and the blood-brain barrier integrity, while promoting neuronal mitochondrial biogenesis and glucose metabolic patterns toward oxidative phosphorylation. This multipronged remodeling strategy achieves a cooperative normalization of brain energy supply and β-amyloid clearance in AD mice, showing profound improvement in cognitive impairment. This work provides an advanced pharmacological option for cross-scale targeted treatment of neurodegenerative diseases associated with neurovascular dysfunction. [Display omitted] • Natural self-assembled SIRT1 activator is developed for cross-scale AD treatment. • REn is programmed to be delivered to cerebral microvessels and parenchymal neurons. • REn activates endothelial SIRT1 to repair neurovascular dysfunction. • REn activates neuronal SIRT1 to improve brain metabolism dyshomeostasis. • REn remodels neurovascular and neurometabolic coupling against AD. [ABSTRACT FROM AUTHOR]

Alzheimer's disease and related dementias (ADRD) are an expanding worldwide crisis. In the absence of scientific breakthroughs, the global prevalence of ADRD will continue to increase as more people are living longer. Racial or ethnic minority groups have an increased risk and incidence of ADRD and have often been neglected by the scientific research community. There is mounting evidence that vascular insults in the brain can initiate a series of biological events leading to neurodegeneration, cognitive impairment, and ADRD. We are a group of researchers interested in developing and expanding ADRD research, with an emphasis on vascular contributions to dementia, to serve our local diverse community. Toward this goal, the primary objective of this review was to investigate and better understand health disparities in Alabama and the contributions of the social determinants of health to those disparities, particularly in the context of vascular dysfunction in ADRD. Here, we explain the neurovascular dysfunction associated with Alzheimer's disease (AD) as well as the intrinsic and extrinsic risk factors contributing to dysfunction of the neurovascular unit (NVU). Next, we ascertain ethnoregional health disparities of individuals living in Alabama, as well as relevant vascular risk factors linked to AD. We also discuss current pharmaceutical and non-pharmaceutical treatment options for neurovascular dysfunction, mild cognitive impairment (MCI) and AD, including relevant studies and ongoing clinical trials. Overall, individuals in Alabama are adversely affected by social and structural determinants of health leading to health disparities, driven by rurality, ethnic minority status, and lower socioeconomic status (SES). In general, these communities have limited access to healthcare and healthy food and other amenities resulting in decreased opportunities for early diagnosis of and pharmaceutical treatments for ADRD. Although this review is focused on the current state of health disparities of ADRD patients in Alabama, future studies must include diversity of race, ethnicity, and region to best be able to treat all individuals affected by ADRD. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common form of dementia. It was first described more than a century ago, and scientists are acquiring new data and learning novel information about the disease every day. Although there are nuances and details continuously being unraveled, many key players were identified in the early 1900's by Dr. Oskar Fischer and Dr. Alois Alzheimer, including amyloid-beta (Aβ), tau, vascular abnormalities, gliosis, and a possible role of infections. More recently, there has been growing interest in and appreciation for neurovascular unit dysfunction that occurs early in mild cognitive impairment (MCI) before and independent of Aβ and tau brain accumulation. In the last decade, evidence that Aβ and tau oligomers are antimicrobial peptides generated in response to infection has expanded our knowledge and challenged preconceived notions. The concept that pathogenic germs cause infections generating an innate immune response (e.g., Aβ and tau produced by peripheral organs) that is associated with incident dementia is worthwhile considering in the context of sporadic AD with an unknown root cause. Therefore, the peripheral amyloid hypothesis to cognitive impairment and AD is proposed and remains to be vetted by future research. Meanwhile, humans remain complex variable organisms with individual risk factors that define their immune status, neurovascular function, and neuronal plasticity. In this focused review, the idea that infections and organ dysfunction contribute to Alzheimer's disease, through the generation of peripheral amyloids and/or neurovascular unit dysfunction will be explored and discussed. Ultimately, many questions remain to be answered and critical areas of future exploration are highlighted. [ABSTRACT FROM AUTHOR]

Alzheimer’s disease and related dementias (ADRD) are an expanding worldwide crisis. In the absence of scientific breakthroughs, the global prevalence of ADRD will continue to increase as more people are living longer. Racial or ethnic minority groups have an increased risk and incidence of ADRD and have often been neglected by the scientific research community. There is mounting evidence that vascular insults in the brain can initiate a series of biological events leading to neurodegeneration, cognitive impairment, and ADRD. We are a group of researchers interested in developing and expanding ADRD research, with an emphasis on vascular contributions to dementia, to serve our local diverse community. Toward this goal, the primary objective of this review was to investigate and better understand health disparities in Alabama and the contributions of the social determinants of health to those disparities, particularly in the context of vascular dysfunction in ADRD. Here, we explain the neurovascular dysfunction associated with Alzheimer’s disease (AD) as well as the intrinsic and extrinsic risk factors contributing to dysfunction of the neurovascular unit (NVU). Next, we ascertain ethnoregional health disparities of individuals living in Alabama, as well as relevant vascular risk factors linked to AD. We also discuss current pharmaceutical and non-pharmaceutical treatment options for neurovascular dysfunction, mild cognitive impairment (MCI) and AD, including relevant studies and ongoing clinical trials. Overall, individuals in Alabama are adversely affected by social and structural determinants of health leading to health disparities, driven by rurality, ethnic minority status, and lower socioeconomic status (SES). In general, these communities have limited access to healthcare and healthy food and other amenities resulting in decreased opportunities for early diagnosis of and pharmaceutical treatments for ADRD. Although this review is focused on the current state of health disparities of ADRD patients in Alabama, future studies must include diversity of race, ethnicity, and region to best be able to treat all individuals affected by ADRD.

Alzheimer’s disease (AD) is the most common form of dementia. It was first described more than a century ago, and scientists are acquiring new data and learning novel information about the disease every day. Although there are nuances and details continuously being unraveled, many key players were identified in the early 1900’s by Dr. Oskar Fischer and Dr. Alois Alzheimer, including amyloid-beta (Aβ), tau, vascular abnormalities, gliosis, and a possible role of infections. More recently, there has been growing interest in and appreciation for neurovascular unit dysfunction that occurs early in mild cognitive impairment (MCI) before and independent of Aβ and tau brain accumulation. In the last decade, evidence that Aβ and tau oligomers are antimicrobial peptides generated in response to infection has expanded our knowledge and challenged preconceived notions. The concept that pathogenic germs cause infections generating an innate immune response (e.g., Aβ and tau produced by peripheral organs) that is associated with incident dementia is worthwhile considering in the context of sporadic AD with an unknown root cause. Therefore, the peripheral amyloid hypothesis to cognitive impairment and AD is proposed and remains to be vetted by future research. Meanwhile, humans remain complex variable organisms with individual risk factors that define their immune status, neurovascular function, and neuronal plasticity. In this focused review, the idea that infections and organ dysfunction contribute to Alzheimer’s disease, through the generation of peripheral amyloids and/or neurovascular unit dysfunction will be explored and discussed. Ultimately, many questions remain to be answered and critical areas of future exploration are highlighted.

Traumatic brain injuries (TBI) often involve vascular dysfunction that leads to long-term alterations in physiological and cognitive functions of the brain. Indeed, all the cells that form blood vessels and that are involved in maintaining their proper function can be altered by TBI. This Review focuses on the different types of cerebrovascular dysfunction that occur after TBI, including cerebral blood flow alterations, autoregulation impairments, subarachnoid hemorrhage, vasospasms, blood-brain barrier disruption, and edema formation. We also discuss the mechanisms that mediate these dysfunctions, focusing on the cellular components of cerebral blood vessels (endothelial cells, smooth muscle cells, astrocytes, pericytes, perivascular nerves) and their known and potential roles in the secondary injury cascade. © 2016 Wiley Periodicals, Inc.

Neurovascular dysfunction, including blood-brain barrier (BBB) breakdown and cerebral blood flow (CBF) dysregulation and reduction, are increasingly recognized to contribute to Alzheimer's disease (AD). The spatial and temporal relationships between different pathophysiological events during preclinical stages of AD, including cerebrovascular dysfunction and pathology, amyloid and tau pathology, and brain structural and functional changes remain, however, still unclear. Recent advances in neuroimaging techniques, i.e., magnetic resonance imaging (MRI) and positron emission tomography (PET), offer new possibilities to understand how the human brain works in health and disease. This includes methods to detect subtle regional changes in the cerebrovascular system integrity. Here, we focus on the neurovascular imaging techniques to evaluate regional BBB permeability (dynamic contrast-enhanced MRI), regional CBF changes (arterial spin labeling- and functional-MRI), vascular pathology (structural MRI), and cerebral metabolism (PET) in the living human brain, and examine how they can inform about neurovascular dysfunction and vascular pathophysiology in dementia and AD. Altogether, these neuroimaging approaches will continue to elucidate the spatio-temporal progression of vascular and neurodegenerative processes in dementia and AD and how they relate to each other.

Alzheimer's disease (AD) is clinically characterized by a progressive loss of cognitive functions and short-term memory. AD patients present two distinctive neuropathological lesions: neuritic plaques and neurofibrillary tangles (NFTs), constituted of beta-amyloid peptide (Aβ) and phosphorylated and truncated tau proteins. Aβ deposits around cerebral blood vessels (cerebral amyloid angiopathy, CAA) is a major contributor to vascular dysfunction in AD. Vascular amyloid deposits could be early events in AD due to dysfunction in the neurovascular unit (NVU) and the blood–brain barrier (BBB), deterioration of the gliovascular unit, and/or decrease of cerebral blood flow (CBF). These pathological events can lead to decreased Aβ clearance, facilitate a neuroinflammatory environment as well as synaptic dysfunction and, finally, lead to neurodegeneration. Here, we review the histopathological AD hallmarks and discuss the two-hit vascular hypothesis of AD, emphasizing the role of neurovascular dysfunction as an early factor that favors vascular Aβ aggregation and neurodegeneration. Addtionally, we emphasize that pericyte degeneration is a key and early element in AD that can trigger amyloid vascular accumulation and NVU/BBB dysfunction. Further research is required to better understand the early pathophysiological mechanisms associated with NVU alteration and CAA to generate early biomarkers and timely treatments for AD. [ABSTRACT FROM AUTHOR]

Summary: Background: Diabetic retinopathy (DR) is a leading cause of blindness in the working-age population, which is characterized by retinal neurodegeneration and vascular dysfunction. Long non-coding RNAs (LncRNAs) have emerged as critical regulators in several biological processes and disease progression. Here we investigated the role of lncRNA AQP4-AS1 in retinal neurovascular dysfunction induced by diabetes. Methods: Quantitative RT-PCR was used to detect the AQP4-AS1 expression pattern upon diabetes mellitus-related stresses. Visual electrophysiology examination, TUNEL staining, Evans blue staining, retinal trypsin digestion and immunofluorescent staining were conducted to detect the role of AQP4-AS1 in retinal neurovascular dysfunction in vivo. MTT assays, TUNEL staining, PI/Calcein-AM staining, EdU incorporation assay transwell assay and tube formation were conducted to detect the role of AQP4-AS1 in retinal cells function in vitro. qRT-PCR, western blot and in vivo studies were conducted to reveal the mechanism of AQP4-AS1-mediated retinal neurovascular dysfunction. Findings: AQP4-AS1 was significantly increased in the clinical samples of diabetic retinopathy patients, high glucose-treated Müller cells, and diabetic retinas of a murine model. AQP4-AS1 silencing in vivo alleviated retinal neurodegeneration and vascular dysfunction as shown by improved retinal capillary degeneration, decreased reactive gliosis, and reduced RGC loss. AQP4-AS1 directly regulated Müller cell function and indirectly affected endothelial cell and RGC function in vitro. Mechanistically, AQP4-AS1 regulated retinal neurovascular dysfunction through affecting AQP4 levels. Interpretation: This study reveals AQP4-AS1 is involved in retinal neurovascular dysfunction and expected to become a promising target for the treatment of neurovascular dysfunction in DR. Funding: This work was generously supported by the grants from the National Natural Science Foundation of China (Grant No. 81800858, 82070983, 81870679 and 81970823), grants from the Medical Science and Technology Development Project Fund of Nanjing (Grant No ZKX17053 and YKK19158), grants from Innovation Team Project Fund of Jiangsu Province (No. CXTDB2017010), and the Science and Technology Development Plan Project Fund of Nanjing (Grant No 201716007, 201805007 and 201803058).

While cardiovascular disease, cancer, and human immunodeficiency virus (HIV) mortality rates have decreased over the past 20 years, Alzheimer's Disease (AD) deaths have risen by 145% since 2010. Despite significant research efforts, effective AD treatments remain elusive due to a poorly defined etiology and difficulty in targeting events that occur too downstream of disease onset. In hopes of elucidating alternative treatment pathways, now, AD is commonly being more broadly defined not only as a neurological disorder but also as a progression of a variety of cerebrovascular pathologies highlighted by the breakdown of the blood-brain barrier. The endothelial glycocalyx (GCX), which is an essential regulator of vascular physiology, plays a crucial role in the function of the neurovascular system, acting as an essential vascular mechanotransducer to facilitate ultimate blood-brain homeostasis. Shedding of the cerebrovascular GCX could be an early indication of neurovascular dysfunction and may subsequently progress neurodegenerative diseases like AD. Recent advances in in vitro modeling, gene/protein silencing, and imaging techniques offer new avenues of scrutinizing the GCX's effects on AD-related neurovascular pathology. Initial studies indicate GCX degradation in AD and other neurodegenerative diseases and have begun to demonstrate a possible link to GCX loss and cerebrovascular dysfunction. This review will scrutinize the GCX's contribution to known vascular etiologies of AD and propose future work aimed at continuing to uncover the relationship between GCX dysfunction and eventual AD-associated neurological deterioration., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 O’Hare, Millican and Ebong.)

Glaucoma is a neurodegenerative disease, which results in characteristic visual field defects. Intraocular pressure (IOP) remains the main risk factor for this leading cause of blindness. Recent studies suggest that disturbances in neurovascular coupling (NVC) may be associated with glaucoma. The resultant imbalance between vascular perfusion and neuronal stimulation in the eye may precede retinal ganglion cell (RGC) loss and increase the susceptibility of the eye to raised IOP and glaucomatous degeneration. Caveolin-1 (Cav-1) is an integral scaffolding membrane protein found abundantly in retinal glial and vascular tissues, with possible involvement in regulating the neurovascular coupling response. Mutations in Cav-1 have been identified as a major genetic risk factor for glaucoma. Therefore, we aim to evaluate the effects of Cav-1 depletion on neurovascular coupling, retinal vessel characteristics, RGC density and the positive scotopic threshold response (pSTR) in Cav-1 knockout (KO) versus wild type C57/Bl6 mice (WT). Following light flicker stimulation of the retina, Cav-1 KO mice showed a smaller increase in perfusion at the optic nerve head and peripapillary arteries, suggesting defective neurovascular coupling. Evaluation of the superficial capillary plexus in Cav-1 KO mice also revealed significant differences in vascular morphology with higher vessel density, junction density and decreased average vessel length. Cav-1 KO mice exhibited higher IOP and lower pSTR amplitude. However, there was no significant difference in RGC density between Cav-1 KO and wild type mice. These findings highlight the role of Cav-1 in regulating neurovascular coupling and IOP and suggest that the loss of Cav-1 may predispose to vascular dysfunction and decreased RGC signaling in the absence of structural loss. Current treatment for glaucoma relies heavily on IOP-lowering drugs, however, there is an immense potential for new therapeutic strategies that increase Cav-1 expression or augment its downstream signaling in order to avert vascular dysfunction and glaucomatous change. [ABSTRACT FROM AUTHOR]

Intracranial arterial stiffening is a potential early marker of emerging cerebrovascular dysfunction and could be mechanistically involved in disease processes detrimental to brain function via several pathways. A prominent consequence of arterial wall stiffening is the increased velocity at which the systolic pressure pulse wave propagates through the vasculature. Previous non-invasive measurements of the pulse wave propagation have been performed on the aorta or extracranial arteries with results linking increased pulse wave velocity to brain pathology. However, there is a lack of intracranial "target-organ" measurements. Here we present a 4D flow MRI method to estimate pulse wave velocity in the intracranial vascular tree. The method utilizes the full detectable branching structure of the cerebral vascular tree in an optimization framework that exploits small temporal shifts that exists between waveforms sampled at varying depths in the vasculature. The method is shown to be stable in an internal consistency test, and of sufficient sensitivity to robustly detect age-related increases in intracranial pulse wave velocity. [ABSTRACT FROM AUTHOR]

Glaucoma is a neurodegenerative disease, which results in characteristic visual field defects. Intraocular pressure (IOP) remains the main risk factor for this leading cause of blindness. Recent studies suggest that disturbances in neurovascular coupling (NVC) may be associated with glaucoma. The resultant imbalance between vascular perfusion and neuronal stimulation in the eye may precede retinal ganglion cell (RGC) loss and increase the susceptibility of the eye to raised IOP and glaucomatous degeneration. Caveolin-1 (Cav-1) is an integral scaffolding membrane protein found abundantly in retinal glial and vascular tissues, with possible involvement in regulating the neurovascular coupling response. Mutations in Cav-1 have been identified as a major genetic risk factor for glaucoma. Therefore, we aim to evaluate the effects of Cav-1 depletion on neurovascular coupling, retinal vessel characteristics, RGC density and the positive scotopic threshold response (pSTR) in Cav-1 knockout (KO) versus wild type C57/Bl6 mice (WT). Following light flicker stimulation of the retina, Cav-1 KO mice showed a smaller increase in perfusion at the optic nerve head and peripapillary arteries, suggesting defective neurovascular coupling. Evaluation of the superficial capillary plexus in Cav-1 KO mice also revealed significant differences in vascular morphology with higher vessel density, junction density and decreased average vessel length. Cav-1 KO mice exhibited higher IOP and lower pSTR amplitude. However, there was no significant difference in RGC density between Cav-1 KO and wild type mice. These findings highlight the role of Cav-1 in regulating neurovascular coupling and IOP and suggest that the loss of Cav-1 may predispose to vascular dysfunction and decreased RGC signaling in the absence of structural loss. Current treatment for glaucoma relies heavily on IOP-lowering drugs, however, there is an immense potential for new therapeutic strategies that increase Cav-1 expression or augment its downstream signaling in order to avert vascular dysfunction and glaucomatous change.

• miR-103-3p regulates Cav-1 and tight junction expression through directly interaction with 3′-UTR of Cav-1. • SAH induces early increase of miR-103-3p and decrease of Cav-1. • Antagomir-mediated inhibition of miR-103-3p exerts neuroprotection after SAH. • Cav-1 is required for the miR-103-3p antagomir-induced neurovascular protection after SAH. Caveolin-1 (Cav-1) is a constitutive structural protein of caveolae in the plasma membrane. It plays an important role in maintaining blood brain barrier (BBB) integrity. In this study, we identified that miR-103-3p, a hypoxia-responsive miRNA, could interact with Cav-1. In endothelial cells, miR-103-3p mimic diminished the expression of Cav-1 and tight junction proteins, which were rescued by the inhibition of miR-103-3p. We found a substantial increase of miR-103-3p and decease of Cav-1 in the rat subarachnoid hemorrhage (SAH) model. Pre-SAH intracerebroventricularly injection of miR-103-3p antagomir relieved Cav-1 loss, sequentially reduced BBB permeability and improved neurological function. Finally, we demonstrated that the salutary effects of miR-103-3p antagomir were abolished in Cav-1 knock-out mice, suggesting that Cav-1 was required for the miR-103-3p inhibition-induced neurovascular protection. Taken together, our findings suggest that the inhibition of miR-103-3p could exert neuroprotective effects through preservation of Cav-1 and BBB integrity, making miR-103-3p a novel therapeutic target for SAH. [ABSTRACT FROM AUTHOR]

Diabetic neuropathy (DN) is the most prevalent chronic complication of diabetes mellitus. The exact pathophysiological mechanisms of DN are unclear; however, communication network dysfunction among axons, Schwann cells, and the microvascular endothelium likely play an important role in the development of DN. Mounting evidence suggests that microRNAs (miRNAs) act as messengers that facilitate intercellular communication and may contribute to the pathogenesis of DN. Deregulation of miRNAs is among the initial molecular alterations observed in diabetics. As such, miRNAs hold promise as biomarkers and therapeutic targets. In preclinical studies, miRNA-based treatment of DN has shown evidence of therapeutic potential. But this therapy has been hampered by miRNA instability, targeting specificity, and potential toxicities. Recent findings reveal that when packaged within extracellular vesicles, miRNAs are resistant to degradation, and their delivery efficiency and therapeutic potential is markedly enhanced. Here, we review the latest research progress on the roles of miRNAs as biomarkers and as potential clinical therapeutic targets in DN. We also discuss the promise of exosomal miRNAs as therapeutics and provide recommendations for future research on miRNA-based medicine.

Diabetic neuropathy (DN) is the most prevalent chronic complication of diabetes mellitus. The exact pathophysiological mechanisms of DN are unclear; however, communication network dysfunction among axons, Schwann cells, and the microvascular endothelium likely play an important role in the development of DN. Mounting evidence suggests that microRNAs (miRNAs) act as messengers that facilitate intercellular communication and may contribute to the pathogenesis of DN. Deregulation of miRNAs is among the initial molecular alterations observed in diabetics. As such, miRNAs hold promise as biomarkers and therapeutic targets. In preclinical studies, miRNA-based treatment of DN has shown evidence of therapeutic potential. But this therapy has been hampered by miRNA instability, targeting specificity, and potential toxicities. Recent findings reveal that when packaged within extracellular vesicles, miRNAs are resistant to degradation, and their delivery efficiency and therapeutic potential is markedly enhanced. Here, we review the latest research progress on the roles of miRNAs as biomarkers and as potential clinical therapeutic targets in DN. We also discuss the promise of exosomal miRNAs as therapeutics and provide recommendations for future research on miRNA-based medicine. [ABSTRACT FROM AUTHOR]

Aims: The aims of this study were to assess vascular dysfunction in patients with Alzheimer disease (AD) by investigating cerebral vasomotor reactivity using transcranial Doppler ultrasound (TCD) and to evaluate any correlations between cerebral vasoreactivity and endothelium dysfunction. Moreover, the frequency of circulating progenitor cells (CPCs) and the blood concentration of vascular/inflammatory markers were evaluated.Materials and Methods: We recruited 35 AD subjects and 17 age-matched, sex-matched, and education-matched healthy control subjects. Cerebral vasomotor reactivity was assessed by means of the TCD-based breath-holding index test (BHI). The level of CPCs was evaluated by means of flow cytometry from venous blood samples, while blood vascular/inflammatory markers were measured by means of enzyme-linked immunosorbent assay.Results: Both cerebral assay blood flow velocity in the middle cerebral artery (MCAFV) and BHI values were significantly lower in AD subjects than in healthy controls (P<0.05). A positive trend was found between MCAFV and BHI values and Mini-Mental State Evaluation (MMSE) scores. Moreover, the hematopoietic progenitor cells' count was found to be lower in patients with AD than in controls (P<0.05). Finally, a significantly higher expression of the plasma chemokine CCL-2 was observed in AD patients than in healthy controls.Conclusions: Our results confirm that cerebral hemodynamic deterioration may be a critical marker of cognitive decline. Further studies are needed to investigate the role of circulating CPCs and chemokines as potential contributors to neurovascular dysfunction. [ABSTRACT FROM AUTHOR]

Diabetic retinopathy is a major cause of ocular complications in patients with type 1 and type 2 diabetes in developed countries. Due to the continued increase in the number of people with obesity and diabetes in the United States of America and globally, the incidence of diabetic retinopathy is expected to increase significantly in the coming years. Diabetic retinopathy is widely accepted as a combination of neurodegenerative and microvascular changes; however, which change occurs first is not yet understood. Although the pathogenesis of diabetic retinopathy is very complex, regulated by numerous signaling pathways and cellular processes, maintaining glucose homeostasis is still an essential component for normal physiological functioning of retinal cells. The maintenance of glucose homeostasis is finely regulated by coordinated interplay between glycolysis, Krebs cycle, and oxidative phosphorylation. Glycolysis is the most conserved metabolic pathway in biology and is tightly regulated to maintain a steady-state concentration of glycolytic intermediates; this regulation is called scheduled or regulated glycolysis. However, an abnormal increase in glycolytic flux generates large amounts of intermediate metabolites that can be shunted into different damaging pathways including the polyol pathway, hexosamine pathway, diacylglycerol-dependent activation of the protein kinase C pathway, and Amadori/advanced glycation end products (AGEs) pathway. In addition, disrupting the balance between glycolysis and oxidative phosphorylation leads to other biochemical and molecular changes observed in diabetic retinopathy including endoplasmic reticulum-mitochondria miscommunication and mitophagy dysregulation. This review will focus on how dysregulation of glycolysis contributes to diabetic retinopathy.

Neurovascular dysfunction is a preclinical manifestation of diabetic complications, including diabetic retinopathy (DR). Herein, we report that a transfer RNA-derived RNA fragment, tRF-3001a, is significantly upregulated under diabetic conditions. tRF-3001a downregulation inhibits Müller cell activation, suppresses endothelial angiogenic effects, and protects against high-glucose-induced retinal ganglion cell injury in vitro. Furthermore, tRF-3001a downregulation alleviates retinal vascular dysfunction, inhibits retinal reactive gliosis, facilitates retinal ganglion cell survival, and preserves visual function and visually guided behaviors in STZ-induced diabetic mice and db/db diabetic mice. Mechanistically, tRF-3001a regulates neurovascular dysfunction in a microRNA-like mechanism by targeting GSK3B. Clinically, tRF-3001a is upregulated in aqueous humor (AH) samples of DR patients. tRF-3001a downregulation inhibits DR-induced human retinal vascular endothelial cell and Müller cell dysfunction in vitro and DR-induced retinal neurovascular dysfunction in C57BL/6J mice. Thus, targeting tRF-3001a-mediated signaling is a promising strategy for the concurrent treatment of vasculopathy and neuropathy in diabetes mellitus., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Graphical abstract Highlights • Oxidative damage is a key feature of AD, the major cause of age-related dementia. • TRPM2 channel is part of a positive feedback loop for Aβ/ROS-induced neuronal death. • TRPM2 channel is required for Aβ-induced microglial cell-mediated neuroinflammation. • TRPM2 channel in endothelial cell mediates Aβ-induced neurovascular dysfunction. • TRPM2 channel has emerged as a novel drug target for intervening AD and dementia. Abstract Alzheimer's disease (AD), an age-related neurodegenerative condition, is the most common cause of dementia among the elder people, but currently there is no treatment. A number of putative pathogenic events, particularly amyloid β peptide (Aβ) accumulation, are believed to be early triggers that initiate AD. However, thus far targeting Aβ generation/aggregation as the mainstay strategy of drug development has not led to effective AD-modifying therapeutics. Oxidative damage is a conspicuous feature of AD, but this remains poorly defined phenomenon and mechanistically ill understood. The TRPM2 channel has emerged as a potentially ubiquitous molecular mechanism mediating oxidative damage and thus plays a vital role in the pathogenesis and progression of diverse neurodegenerative diseases. This article will review the emerging evidence from recent studies and propose a novel 'hypothesis' that multiple TRPM2-mediated cellular and molecular mechanisms cascade Aβ and/or oxidative damage to AD pathologies. The 'hypothesis' based on these new findings discusses the prospect of considering the TRPM2 channel as a novel therapeutic target for intervening AD and age-related dementia. [ABSTRACT FROM AUTHOR]

Women seem to have a higher vulnerability to Alzheimer's disease (AD), but the underlying mechanisms of this sex dichotomy are not well understood. Here, we first determined the influence of sex on various aspects of Alzheimer's pathology in transgenic CRND8 mice. We demonstrate that beta‐amyloid (Aβ) plaque burden starts to be more severe around P180 (moderate disease stage) in female transgenics when compared to males and that aging aggravates this sex‐specific difference. Furthermore, we show that female transgenics suffer from higher levels of neurovascular dysfunction around P180, resulting in impaired Aβ peptide clearance across the blood‐brain‐barrier at P360. Female transgenics show also higher levels of diffuse microgliosis and inflammation, but the density of microglial cells surrounding Aβ plaques is less in females. In line with this finding, testosterone compared to estradiol was able to improve microglial viability and Aβ clearance in vitro. The spatial memory of transgenics was in general poorer than in wildtypes and at P360 worse in females irrespective of their genotype. This difference was accompanied by a slightly diminished dendritic complexity in females. While all the above‐named sex‐differences emerged after the onset of Aβ pathology, kallikrein‐8 (KLK8) protease levels were, as an exception, higher in female than in male brains very early when virtually no plaques were detectable. In a second step, we quantified cerebral KLK8 levels in AD patients and healthy controls, and could ascertain, similar to mice, higher KLK8 levels not only in AD‐affected but also in healthy brains of women. Accordingly, we could demonstrate that estradiol but not testosterone induces KLK8 synthesis in neuronal and microglial cells. In conclusion, multiple features of AD are more pronounced in females. Here, we show for the first time that this sex‐specific difference may be meditated by estrogen‐induced KLK8 overproduction long before AD pathology emerges. [ABSTRACT FROM AUTHOR]

Introduction We examined whether cortical microvascular blood volume and hemodynamics in Alzheimer's disease (AD) are consistent with tissue hypoxia and whether they correlate with cognitive performance and the degree of cortical thinning. Methods Thirty-two AD patients underwent cognitive testing, structural magnetic resonance imaging (MRI), and perfusion MRI at baseline and after 6 months. We measured cortical thickness, microvascular cerebral blood volume (CBV), cerebral blood flow (CBF), mean transit time (MTT), and capillary transit time heterogeneity (CTH) and estimated tissue oxygen tension (P t O 2 ). Results At baseline, poor cognitive performance and regional cortical thinning correlated with lower CBF and CBV, with higher MTT and CTH and with low P t O 2 across the cortex. Cognitive decline over time was associated with increasing whole brain relative transit time heterogeneity (RTH = CTH/MTT). Discussion Our results confirm the importance of microvascular pathology in AD. Deteriorating microvascular hemodynamics may cause hypoxia, which is known to precipitate amyloid retention. [ABSTRACT FROM AUTHOR]

Human Albumin is a unique pleiotropic protein with multiple properties. Previous clinical and laboratory studies have indicated a possible beneficial effect of Albumin in subarachnoid hemorrhage (SAH). The present study aimed to further define the preclinical characteristics of Albumin. SAH was induced by endovascular perforation in Sprague–Dawley rats. In the dose-escalation study, Albumin ranging from 0.02 g/kg to 1.0 g/kg was intravenously infused immediately after SAH. In the therapeutic window study, 1.0 g/kg Albumin was administered at 0 h, 2 h, 4 h or 8 h after SAH. Physiologic variables were monitored in different Albumin treatment regimens. One day after SAH, neurological scores, SAH scores, blood–brain barrier permeability, neural degeneration and apoptosis were examined. The efficacy of Albumin for SAH was also determined in female rats and in spontaneously hypertensive rats. We found that 0.2 g/kg and 1.0 g/kg Albumin significantly attenuated sensorimotor deficits, brain edema, IgG leakage, and neuronal degeneration after SAH. The benefits of Albumin existed even when the administration was delayed to 4 h after SAH onset. No significant difference was found between 0.2 g/kg and 1.0 g/kg Albumin groups. In female rats and spontaneously hypertensive rats, Albumin likewise improved neurological outcomes and early brain injury. In conclusion, Albumin could reduce both cerebral lesions and functional deficits in the early stage of SAH. The beneficial regimen occurs within a favorable therapeutic window and is reproducible in different high-risk subjects. [ABSTRACT FROM AUTHOR]

Lysosome is a primary degradative organelle and is crucial in cellular homeostasis. A reduction in its function due to ageing has been associated with the development of Alzheimer's disease (AD), a common neurodegenerative disorder characterised by the deposition of neurotoxic amyloid plaque in the brain and cerebral vessel walls. The breakdown of the blood-brain barrier (BBB) plays a vital role in the pathogenesis of AD. However, the impact of lysosomal dysfunction on brain endothelial cells, the key component of the BBB, in the disease progression is yet to be fully understood. In this study, human brain endothelial cells (HBEC-5i) were exposed to a lysosomotropic compound, chloroquine (CQ) for 24 h. Cell viability was assessed with the 3-(4,5-dimethylthiazol-2-yl)− 2,5-diphenyltetrazolium bromide (MTT) assay to determine the inhibitory concentration (IC) at IC 10 (17.5 µM), IC 25 (70.5 µM), and IC 50 (125 µM). The morphological changes observed include vacuoles arrested in the cytosols and cell shrinkage that were more prominent at IC 25 and IC 50. Lysosomal dysfunction was evaluated by measuring the lysosomal-associated membrane protein-1 (LAMP-1) and microtubule-associated protein light chain 3-II (LC3-II) using the capillary-based immunoassay. LC3-II was significantly increased at IC 25 and IC 50 (p < 0.05 and p < 0.001 , res p ectively). The concentration of intracellular and extracellular Aβ42 was quantitated using the enzyme-linked immunosorbent assay, which demonstrated a significant increase (p < 0.05) in intracellular Aβ42 at IC 25. This study showed that perturbation of lysosomal function impairs autophagy that leads to intracellular increment of Aβ, indicating the important roles of lysosomes in endothelial cells homeostasis and disease progression. [Display omitted] • Chloroquine, a lysosomotropic compound, induced a dose-dependent response on HBEC-5i. • Chloroquine blocks autophagosome-lysosome fusion indicating lysosome dysfunction. • Lysosome dysfunction led to autophagosome accumulation and increased intracellular Aβ. • Healthy lysosomes are crucial for maintaining homeostatic and normal BEC function. [ABSTRACT FROM AUTHOR]

Acquired brain injury (ABI) is the most common disease of the nervous system, involving complex pathological processes, which often leads to a series of nervous system disorders. The structural destruction and dysfunction of the Neurovascular Unit (NVU) are prominent features of ABI. Therefore, understanding the molecular mechanism underlying NVU destruction and its reconstruction is the key to the treatment of ABI. SUMOylation is a protein post-translational modification (PTM), which can degrade and stabilize the substrate dynamically, thus playing an important role in regulating protein expression and biological signal transduction. Understanding the regulatory mechanism of SUMOylation can clarify the molecular mechanism of the occurrence and development of neurovascular dysfunction after ABI and is expected to provide a theoretical basis for the development of potential treatment strategies. This article reviews the role of SUMOylation in vascular events related to ABI, including NVU dysfunction and vascular remodeling, and puts forward therapeutic prospects., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Luo, Li, Huang, Mao, Lou, Ruan, Chen, Tang, Shi, Zhou and Yang.)

Objective: Subarachnoid hemorrhage results in significant long-lasting neurologic sequelae. Here, we investigated whether human albumin improves long-term outcomes in experimental subarachnoid hemorrhage and whether neurovascular remodeling is involved in the protection of albumin.Design: Laboratory investigation.Setting: Hospital research laboratory.Subjects: Male Sprague-Dawley rats.Interventions: Rats underwent subarachnoid hemorrhage by endovascular perforation. Albumin of either 0.63 or 1.25 g/kg was injected IV immediately after the surgery. Modified Garcia test, beam-walking test, novel object recognition, and Morris water maze were employed to determine the behavioral deficits. The effects of albumin on early neurovascular dysfunction and chronic synaptic plasticity were also studied.Measurements and Main Results: Both doses of albumin significantly improved the sensorimotor scores (F = 31.277; p = 0.001) and cognitive performance (F = 7.982; p = 0.001 in novel object recognition test; and F = 3.431; p = 0.026 in the latency analysis of Morris water maze test) for at least 40 days after subarachnoid hemorrhage. There were remarkable microvasculature hypoperfusion, intracranial pressure rise, early vasoconstriction, neural apoptosis, and degeneration in subarachnoid hemorrhage rats, with albumin significantly attenuating such neurovascular dysfunction. Furthermore, albumin markedly prevented blood-brain barrier disruption, as indicated by less blood-brain barrier leakage, preserved blood-brain barrier-related proteins, and dampened gelatinase activities. The expressions of key synaptic elements were up-regulated with albumin supplementation in both acute and chronic phases. Accordingly, a higher dendritic spine density was observed in the prefrontal and hippocampal areas of albumin-treated subarachnoid hemorrhage animals.Conclusions: Albumin at low-to-moderate doses markedly improves long-term neurobehavioral sequelae after subarachnoid hemorrhage, which may involve an integrated process of neurovascular remodeling. [ABSTRACT FROM AUTHOR]

There is growing recognition that cerebral hypoperfusion is related to the pathogenesis of Alzheimer's disease (AD), implicating the measurement of cerebral blood flow (CBF) as a possible biomarker of AD. The ability to identify the earliest and most reliable markers of incipient cognitive decline and clinical symptoms is critical to develop effective preventive strategies and interventions for AD. Arterial spin labeling (ASL) magnetic resonance imaging (MRI) measures CBF by magnetically labeling arterial water and using it as an endogenous tracer. Studies using ASL MRI in humans indicate that CBF changes are present several years before the development of the clinical symptoms of AD. Moreover, ASL-measured CBF has been shown to distinguish between cognitively normal individuals, adults at risk for AD, and persons diagnosed with AD. Some studies indicate that CBF may even be sensitive for predicting cognitive decline and conversion to mild cognitive impairment and AD over time. Taken together, evidence suggests that the current staging models of AD biomarker pathology should incorporate early changes in CBF as a useful biomarker, possibly present even earlier than amyloid-β accumulation. Though still a research tool, ASL imaging is a promising non-invasive and reliable method with the potential to serve as a future clinical tool for the measurement of CBF in preclinical AD. [ABSTRACT FROM AUTHOR]

Blood-brain barrier (BBB) dysfunction is a hallmark of neurological conditions such as multiple sclerosis (MS) and stroke. However, the molecular mechanisms underlying neurovascular dysfunction during BBB breakdown remain elusive. MicroRNAs (miRNAs) have recently emerged as key regulators of pathogenic responses, although their role in central nervous system (CNS) microvascular disorders is largely unknown. We have identified miR-155 as a critical miRNA in neuroinflammation at the BBB. miR-155 is expressed at the neurovascular unit of individuals with MS and of mice with experimental autoimmune encephalomyelitis (EAE). In mice, loss of miR-155 reduced CNS extravasation of systemic tracers, both in EAE and in an acute systemic inflammation model induced by lipopolysac-charide. In cultured human brain endothelium, miR-155 was strongly and rapidly upregulated by inflammatory cytokines. miR-155 up-regulation mimicked cytokine-induced alterations in junctional organization and permeability, whereas inhibition of endogenous miR-155 partially prevented a cytokine-induced increase in permeability. Furthermore, miR-155 modulated brain endothelial harrier function by targeting not only cell-cell complex molecules such as annexin-2 and claudin-1, hut also focal adhesion components such as DOCK-1 and syntenin-1. We propose that brain endothelial miR-155 is a negative regulator of BBB function that may constitute a novel therapeutic target for CNS neuroinflammatory disorders. [ABSTRACT FROM AUTHOR]

Abstract: It is widely accepted that hypoperfusion and changes in capillary morphology are involved in the etiopathogenesis of Alzheimer''s disease (AD). This is difficult to reconcile with the hyperperfusion observed in young high-risk subjects. Differences in the way cerebral blood flow (CBF) is coupled with the local metabolic needs during different phases of the disease can explain this apparent paradox. This review describes this coupling in terms of a model of cerebral oxygen availability that takes into consideration the heterogeneity of capillary blood flow patterns. The model predicts that moderate increases in heterogeneity requires elevated CBF in order to maintain adequate oxygenation. However, with progressive increases in heterogeneity, the resulting low tissue oxygen tension will require a suppression of CBF in order to maintain tissue metabolism. The observed biphasic nature of CBF responses in preclinical AD and AD is therefore consistent with progressive disturbances of capillary flow patterns. Salient features of the model are discussed in the context of AD pathology along with potential sources of increased capillary flow heterogeneity. [Copyright &y& Elsevier]

Background: Diabetic retinopathy (DR) is a leading cause of blindness in the working-age population, which is characterized by retinal neurodegeneration and vascular dysfunction. Long non-coding RNAs (LncRNAs) have emerged as critical regulators in several biological processes and disease progression. Here we investigated the role of lncRNA AQP4-AS1 in retinal neurovascular dysfunction induced by diabetes., Methods: Quantitative RT-PCR was used to detect the AQP4-AS1 expression pattern upon diabetes mellitus-related stresses. Visual electrophysiology examination, TUNEL staining, Evans blue staining, retinal trypsin digestion and immunofluorescent staining were conducted to detect the role of AQP4-AS1 in retinal neurovascular dysfunction in vivo. MTT assays, TUNEL staining, PI/Calcein-AM staining, EdU incorporation assay transwell assay and tube formation were conducted to detect the role of AQP4-AS1 in retinal cells function in vitro. qRT-PCR, western blot and in vivo studies were conducted to reveal the mechanism of AQP4-AS1-mediated retinal neurovascular dysfunction., Findings: AQP4-AS1 was significantly increased in the clinical samples of diabetic retinopathy patients, high glucose-treated Müller cells, and diabetic retinas of a murine model. AQP4-AS1 silencing in vivo alleviated retinal neurodegeneration and vascular dysfunction as shown by improved retinal capillary degeneration, decreased reactive gliosis, and reduced RGC loss. AQP4-AS1 directly regulated Müller cell function and indirectly affected endothelial cell and RGC function in vitro. Mechanistically, AQP4-AS1 regulated retinal neurovascular dysfunction through affecting AQP4 levels., Interpretation: This study reveals AQP4-AS1 is involved in retinal neurovascular dysfunction and expected to become a promising target for the treatment of neurovascular dysfunction in DR., Funding: This work was generously supported by the grants from the National Natural Science Foundation of China (Grant No. 81800858, 82070983, 81870679 and 81970823), grants from the Medical Science and Technology Development Project Fund of Nanjing (Grant No ZKX17053 and YKK19158), grants from Innovation Team Project Fund of Jiangsu Province (No. CXTDB2017010), and the Science and Technology Development Plan Project Fund of Nanjing (Grant No 201716007, 201805007 and 201803058)., Competing Interests: Declaration of interests No potential conflicts of interest relevant to this article were reported., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Diabetic retinopathy is a major cause of ocular complications in patients with type 1 and type 2 diabetes in developed countries. Due to the continued increase in the number of people with obesity and diabetes in the United States of America and globally, the incidence of diabetic retinopathy is expected to increase significantly in the coming years. Diabetic retinopathy is widely accepted as a combination of neurodegenerative and microvascular changes; however, which change occurs first is not yet understood. Although the pathogenesis of diabetic retinopathy is very complex, regulated by numerous signaling pathways and cellular processes, maintaining glucose homeostasis is still an essential component for normal physiological functioning of retinal cells. The maintenance of glucose homeostasis is finely regulated by coordinated interplay between glycolysis, Krebs cycle, and oxidative phosphorylation. Glycolysis is the most conserved metabolic pathway in biology and is tightly regulated to maintain a steady-state concentration of glycolytic intermediates; this regulation is called scheduled or regulated glycolysis. However, an abnormal increase in glycolytic flux generates large amounts of intermediate metabolites that can be shunted into different damaging pathways including the polyol pathway, hexosamine pathway, diacylglycerol-dependent activation of the protein kinase C pathway, and Amadori/advanced glycation end products (AGEs) pathway. In addition, disrupting the balance between glycolysis and oxidative phosphorylation leads to other biochemical and molecular changes observed in diabetic retinopathy including endoplasmic reticulum-mitochondria miscommunication and mitophagy dysregulation. This review will focus on how dysregulation of glycolysis contributes to diabetic retinopathy. [ABSTRACT FROM AUTHOR]

The mechanisms responsible for cardiovascular and neurodegenerative diseases have been the focus of experimental and clinical studies for decades. The relationship between the gut microbiota and the organs and system tissues represents the research field that has generated the highest number of publications. Homeostasis of the gut microbiota is important to the host because it promotes maturation of the autoimmune system, harmonic integrative functions of the brain, and the normal function of organs related to cardiovascular and metabolic systems. On the other hand, when a gut microbiota dysbiosis occurs, the target organs become vulnerable to the onset or aggravation of complex chronic conditions, such as cardiovascular (e.g., arterial hypertension) and neurodegenerative (e.g., dementia) diseases. In the present brief review, we discuss the main mechanisms involved in those disturbances and the promising beneficial effects that have been revealed using functional food (nutraceuticals), such as the traditional probiotic Kefir. Here, we highlight the current scientific advances, concerns, and limitations about the use of this nutraceutical. The focus of our discussion is the endothelial dysfunction that accompanies hypertension and the neurovascular dysfunction that characterizes ageing-related dementia in patients suffering from Alzheimer's disease., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: The pathological impact of chronic cerebral hypoperfusion (CCH) on Alzheimer's disease (AD) is still poorly understood. In the present study, we investigated the role of CCH on an AD mouse model in phosphorylated tau and α-synuclein pathology, neurovascular unit, cerebrovascular remodeling, and neurovascular trophic coupling. Moreover, examined protective effect of a new antioxidant Twendee X (TwX).Methods: APP23 mice were implanted to bilateral common carotid arteries stenosis with ameroid constrictors to gradually decrease the cerebral blood flow. The effects of the administration of TwX were evaluated by immunohistochemical analysis and Immunofluorescent histochemistry.Results: The present study revealed that the expressions of phospho-tau and phospho-α-synuclein were significantly increased in the APP23 + CCH mice group as compared with wild type and APP23 mice groups (*P < .05 and ⁎⁎P < .01 versus WT; #P < .05 and ##P < .01 versus APP23). In addition, CCH significantly exacerbated MMP-9 activation relating to blood-brain barrier destruction (⁎⁎P < .01 versus WT; #P < .05, and ##P < .01 versus APP23), enhanced neurovascular remodeling, and impaired a neurovascular trophic coupling in the vascular endothelial BDNF expression of the APP23 + CCH group. TwX treatment (20 mg/kg/day, from 4.5 to 12 months) significantly reduced tau and α-synuclein pathologies, ameliorated neurovascular dysfunction compared with APP23 + CCH group.Conclusions: Our findings indicate that administration of a new antioxidative mixture TwX substantially reduced the above neuropathologic abnormalities, suggesting a potential therapeutic benefit of TwX for AD with CCH. [ABSTRACT FROM AUTHOR]