Astrocytes, also called astroglia, maintain homoeostasis of the brain by providing trophic and metabolic support to neurons. They recycle neurotransmitters, stimulate synaptogenesis and synaptic ...neurotransmission, form part of the blood–brain barrier, and regulate regional blood flow. Although astrocytes have been known to display morphological alterations in Alzheimer's disease for more than a century, research has remained neurocentric. Emerging evidence suggests that these morphological changes reflect functional alterations that affect disease.
Genetic studies indicate that most of the risk of developing late onset Alzheimer's disease, the most common form of the disease, affecting patients aged 65 years and older, is associated with genes (ie, APOE, APOJ, and SORL) that are mainly expressed by glial cells (ie, astrocytes, microglia, and oligodendrocytes). This insight has moved the focus of research away from neurons and towards glial cells and neuroinflammation. Molecular studies in rodent models suggest a direct contribution of astrocytes to neuroinflammatory and neurodegenerative processes causing Alzheimer's disease; however, these models might insufficiently mimic the human disease, because rodent astrocytes differ considerably in morphology, functionality, and gene expression. In-vivo studies using stem-cell derived human astrocytes are allowing exploration of the human disease and providing insights into the neurotoxic or protective contributions of these cells to the pathogenesis of disease. The first attempts to develop astrocytic biomarkers and targeted therapies are emerging.
Single-cell transcriptomics allows the fate of individual astrocytes to be followed in situ and provides the granularity needed to describe healthy and pathological cellular states at different stages of Alzheimer's disease. Given the differences between human and rodent astroglia, study of human cells in this way will be crucial. Although refined single-cell transcriptomic analyses of human post-mortem brains are important for documentation of pathology, they only provide snapshots of a dynamic reality. Thus, functional work studying human astrocytes generated from stem cells and exposed to pathological conditions in rodent brain or cell culture are needed to understand the role of these cells in the pathogenesis of Alzheimer's disease. These studies will lead to novel biomarkers and hopefully a series of new drug targets to tackle this disease.
Lee et al.1 report that loss of the Alzheimer’s disease risk factor SORL1 results in neuron-specific reduction in APOE and CLU, altered lipid homeostasis, and increased Aβ levels and phosphorylated ...Tau, both rescued by stabilizing retromer or enhancing autophagy.
Lee et al.1 report that loss of the Alzheimer’s disease risk factor SORL1 results in neuron-specific reduction in APOE and CLU, altered lipid homeostasis, and increased Aβ levels and phosphorylated Tau, both rescued by stabilizing retromer or enhancing autophagy.
Astrocytes perform a wide variety of essential functions defining normal operation of the nervous system and are active contributors to the pathogenesis of neurodegenerative disorders such as ...Alzheimer's among others. Recent data provide compelling evidence that distinct astrocyte states are associated with specific stages of Alzheimer´s disease. The advent of transcriptomics technologies enables rapid progress in the characterisation of such pathological astrocyte states. In this review, we provide an overview of the origin, main functions, molecular and morphological features of astrocytes in physiological as well as pathological conditions related to Alzheimer´s disease. We will also explore the main roles of astrocytes in the pathogenesis of Alzheimer´s disease and summarize main transcriptional changes and altered molecular pathways observed in astrocytes during the course of the disease.
The mitochondrial intramembrane rhomboid protease PARL has been implicated in diverse functions in vitro, but its physiological role in vivo remains unclear. Here we show that Parl ablation in mouse ...causes a necrotizing encephalomyelopathy similar to Leigh syndrome, a mitochondrial disease characterized by disrupted energy production. Mice with conditional PARL deficiency in the nervous system, but not in muscle, develop a similar phenotype as germline Parl KOs, demonstrating the vital role of PARL in neurological homeostasis. Genetic modification of two major PARL substrates, PINK1 and PGAM5, do not modify this severe neurological phenotype. Parl
−/− brain mitochondria are affected by progressive ultrastructural changes and by defects in Complex III (CIII) activity, coenzyme Q (CoQ) biosynthesis, and mitochondrial calcium metabolism. PARL is necessary for the stable expression of TTC19, which is required for CIII activity, and of COQ4, which is essential in CoQ biosynthesis. Thus, PARL plays a previously overlooked constitutive role in the maintenance of the respiratory chain in the nervous system, and its deficiency causes progressive mitochondrial dysfunction and structural abnormalities leading to neuronal necrosis and Leigh-like syndrome.
Evolution of neuroglia Verkhratsky, Alexei; Arranz, Amaia M.; Ciuba, Katarzyna ...
Annals of the New York Academy of Sciences,
December 2022, 2022-12-00, 20221201, Letnik:
1518, Številka:
1
Journal Article
Recenzirano
The evolution of the nervous system progressed through cellular diversification and specialization of functions. Conceptually, the nervous system is composed of electrically excitable neuronal ...networks connected by chemical synapses and nonexcitable glial cells that provide for homeostasis and defense. The evolution of neuroglia began with the emergence of the centralized nervous system and proceeded through a continuous increase in their complexity. In the primate brain, especially in the brain of humans, the astrocyte lineage is exceedingly complex, with the emergence of new types of astroglial cells possibly involved in interlayer communication and integration.
This paper describes the evolution of neuroglia, which began with the emergence of the centralized nervous system and proceeded through a continuous increase in their complexity. In the primate brain, especially in the brain of humans, the astrocyte lineage is exceedingly complex, with the emergence of new types of astroglial cells possibly involved in interlayer communication and integration.
Neuronal cell loss is a defining feature of Alzheimer’s disease (AD), but the underlying mechanisms remain unclear. We xenografted human or mouse neurons into the brain of a mouse model of AD. Only ...human neurons displayed tangles, Gallyas silver staining, granulovacuolar neurodegeneration (GVD), phosphorylated tau blood biomarkers, and considerable neuronal cell loss. The long noncoding RNA
MEG3
was strongly up-regulated in human neurons
.
This neuron-specific long noncoding RNA is also up-regulated in AD patients.
MEG3
expression alone was sufficient to induce necroptosis in human neurons in vitro. Down-regulation of
MEG3
and inhibition of necroptosis using pharmacological or genetic manipulation of receptor-interacting protein kinase 1 (RIPK1), RIPK3, or mixed lineage kinase domain-like protein (MLKL) rescued neuronal cell loss in xenografted human neurons. This model suggests potential therapeutic approaches for AD and reveals a human-specific vulnerability to AD.
Editor’s summary
Neurons are one of the longest-living and enduring cell types of the human body. Balusu
et al
. xenografted human neurons into mouse brains containing amyloid plaques (see the Perspective by Sirkis and Yokoyama). The human neurons, but not the mouse neurons, displayed severe Alzheimer’s pathology, including tangles and necroptosis. Human neurons up-regulated the neuron-specific maternally expressed gene 3 (MEG3) in response to amyloid plaques. Down-regulation of MEG3 protected the neurons from dying in the xenograft model of Alzheimer’s disease. Downstream of MEG3, genetic or pharmacological manipulation of signaling kinases in the necroptosis pathway also protected neurons, suggesting a potential lead toward therapeutic approaches for Alzheimer’s disease. —Stella M. Hurtley
In models of Alzheimer’s disease, a long noncoding RNA activates necroptosis and necroptosis inhibition rescues neuronal loss.
Human pluripotent stem cells (PSCs) provide a unique entry to study species-specific aspects of human disorders such as Alzheimer’s disease (AD). However, in vitro culture of neurons deprives them of ...their natural environment. Here we transplanted human PSC-derived cortical neuronal precursors into the brain of a murine AD model. Human neurons differentiate and integrate into the brain, express 3R/4R Tau splice forms, show abnormal phosphorylation and conformational Tau changes, and undergo neurodegeneration. Remarkably, cell death was dissociated from tangle formation in this natural 3D model of AD. Using genome-wide expression analysis, we observed upregulation of genes involved in myelination and downregulation of genes related to memory and cognition, synaptic transmission, and neuron projection. This novel chimeric model for AD displays human-specific pathological features and allows the analysis of different genetic backgrounds and mutations during the course of the disease.
•Human-mouse chimeric model of Alzheimer’s disease•PSC-derived human neurons grafted into an AD mouse•Major degeneration and loss of human neurons in chimeric AD mice•Absence of tangle pathology in degenerating human neurons in vivo
Espuny-Camacho, Arranz et al. show in this article a novel chimeric model of Alzheimer’s disease generated using human neurons derived from pluripotent stem cells. This new chimeric model shows degeneration and major loss of human neurons without the presence of Tau tangles.
Mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with Parkinson’s disease, but the precise physiological function of the protein remains ill-defined. Recently, our group proposed a ...model in which LRRK2 kinase activity is part of an EndoA phosphorylation cycle that facilitates efficient vesicle formation at synapses in the Drosophila melanogaster neuromuscular junctions.Flies harbor only one Lrrk gene, which might encompass the functions of both mammalian LRRK1 and LRRK2. We therefore studied the role of LRRK2 in mammalian synaptic function and provide evidence that knockout or pharmacological inhibition of LRRK2 results in defects in synaptic vesicle endocytosis, altered synaptic morphology and impairments in neurotransmission. In addition, our data indicate that mammalian endophilin A1 (EndoA1,also known as SH3GL2) is phosphorylated by LRRK2 in vitro at T73 and S75, two residues in the BAR domain. Hence, our results indicate that LRRK2 kinase activity has an important role in the regulation of clathrin-mediated endocytosis of synaptic vesicles and subsequent neurotransmission at the synapse.
Mutant mice deficient in hyaluronan (HA) have an epileptic phenotype. HA is one of the major constituents of the brain extracellular matrix. HA has a remarkable hydration capacity, and a lack of HA ...causes reduced extracellular space (ECS) volume in the brain. Reducing ECS volume can initiate or exacerbate epileptiform activity in many
models of epilepsy. There is both
and
evidence of a positive feedback loop between reduced ECS volume and synchronous neuronal activity. Reduced ECS volume promotes epileptiform activity primarily via enhanced ephaptic interactions and increased extracellular potassium concentration; however, the epileptiform activity in many models, including the brain slices from HA synthase-3 knockout mice, may still require glutamate-mediated synaptic activity. In brain slice epilepsy models, hyperosmotic solution can effectively shrink cells and thus increase ECS volume and block epileptiform activity. However,
, the intravenous administration of hyperosmotic solution shrinks both brain cells and brain ECS volume. Instead, manipulations that increase the synthesis of high-molecular-weight HA or decrease its breakdown may be used in the future to increase brain ECS volume and prevent seizures in patients with epilepsy. The prevention of epileptogenesis is also a future target of HA manipulation. Head trauma, ischemic stroke, and other brain insults that initiate epileptogenesis are known to be associated with an early decrease in high-molecular-weight HA, and preventing that decrease in HA may prevent the epileptogenesis.
The origins of bread have long been associated with the emergence of agriculture and cereal domestication during the Neolithic in southwest Asia. In this study we analyze a total of 24 charred food ...remains from Shubayqa 1, a Natufian hunter-gatherer site located in northeastern Jordan and dated to 14.6–11.6 ka cal BP. Our finds provide empirical data to demonstrate that the preparation and consumption of bread-like products predated the emergence of agriculture by at least 4,000 years. The interdisciplinary analyses indicate the use of some of the “founder crops” of southwest Asian agriculture (e.g., Triticum boeoticum, wild einkorn) and root foods (e.g., Bolboschoenus glaucus, club-rush tubers) to produce flat bread-like products. The available archaeobotanical evidence for the Natufian period indicates that cereal exploitation was not common during this time, and it is most likely that cereal-based meals like bread become staples only when agriculture was firmly established.
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