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Acta Neuropathologica Communications Mar 2023In the contexts of aging, injury, or neuroinflammation, activated microglia signaling with TNF-α, IL-1α, and C1q induces a neurotoxic astrocytic phenotype, classified... (Review)
Review
In the contexts of aging, injury, or neuroinflammation, activated microglia signaling with TNF-α, IL-1α, and C1q induces a neurotoxic astrocytic phenotype, classified as A1, A1-like, or neuroinflammatory reactive astrocytes. In contrast to typical astrocytes, which promote neuronal survival, support synapses, and maintain blood-brain barrier integrity, these reactive astrocytes downregulate supportive functions and begin to secrete neurotoxic factors, complement components like C3, and chemokines like CXCL10, which may facilitate recruitment of immune cells across the BBB into the CNS. The proportion of pro-inflammatory reactive astrocytes increases with age through associated microglia activation, and these pro-inflammatory reactive astrocytes are particularly abundant in neurodegenerative disorders. As the identification of astrocyte phenotypes progress, their molecular and cellular effects are characterized in a growing array of neuropathologies.
Topics: Humans; Astrocytes; Microglia; Central Nervous System; Blood-Brain Barrier; Chemokines; Neurotoxicity Syndromes
PubMed: 36915214
DOI: 10.1186/s40478-023-01526-9 -
The Journal of Headache and Pain Jun 2022Several preclinical and clinical lines of evidence suggest a role of neuroinflammation in migraine. Neuroimaging offers the possibility to investigate and localize... (Review)
Review
Several preclinical and clinical lines of evidence suggest a role of neuroinflammation in migraine. Neuroimaging offers the possibility to investigate and localize neuroinflammation in vivo in patients with migraine, and to characterize specific inflammatory constituents, such as vascular permeability, and macrophage or microglia activity. Despite all imaging data accumulated on neuroinflammation across the past three decades, an overview of the imaging evidence of neuroinflammation in migraine is still missing.We conducted a systematic review in the Pubmed and Embase databases to evaluate existing imaging data on inflammation in migraine, and to identify gaps in the literature. We included 20 studies investigating migraine without aura (N = 4), migraine with aura (N = 8), both migraine with and without aura (N = 3), or hemiplegic migraine (N = 5).In migraine without aura, macrophage activation was not evident. In migraine with aura, imaging evidence suggested microglial and parameningeal inflammatory activity. Increased vascular permeability was mostly found in hemiplegic migraine, and was atypical in migraine with and without aura. Based on the weight of existing and emerging data, we show that most studies have concentrated on demonstrating increased vascular permeability as a marker of neuroinflammation, with tools that may not have been optimal. In the future, novel, more sensitive techniques, as well as imaging tracers delineating specific inflammatory pathways may further bridge the gap between preclinical and clinical findings.
Topics: Epilepsy; Hemiplegia; Humans; Migraine with Aura; Migraine without Aura; Phenotype
PubMed: 35650524
DOI: 10.1186/s10194-022-01430-y -
Cells Dec 2023The greatest risk factor for neurodegeneration is the aging of the multiple cell types of human CNS, among which microglia are important because they are the "sentinels"... (Review)
Review
The greatest risk factor for neurodegeneration is the aging of the multiple cell types of human CNS, among which microglia are important because they are the "sentinels" of internal and external perturbations and have long lifespans. We aim to emphasize microglial signatures in physiologic brain aging and Alzheimer's disease (AD). A systematic literature search of all published articles about microglial senescence in human healthy aging and AD was performed, searching for PubMed and Scopus online databases. Among 1947 articles screened, a total of 289 articles were assessed for full-text eligibility. Microglial transcriptomic, phenotypic, and neuropathological profiles were analyzed comprising healthy aging and AD. Our review highlights that studies on animal models only partially clarify what happens in humans. Human and mice microglia are hugely heterogeneous. Like a two-sided coin, microglia can be protective or harmful, depending on the context. Brain health depends upon a balance between the actions and reactions of microglia maintaining brain homeostasis in cooperation with other cell types (especially astrocytes and oligodendrocytes). During aging, accumulating oxidative stress and mitochondrial dysfunction weaken microglia leading to dystrophic/senescent, otherwise over-reactive, phenotype-enhancing neurodegenerative phenomena. Microglia are crucial for managing Aβ, pTAU, and damaged synapses, being pivotal in AD pathogenesis.
Topics: Humans; Mice; Animals; Alzheimer Disease; Microglia; Healthy Aging; Aging; Brain
PubMed: 38132144
DOI: 10.3390/cells12242824 -
Ageing Research Reviews Aug 2023The associations between lipocalin-2 (LCN2) with mild cognitive impairment (MCI) and dementia have gained growing interest. However, population-based studies have... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The associations between lipocalin-2 (LCN2) with mild cognitive impairment (MCI) and dementia have gained growing interest. However, population-based studies have yielded inconsistent findings. Therefore, we conducted this essential systematic review and meta-analysis to analyze and summarize the existing population-based evidence.
METHODS
PubMed, EMBASE, and Web of Science were systematically searched until Mar 18, 2022. Meta-analysis was performed to generate the standard mean difference (SMD) of peripheral blood and cerebrospinal fluid (CSF) LCN2. A qualitative review was performed to summarize the evidence from postmortem brain tissue studies.
RESULTS
In peripheral blood, the overall pooled results showed no significant difference in LCN2 across Alzheimer's disease (AD), MCI and control groups. Further subgroup analysis revealed higher serum LCN2 levels in AD compared to controls (SMD =1.28 [0.44;2.13], p = 0.003), while the difference remained insignificant in plasma (SMD =0.04 [-0.82;0.90], p = 0.931). Besides, peripheral blood LCN2 were higher in AD when age difference between AD and controls ≥ 4 years (SMD =1.21 [0.37;2.06], p = 0.005). In CSF, no differences were found in LCN2 across groups of AD, MCI and controls. However, CSF LCN2 was higher in vascular dementia (VaD) compared to controls (SMD =1.02 [0.17;1.87], p = 0.018), as well as compared to AD (SMD =1.19 [0.58;1.80], p < 0.001). Qualitative analysis supported that LCN2 was increased in the brain tissue of AD-related areas, especially in astrocytes and microglia; while LCN2 increased in infarct-related brain areas and over-expressed in astrocytes and macrophages in mixed dementia (MD).
CONCLUSION
The difference in peripheral blood LCN2 between AD and controls may be affected by the type of biofluid and age. No differences were found in CSF LCN2 across AD, MCI and controls groups. In contrast, CSF LCN2 was elevated in VaD patients. Moreover, LCN2 was increased in AD-related brain areas and cells in AD, while in infarcts-related brain areas and cells in MD.
Topics: Humans; Alzheimer Disease; Biomarkers; Cognitive Dysfunction; Dementia, Vascular; Lipocalin-2; Mixed Dementias
PubMed: 37330019
DOI: 10.1016/j.arr.2023.101984 -
Phytomedicine : International Journal... Oct 2023Neurovascular glial unit (NVGU) dysfunction has been reported to be an early and critical event in the pathophysiology of Alzheimer's disease (AD) and vascular dementia...
BACKGROUND
Neurovascular glial unit (NVGU) dysfunction has been reported to be an early and critical event in the pathophysiology of Alzheimer's disease (AD) and vascular dementia (VD). Although herbal medicines, with their favorable safety profiles and low adverse effects, have been suggested to be useful for the treatment of cognitive impairment, the potential role of the NVGU as the target of the effects of herbal medicines is still unclear.
PURPOSE
This review aimed to retrieve evidence from experimental studies of phytopharmaceuticals targeting the NVGU for the treatment of cognitive impairment in AD and VD, and discussed the potential of phytopharmaceuticals to improve cognitive impairment from the perspective of the NVGU.
STUDY DESIGN AND METHODS
We systematically searched PubMed, Google Scholar, Web of Science, and CNKI. The keywords used for searching information on the NVGU in the treatment of cognitive impairments included "Alzheimer's disease," "Vascular dementia," "Herbal medicines," "Natural products," "Neurovascular," "Adverse reaction," and "Toxicity, etc." We selected studies on the basis of predefined eligibility criteria.
RESULTS
NVGU mainly consists of endothelial cells, pericytes, astrocytes, microglia, oligodendrocytes, and neurons, and damage to these cells can induce cognitive impairment by impairing the blood-brain barrier (BBB) and cerebral blood flow (CBF) as well as neuronal function. The active components of herbal medicines, including Ginkgo biloba L., Ginseng Radix et Rhizoma, Epimedium Folium, Chuanxiong Rhizoma, Carthami flos, and Acorus tatarinowii Schott, as well as traditional Chinese medicine prescriptions have shown the potential to improve BBB function and increase CBF to prevent cognitive impairment by inhibiting astrocyte and microglia activation, protecting oligodendrocyte myelin function, reducing neuronal apoptosis, and promoting angiogenesis.
CONCLUSIONS
Herbal medicines demonstrate great potential to prevent cognitive impairment. Multiple components from herbal medicines may function through different signaling pathways to target the NVGU. Future studies using novel drug-carrier or delivery systems targeting the NVGU will certainly facilitate the development of phytopharmaceuticals for AD and VD.
Topics: Alzheimer Disease; Cognitive Dysfunction; Dementia, Vascular; Drugs, Chinese Herbal; Endothelial Cells; Phytotherapy; Plant Extracts; Plants, Medicinal; Humans
PubMed: 37573807
DOI: 10.1016/j.phymed.2023.155009 -
Biomedicines Dec 2022Lafora disease (LD) is a neurodegenerative condition characterized by the accumulation of polyglucosan bodies (PBs) throughout the brain. Alongside metabolic and... (Review)
Review
BACKGROUND
Lafora disease (LD) is a neurodegenerative condition characterized by the accumulation of polyglucosan bodies (PBs) throughout the brain. Alongside metabolic and molecular alterations, neuroinflammation has emerged as another key histopathological feature of LD.
METHODS
To investigate the role of astrocytes and microglia in LD, we performed a systematic review according to the PRISMA statement. PubMed, Scopus, and Web-of-Science database searches were performed independently by two reviewers.
RESULTS
Thirty-five studies analyzing the relationship of astrocytes and microglia with LD and/or the effects of anti-inflammatory treatments in LD animal models were identified and included in the review. Although LD has long been dominated by a neuronocentric view, a growing body of evidence suggests a role of glial cells in the disease, starting with the finding that these cells accumulate PBs. We discuss the potential meaning of glial PB accumulations, the likely factors activating glial cells, and the possible contribution of glial cells to LD neurodegeneration and epilepsy.
CONCLUSIONS
Given the evidence for the role of neuroinflammation in LD, future studies should consider glial cells as a potential therapeutic target for modifying/delaying LD progression; however, it should be kept in mind that these cells can potentially assume multiple reactive phenotypes, which could influence the therapeutic response.
PubMed: 36551859
DOI: 10.3390/biomedicines10123103 -
Journal of Psychiatric Research Nov 2020Although the precise pathophysiologies underlying autism spectrum disorder (ASD) has not yet been fully clarified, growing evidence supports the involvement of... (Review)
Review
BACKGROUND
Although the precise pathophysiologies underlying autism spectrum disorder (ASD) has not yet been fully clarified, growing evidence supports the involvement of neuroinflammation in the pathogenesis of this disorder, with microglia being particular relevance in the pathophysiologic processes.
OBJECTIVE
The present review aimed to systematically characterize existing literature regarding the role of microglia mediated neuroinflammation in the etiology of ASD.
METHODS
A systematic search was conducted for records indexed within Pubmed, EMBASE, or Web of Science to identify potentially eligible publications. Study selection and data extraction were performed by two authors, and the discrepancies in each step were settled through discussions.
RESULTS
A total of 14 studies comprising 1007 subjects met the eligibility criteria for this review, including 8 immunohistochemistry (IHC) studies, 5 genetic analysis studies, and 1 positron emission tomography (PET) studies. Although small in quantity, the included studies collectively pointed to a role of microglia mediated neuroinflammation in the pathogenesis of ASD.
CONCLUSION
Findings generated from this review consistently supported the involvement of neuroinflammation in the development of ASD, confirmed by the activation of microglia in different brain regions, involving increased cell number or cell density, morphological alterations, and phenotypic shifts.
Topics: Autism Spectrum Disorder; Brain; Humans; Inflammation; Microglia; Positron-Emission Tomography
PubMed: 32823050
DOI: 10.1016/j.jpsychires.2020.07.013 -
Injury Nov 2020To acquire evidence-based knowledge in temporal and spatial patterns of microglia/macrophages changes to facilitate finding proper intervention time for functional... (Review)
Review
OBJECTIVE
To acquire evidence-based knowledge in temporal and spatial patterns of microglia/macrophages changes to facilitate finding proper intervention time for functional restoration after traumatic spinal cord injury (TSCI).
SETTING
Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences, Tehran, Iran.
METHODS
We searched PubMed and EMBASE via Ovid SP with no temporal and linguistic restrictions. Besides, hand-search was performed in the bibliographies of relevant studies. The experimental non-interventional and non-transgenic animal studies confined to the rat species which assess the pathological change of microglia /macrophages at the specified time were included.
RESULTS
We found 15,315 non-duplicate studies. Screening through title and abstract narrowed down to 607 relevant articles, 31 of them were selected based on the inclusion criteria. The reactivity of the microglia/macrophages initiates in early hours PI in contusion, compression and transection models. Cells activity reached a maximum within 48 h to 28 days in compression, 7 days in contusion and between 4 and 60 days in transection models. Inflammatory response occurred at the epicenter, in or near the lesion site in both gray and white matter in all three injury models with a maximum extension of one centimeter caudal and rostral to the epicenter in the gray matter in contusion and transection models.
CONCLUSION
This study was designed to study spatial-temporal changes in the activation of microglia/macrophages overtime after TSCI. We were able to demonstrate time-dependent cell morphological changes after TSCI. The peak times of cell reactivity and the areas where the cells responded to the injury were determined.
Topics: Animals; Contusions; Disease Models, Animal; Iran; Macrophages; Microglia; Rats; Spinal Cord; Spinal Cord Injuries
PubMed: 32665068
DOI: 10.1016/j.injury.2020.07.007 -
Neuroscience and Biobehavioral Reviews Jul 2023Exposure to stress during early development may lead to altered neurobiological functions, thus increasing the risk for psychiatric illnesses later in life. One... (Meta-Analysis)
Meta-Analysis Review
Exposure to stress during early development may lead to altered neurobiological functions, thus increasing the risk for psychiatric illnesses later in life. One potential mechanism associated with those outcomes is the disruption of glial density and morphology, despite results from rodent studies have been conflicting. To address that we performed a systematic review and meta-analysis of rodent studies that investigated the effects of prenatal stress (PNS) and early life stress (ELS) on microglia, astrocyte, and oligodendrocyte density and morphology within the offspring. Our meta-analysis demonstrates that animals exposed to PNS or ELS showed significant increase in microglia density, as well as decreased oligodendrocyte density. Moreover, ELS exposure induced an increase in microglia soma size. However, we were unable to identify significant effects on astrocytes. Meta-regression indicated that experimental stress protocol, sex, age, and type of tissue analyzed are important covariates that impact those results. Importantly, PNS microglia showed higher estimates in young animals, while the ELS effects were stronger in adult animals. This set of data reinforces that alterations in glial cells could play a role in stress-induced dysfunctions throughout development.
Topics: Animals; Female; Pregnancy; Astrocytes; Microglia; Oligodendroglia; Rodentia; Stress, Psychological
PubMed: 37116770
DOI: 10.1016/j.neubiorev.2023.105202 -
Biomedicine & Pharmacotherapy =... Sep 2023Neurodegenerative diseases (NDDs) encompass a range of conditions that involve progressive deterioration and dysfunction of the nervous system. Some of the common NDDs... (Review)
Review
Neurodegenerative diseases (NDDs) encompass a range of conditions that involve progressive deterioration and dysfunction of the nervous system. Some of the common NDDs include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Although significant progress has been made in understanding the pathological mechanisms of NDDs in recent years, the development of targeted and effective drugs for their treatment remains challenging. Kaempferol is a flavonoid whose derivatives include kaempferol-O-rhamnoside, 3-O-β-rutinoside/6-hydroxykaempferol 3,6-di-O-β-d-glucoside, and kaempferide. Emerging studies have suggested that kaempferol and its derivatives possess neuroprotective properties and may have potential therapeutic benefits in NDDs. Here, we aimed to provide a theoretical basis for the use of kaempferol and its derivatives in the clinical treatment of NDDs. We systematically reviewed the literature in the PubMed, Web of Science, and Science Direct databases until June 2022 using the search terms "kaempferol," "kaempferol derivatives," "NDDs," "pharmacokinetics," and "biosynthesis" according to the reporting items for systematic review (PRISMA) standard. Based on combined results of in vivo and in vitro studies, we summarize the basic mechanisms and targets of kaempferol and its derivatives in the management of AD, PD, HD, and ALS. Kaempferol and its derivatives exert a neuroprotective role mainly by preventing the deposition of amyloid fibrils (such as Aβ, tau, and α-synuclein), inhibiting microglia activation, reducing the release of inflammatory factors, restoring the mitochondrial membrane to prevent oxidative stress, protecting the blood-brain barrier, and inhibiting specific enzyme activities (such as cholinesterase). Kaempferol and its derivatives are promising natural neuroprotective agents. By determining their pharmacological mechanism, kaempferol and its derivatives may be new candidate drugs for the treatment of NDDs.
Topics: Humans; Neurodegenerative Diseases; Neuroprotective Agents; Amyotrophic Lateral Sclerosis; Kaempferols; Alzheimer Disease; Parkinson Disease; Huntington Disease
PubMed: 37494786
DOI: 10.1016/j.biopha.2023.115215