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Dysregulation of cellular processes in reactive astrocytes. The figure illustrates a reactive astrocyte displaying differentially regulated processes in response to Aβ pathology. Aβ pathology does not only impact astrocyte function at the single-cell level, but affects the entire astrocyte network. Long-term astrocyte reactivity is associated with a pro-inflammatory transcriptional profile and the decreased expression of neuronal support genes. Functionally, reactive astrocytes display an increase in calcium-wave signaling, which is associated with the increased release of gliotransmitters, including glutamate and GABA. Reactive astrocytes additionally upregulate the expression of several receptors which further stimulates gliotransmitter release. Simultaneously, reactive astrocytes downregulate the expression of glutamate transporters (GLAST/GLT-1), which promotes the presence of glutamate in the synapse. This is further stimulated by the decreased expression of GS. Astrocytes are furthermore important for maintenance of the K⁺ homeostasis and its dysfunction has been implicated in more advanced stages of AD progression, characterized by the decreased expression of Kir4.1 mRNA and impaired gap-junction coupling. In early-stage AD, however, reactive astrocytes ameliorate disease progression by the upregulation of Kir4.1 protein expression near Aβ-plaque enriched areas and protect against Aβ pathology through their active participation in Aβ clearance and the formation of a protective border surrounding the Aβ plaque. Figure was created with the help of BioRender.com
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Alzheimer’s disease (AD) causes the majority of dementia cases worldwide. Early pathological hallmarks include the accumulation of amyloid-ß (Aß) and activation of both astrocytes and microglia. Neurons form the building blocks of the central nervous system, and astrocytes and microglia provide essential input for its healthy functioning. Their fun...
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Neuronal signalling is a key element in neuronal communication and is essential for the proper functioning of the CNS. Astrocytes, the most prominent glia in the brain play a key role in modulating neuronal signalling at the molecular, synaptic, cellular, and network levels. Over the past few decades, our knowledge about astrocytes and their functi...
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... Our hypothesis, supported by the current tissue analysis, is that GM changes induced by Lactobacilli would affect the brain, probably via modulation of circulating pro-inflammation markers secreted by locally reduced astrocytes and/or microglia. It is well established that taming neuroinflammation would positively impact the neuronal population (Chitnis and Weiner, 2017;Kaur et al., 2019;Huffels et al., 2022), resulting in healthier neuronal pathways (e.g., EC-Hippocampus), with subsequent improved memory performance. In our studies, 3xTg-AD mice on a regular diet showed consistently increased counts of glial cells in both the EC (Figures 3, 4) and the hippocampus (Figure 6), suggestive of hyperplasia and early stages of reactive gliosis. ...
The lack of affordable and effective therapeutics against cognitive impairment has promoted research toward alternative approaches to the treatment of neurodegeneration. In recent years, a bidirectional pathway that allows the gut to communicate with the central nervous system has been recognized as the gut-brain axis. Alterations in the gut microbiota, a dynamic population of trillions of microorganisms residing in the gastrointestinal tract, have been implicated in a variety of pathological states, including neurodegenerative disorders such as Alzheimer’s disease (AD). However, probiotic treatment as an affordable and accessible adjuvant therapy for the correction of dysbiosis in AD has not been thoroughly explored. Here, we sought to correct the dysbiosis in an AD mouse model with probiotic supplementation, with the intent of exploring its effects on disease progression. Transgenic 3xTg-AD mice were fed a control or a probiotic diet (Lactobacillus plantarum KY1032 and Lactobacillus curvatus HY7601) for 12 weeks, with the latter leading to a significant increase in the relative abundance of Bacteroidetes. Cognitive functions were evaluated via Barnes Maze trials and improvements in memory performance were detected in probiotic-fed AD mice. Neural tissue analysis of the entorhinal cortex and hippocampus of 10-month-old 3xTg-AD mice demonstrated that astrocytic and microglial densities were reduced in AD mice supplemented with a probiotic diet, with changes more pronounced in probiotic-fed female mice. In addition, elevated numbers of neurons in the hippocampus of probiotic-fed 3xTg-AD mice suggested neuroprotection induced by probiotic supplementation. Our results suggest that probiotic supplementation could be effective in delaying or mitigating early stages of neurodegeneration in the 3xTg-AD animal model. It is vital to explore new possibilities for palliative care for neurodegeneration, and probiotic supplementation could provide an inexpensive and easily implemented adjuvant clinical treatment for AD.
... Therefore, the underlying mechanism of SSE/L was the activation of Akt signaling, leading to upregulation of Nrf2/HO-1 expression and attenuation of oxidative stress. Prior studies noted that the accumulation of Aβ and activation of both astrocytes and microglia are early pathological hallmarks of AD [47]. Moreover, Aβ 1-42 infusion led to an activation of glial cells and an increase in levels of NF-κB, phosphor-IKKβ, and inflammatory mediators including iNOS, TNF-α and IL-1β [2]. ...
The accumulation of amyloid-beta (Aβ) peptides is a crucial factor in the neuronal degeneration of Alzheimer’s disease (AD). The current study investigated the underlying neuroprotective mechanisms of shrimp shell extract (SSE) and liposome-encapsulated SSE (SSE/L) against Aβ1-42-induced neuronal damage and death in rats. Intracerebroventricular infusion of Aβ1-42 effectively induced memory decline, as observed in a reduction of the rat’s discriminating ability in the novel object recognition and novel object location tasks. Oral pretreatment with 100 mg/kg of SSE demonstrated no preventive effect on the memory decline induced by Aβ1-42 infusion. However, treatment with SSE/L 100 mg/kg BW effectively attenuated memory deficits in both behavioral assessments following two and four weeks after Aβ1-42 infusion. Moreover, SSE/L exerted neuroprotective effects by reducing lipid peroxidation and increasing Nrf2/HO-1 expression. There was a significant decrease in Iba1 and GFAP (biomarkers of microglia and astrocyte activity, respectively), as well as a decrease in the levels of NF-κB expression and the inflammatory cytokines TNF-α and IL-6 in the cortical and hippocampal tissues. Treatment with SSE/L also reduced the pro-apoptotic proteins Bax and cleaved caspase-3 while raising the anti-apoptotic protein Bcl2. In addition, the beneficial effects of SSE/L were along with the effects of a positive control commercial astaxanthin (AST). The findings of this study indicated that SSE/L provided neuroprotective effects on Aβ1-42-induced AD rats by ameliorating oxidative stress, neuroinflammation and apoptotic cell death. Therefore, SSE/L might be employed to prevent and mitigate Aβ accumulation-induced neurotoxicity in AD.
... Astrocytes completely surround the capillaries with their endfeet, serve as the outer surface of the BBB and significantly contribute to the maintenance of the BBB [16]. They play a crucial role in neurotransmitter recycling, maintenance of tissue ion homeostasis and the regulation of synaptic transmission via the release of gliotransmitters [21]. ...
Alzheimer’s disease (AD) is a progressive neurodegenerative disease representing the most common type of dementia in older adults. The major risk factors include increased age, genetic predisposition and socioeconomic factors. Among the genetic factors, the apolipoprotein E (ApoE) ε4 allele poses the greatest risk. Growing evidence suggests that cerebrovascular dysfunctions, including blood–brain barrier (BBB) leakage, are also linked to AD pathology. Within the scope of this paper, we, therefore, look upon the relationship between ApoE, BBB integrity and AD. In doing so, both brain-derived and peripheral ApoE will be considered. Despite the considerable evidence for the involvement of brain-derived ApoE ε4 in AD, information about the effect of peripheral ApoE ε4 on the central nervous system is scarce. However, a recent study demonstrated that peripheral ApoE ε4 might be sufficient to impair brain functions and aggravate amyloid-beta pathogenesis independent from brain-based ApoE ε4 expression. Building upon recent literature, we provide an insight into the latest research that has enhanced the understanding of how ApoE ε4, secreted either in the brain or the periphery, influences BBB integrity and consequently affects AD pathogenesis. Subsequently, we propose a pathway model based on current literature and discuss future research perspectives.
... Both datasets originated from the prefrontal cortex of post-mortem brains and were part of the same cohort studies on aging and dementia, specifically the ROSMAP project ( Figure 1a). Recent studies underline that the accumulation of Aβ not only leads to glial activation but also markedly compromises glial functionality (Huffels et al., 2023;Sierksma et al., 2020;Zeng et al., 2023). In our previous work, we observed that Aβ42 overexpression caused reduction in glial H3K9ac and led to PHP impairment in Drosophila AD models (Yin et al., 2023). ...
Synaptic homeostatic plasticity is a foundational regulatory mechanism that maintains the stability of synaptic and neural functions within the nervous system. Impairment of homeostatic regulation has been linked to synapse destabilization during the progression of Alzheimer's disease (AD). Recent epigenetic and transcriptomic characterizations of the nervous system have revealed intricate molecular details about the aging brain and the pathogenesis of neurodegenerative diseases. Yet, how abnormal epigenetic and transcriptomic alterations in different cell types in AD affect synaptic homeostatic plasticity remains to be elucidated. Various glial cell types play critical roles in modulating synaptic functions both during the aging process and in the context of AD. Here, we investigated the impact of glial dysregulation of histone acetylation and transcriptome in AD on synaptic homeostatic plasticity, using computational analysis combined with electrophysiological methods in Drosophila . By integrating snRNA‐seq and H3K9ac ChIP‐seq data from the same AD patient cohort, we pinpointed cell type‐specific signature genes that were transcriptionally altered by histone acetylation. We subsequently investigated the role of these glial genes in regulating presynaptic homeostatic potentiation in Drosophila . Remarkably, nine glial‐specific genes, which were identified through our computational method as targets of H3K9ac and transcriptional dysregulation, were found to be crucial for the regulation of synaptic homeostatic plasticity in Drosophila . Our genetic evidence connects abnormal glial transcriptomic changes in AD with the impairment of homeostatic plasticity in the nervous system. In summary, our integrative computational and genetic studies highlight specific glial genes as potential key players in the homeostatic imbalance observed in AD.
... Alterations in the complement pathway are described already in the early stages of the disease [189]. Aβ per se in fact can bind and activate the complement system [196] and induce the microglia release of the C1p complement factor, which increases the astrocytic release of C3, finally leading to synaptic phagocytosis [189,197]. Accordingly, the levels of C1q and C3 were found upregulated in an AD mouse model, and the deficiency of C1q, C3 and its receptor C3R rescued synaptic density [189]. ...
Microglia are the resident immune cells of the central nervous system that guarantee immune surveillance and exert also a modulating role on neuronal synaptic development and function. Upon injury, microglia get activated and modify their morphology acquiring an ameboid phenotype and pro- or anti-inflammatory features. The active role of microglia in blood–brain barrier (BBB) function and their interaction with different cellular components of the BBB—endothelial cells, astrocytes and pericytes—are described. Here, we report the specific crosstalk of microglia with all the BBB cell types focusing in particular on the involvement of microglia in the modulation of BBB function in neuroinflammatory conditions that occur in conjunction with an acute event, such as a stroke, or in a slow neurodegenerative disease, such as Alzheimer’s disease. The potential of microglia to exert a dual role, either protective or detrimental, depending on disease stages and environmental conditioning factors is also discussed.
... Neurotransmitters can stimulate astrocytes to release gliotransmitters, but not all of them have this effect. Both purinergic receptor P2Y1 and protease-activated receptor 1 (PAR1), for instance, cause an increase in calcium levels in the astrocytes of the hippocampal nucleus [100], but only PAR1 receptors cause astrocytes to release gliotransmitters, because glutamate released by astrocytes during this process activates N-methyl-D-aspartate receptor (NMDAR) neurons [101]. Depending on the type of receptor it contacts, the various gliotransmitters generated by astrocytes can potentially affect synaptic communication. ...
Depression is a mental illness that has a serious negative impact on physical and mental health. The pathophysiology of depression is still unknown, and therapeutic medications have drawbacks, such as poor effectiveness, strong dependence, adverse drug withdrawal symptoms, and harmful side effects. Therefore, the primary purpose of contemporary research is to understand the exact pathophysiology of depression. The connection between astrocytes, neurons, and their interactions with depression has recently become the focus of great research interest. This review summarizes the pathological changes of neurons and astrocytes, and their interactions in depression, including the alterations of mid-spiny neurons and pyramidal neurons, the alterations of astrocyte-related biomarkers, and the alterations of gliotransmitters between astrocytes and neurons. In addition to providing the subjects of this research and suggestions for the pathogenesis and treatment techniques of depression, the intention of this article is to more clearly identify links between neuronal–astrocyte signaling processes and depressive symptoms.
... Spatiotemporal progression analysis based on magnetic resonance imaging revealed the earliest signs of atrophy in the amygdala and hippocampus, followed by middle temporal gyrus, entorhinal, parahippocampal and other temporal cortex areas, then thalamus and striatum and finally frontal, cingular, parietal and insular cortex as well as pallidum [5]. A multitude of molecular and cellular mechanisms preceding neuronal loss have been uncovered and linked to the development of AD, such as inflammatory processes and microglia activation, reactive astrocytes, disturbance of calcium signaling, and synapse dysfunction and loss [6]. Additionally, the neural extracellular matrix (ECM), a macromolecular meshwork of glycoproteins, proteoglycans, link proteins and hyaluronan, was reported to undergo rearrangements in human AD brains as well as in animal models for AD. ...
The brain’s extracellular matrix (ECM) is assumed to undergo rearrangements in Alzheimer’s disease (AD). Here, we investigated changes of key components of the hyaluronan-based ECM in independent samples of post-mortem brains (N = 19), cerebrospinal fluids (CSF; N = 70), and RNAseq data (N = 107; from The Aging, Dementia and TBI Study) of AD patients and non-demented controls. Group comparisons and correlation analyses of major ECM components in soluble and synaptosomal fractions from frontal, temporal cortex, and hippocampus of control, low-grade, and high-grade AD brains revealed a reduction in brevican in temporal cortex soluble and frontal cortex synaptosomal fractions in AD. In contrast, neurocan, aggrecan and the link protein HAPLN1 were up-regulated in soluble cortical fractions. In comparison, RNAseq data showed no correlation between aggrecan and brevican expression levels and Braak or CERAD stages, but for hippocampal expression of HAPLN1, neurocan and the brevican-interaction partner tenascin-R negative correlations with Braak stages were detected. CSF levels of brevican and neurocan in patients positively correlated with age, total tau, p-Tau, neurofilament-L and Aβ1-40. Negative correlations were detected with the Aβ ratio and the IgG index. Altogether, our study reveals spatially segregated molecular rearrangements of the ECM in AD brains at RNA or protein levels, which may contribute to the pathogenic process.
... Synaptic integration between neurons, astrocytes, and microglia ensures optimal brain function and cognitive performance. When Aβ accumulates, the synapse is pushed from its healthy equilibrium toward a pathological state, and similar alterations in astrocyte and microglia function also participate in this transition [41]. In the early stages of AD, astrocytes and microglia act protectively and attempt to correct aberrant synaptic transmission by taking part in the Aβ clearance and the compensatory production of functional proteins. ...
Recent observations from clinical trials using monoclonal antibodies against Aβ seem to suggest that Aβ-targeting is modestly effective and not sufficiently based on an effective challenge of the role of Aβ from physiological to pathological. After an accelerated approval procedure for aducanumab, and more recently lecanemab, their efficacy and safety remain to be fully defined despite previous attempts with various monoclonal antibodies, and both academic institutions and pharmaceutical companies are actively searching for novel treatments. Aβ needs to be clarified further in a more complicated context, taking into account both its accumulation and its biological functions during the course of the disease. In this review, we discuss the border between activities affecting early, potentially reversible dysfunctions of the synapse and events trespassing the threshold of inflammatory, self-sustaining glial activation, leading to irreversible damage. We detail a clear understanding of the biological mechanisms underlying the derangement from function to dysfunction and the switch of the of Aβ role from physiological to pathological. A picture is emerging where the optimal therapeutic strategy against AD should involve a number of allied molecular processes, displaying efficacy not only in reducing the well-known AD pathogenesis players, such as Aβ or neuroinflammation, but also in preventing their adverse effects.
... The article will give examples of this mode of regulation as well the mechanisms involved. Since many astrocytic neurosupportive functions decline in age and disease [8][9][10], knowledge of how they are regulated in the healthy brain may point to ways in which they can be manipulated for therapeutic effect. ...
The brain is a complex organ even when viewed from a cell biological perspective. Neuronal networks are embedded in a dense milieu of diverse and specialised cell types, including several types of vascular, immune, and macroglial cells. To view each cell as a small cog in a highly complex machine is itself an oversimplification. Not only are they functionally coupled to enable the brain to operate, each cell type's functions are themselves influenced by each other, in development, maturity, and also in disease. Astrocytes are a type of macroglia that occupy a significant fraction of the human forebrain. They play a critical role in sustaining functional neuronal circuits across the lifespan through myriad homeostatic functions including the maintenance of redox balance, ionic gradients, neurotransmitter clearance, and bioenergetic support. It is becoming apparent that astrocytes' capacity to carry out these and other neurosupportive roles is not fixed, but is regulated by signals coming from the neurons themselves, both in the healthy brain but also in response to neuron-derived disease pathology. Here, we review mechanisms by which neurons control the properties of astrocytes long term in order to alter their homeostatic capacity both in development and maturity. Our working hypothesis is that these signals are designed to change and maintain the homeostatic capacity of local astrocytes to suit the needs of nearby neurons. Knowledge of the external signals that can control core aspects of a healthy astrocytic phenotype are being uncovered, raising the question as to whether this knowledge can be harnessed to promote astrocyte-mediated neurosupport in brain disorders.
... Astrocytes are engaged in the regulation of synaptic function through the release of gliotransmitters such as glutamate, glycine, gamma-aminobutyric acid (GABA), D-serine and ATP [114]. Cumulative and recent evidence highlight the role of astrocytic GABAergic systems in the pathophysiology of AD, as well as a possible target for pharmacological interventions (for review see [115]). ...
Alzheimer’s disease (AD) is a frequent and disabling neurodegenerative disorder, in which astrocytes participate in several pathophysiological processes including neuroinflammation, excitotoxicity, oxidative stress and lipid metabolism (along with a critical role in apolipoprotein E function). Current evidence shows that astrocytes have both neuroprotective and neurotoxic effects depending on the disease stage and microenvironmental factors. Furthermore, astrocytes appear to be affected by the presence of amyloid-beta (Aβ), with alterations in calcium levels, gliotransmission and proinflammatory activity via RAGE-NF-κB pathway. In addition, astrocytes play an important role in the metabolism of tau and clearance of Aβ through the glymphatic system. In this review, we will discuss novel pharmacological and non-pharmacological treatments focused on astrocytes as therapeutic targets for AD. These interventions include effects on anti-inflammatory/antioxidant systems, glutamate activity, lipid metabolism, neurovascular coupling and glymphatic system, calcium dysregulation, and in the release of peptides which affects glial and neuronal function. According to the AD stage, these therapies may be of benefit in either preventing or delaying the progression of the disease.
