Targeting Astrocytes Research Articles

Astrocytes and Memory: Implications for the Treatment of Memory-related Disorders.

Memory refers to the imprint accumulated in the brain by life experiences and represents the basis for humans to engage in advanced psychological activities such as thinking and imagination. Previously, research activities focused on memory have always targeted neurons. However, in addition to neurons, astrocytes are also involved in the encoding, consolidation, and extinction of memory. In particular, astrocytes are known to affect the recruitment and function of neurons at the level of local synapses and brain networks. Moreover, the involvement of astrocytes in memory and memory-related disorders, especially in Alzheimer's disease (AD) and post-traumatic stress disorder (PTSD), has been investigated extensively. In this review, we describe the unique contributions of astrocytes to synaptic plasticity and neuronal networks and discuss the role of astrocytes in different types of memory processing. In addition, we also explore the roles of astrocytes in the pathogenesis of memory-related disorders, such as AD, brain aging, PTSD and addiction, thus suggesting that targeting astrocytes may represent a potential strategy to treat memory-related neurological diseases. In conclusion, this review emphasizes that thinking from the perspective of astrocytes will provide new ideas for the diagnosis and therapy of memory-related neurological disorders.

Targeting astrocytes polarization after spinal cord injury: a promising direction.

Spinal cord injury (SCI) is a serious neurological injury that causes severe trauma to motor and sensory functions. Although long considered incurable, recent research has brought new hope for functional recovery from SCI. After SCI, astrocytes are activated into many polarization states. Here we discuss the two most important classical phenotypes: the 'A1' neurotoxic phenotype and the 'A2' neuroprotective phenotype, with A1 astrocytes being neurotoxic and impeding neurorecovery, and A2 astrocytes being neuroprotective. This paper discusses the changes in astrocyte responsiveness after SCI and the pros and cons of their polarization in SCI. It also elucidates the feasibility of astrocyte polarization as a therapeutic target for neuroprotection. In the future, multiple intervention strategies targeting astrocyte polarization are expected to gain wider clinical application, ultimately improving motor-sensory function and quality of life in SCI patients.

Astroglial membrane camouflaged Ptbp1 siRNA delivery hinders glutamate homeostasis via SDH/Nrf2 pathway

Polypyrimidine tract-binding protein 1 (PTBP1) regulates numerous alternative splicing events during tumor progression and neurogenesis. Previously, PTBP1 downregulation was reported to convert astrocytes into functional neurons; however, how PTBP1 regulates astrocytic physiology remains unclear. In this study, we revealed that PTBP1 modulated glutamate uptake via ATP1a2, a member of Na+/K+-ATPases, and glutamate transporters in astrocytes. Ptbp1 knockdown altered mitochondrial function and energy metabolism, which involved PTBP1 regulating mitochondrial redox homeostasis via the succinate dehydrogenase (SDH)/Nrf2 pathway. The malfunction of glutamate transporters following Ptbp1 knockdown resulted in enhanced excitatory synaptic transmission in the cortex. Notably, we developed a biomimetic cationic triblock polypeptide system, i.e., polyethylene glycol44-polylysine30-polyleucine10 (PEG44-PLL30-PLLeu10) with astrocytic membrane coating to deliver Ptbp1 siRNA in vitro and in vivo, which approach allowed Ptbp1 siRNA to efficiently cross the blood-brain barrier and target astrocytes in the brain. Collectively, our findings suggest a framework whereby PTBP1 serves as a modulator in glutamate transport machinery, and indicate that biomimetic methodology is a promising route for in vivo siRNA delivery.

The Roles of Non-coding RNA Targeting Astrocytes in Cerebral Ischemia.

Astrocytes are key targets for treating cerebral ischemia in the central nervous system. Non-coding RNAs (ncRNAs) participate in the pathological processes of astrocytes in cerebral ischemia. Recent reports suggest that ncRNAs ameliorate the outcome of cerebral ischemia by mediating astrocytes' inflammatory reaction, oxidative stress, excitotoxicity, autophagy, and apoptosis. Reconstructing cellular systems might offer a promising strategy for treating cerebral ischemia. This review briefly discusses the potential of ncRNAs as drug targets and explores the molecular regulatory mechanisms through which ncRNAs target astrocytes in cerebral ischemia. It provides an overview of the current research, discusses ncRNAs' implications as clinical markers for cerebral ischemia, and anticipates that ongoing research on ncRNAs may contribute to novel therapeutic approaches for treating this condition.

Synopsis Theme: Targeting Astrocytes for Poststroke Recovery.

Synopsis Theme: Targeting Astrocytes for Poststroke Recovery.

Inhibition of spinal Rac1 attenuates chronic inflammatory pain by regulating the activation of astrocytes

BackgroundSpinal astrocyte-mediated neuroinflammation is an important mechanism for the maintenance of chronic inflammatory pain. Previous studies have investigated that Ras-related C3 botulinum toxin substrate 1 (Rac1) is closely related to astrocyte activation after central nervous system injury. However, the role of Rac1 in astrocyte activation in chronic inflammatory pain has not been reported. MethodsComplete Freund's adjuvant (CFA)-induced chronic inflammatory pain model and LPS-stimulated astrocytes were used to investigate the role of Rac1 in astrocyte activation and the underlying mechanism. Rac1-interfering adeno-associated virus (AAV) targeting astrocytes was delivered to spinal astrocytes by intrathecal administration and a Rac1 specific inhibitor, NSC23766, was used to block cultured astrocytes. The glial fibrillary acidic protein (GFAP), proinflammatory cytokines, p-NF-κB, and nod-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome were detected by RT-qPCR, Western blotting, and immunofluorescence to investigate the activation of astrocytes. ResultsCFA induced spinal astrocyte activation and increased the expression of active Rac1 in spinal astrocytes. Knockdown of astrocyte Rac1 alleviated chronic inflammatory pain and inhibited astrocyte activation. Inhibition of Rac1 activation in cultured astrocytes decreased the expression of GFAP and proinflammatory cytokines. Knockdown of Rac1 inhibited the increase of expression of NLRP3 inflammasome and phosphorylation of NF-κB in the spinal lumbar enlargement after CFA injection. Similarly, the inhibition of Rac1 suppressed the increase of NLRP3 inflammasome and p-NF-κB protein level after LPS stimulation. ConclusionKnockdown of astrocyte Rac1 attenuated CFA-induced hyperalgesia and astrocyte activation possibly by blocking the expression of NLRP3 inflammasome and phosphorylation of NF-κB.

The Similar and Distinct Roles of Satellite Glial Cells and Spinal Astrocytes in Neuropathic Pain.

Preclinical studies have identified glial cells as pivotal players in the genesis and maintenance of neuropathic pain after nerve injury associated with diabetes, chemotherapy, major surgeries, and virus infections. Satellite glial cells (SGCs) in the dorsal root and trigeminal ganglia of the peripheral nervous system (PNS) and astrocytes in the central nervous system (CNS) express similar molecular markers and are protective under physiological conditions. They also serve similar functions in the genesis and maintenance of neuropathic pain, downregulating some of their homeostatic functions and driving pro-inflammatory neuro-glial interactions in the PNS and CNS, i.e., "gliopathy". However, the role of SGCs in neuropathic pain is not simply as "peripheral astrocytes". We delineate how these peripheral and central glia participate in neuropathic pain by producing different mediators, engaging different parts of neurons, and becoming active at different stages following nerve injury. Finally, we highlight the recent findings that SGCs are enriched with proteins related to fatty acid metabolism and signaling such as Apo-E, FABP7, and LPAR1. Targeting SGCs and astrocytes may lead to novel therapeutics for the treatment of neuropathic pain.

Targeting Astrocyte Signaling Alleviates Cerebrovascular and Synaptic Function Deficits in a Diet-Based Mouse Model of Small Cerebral Vessel Disease.

Despite the indispensable role that astrocytes play in the neurovascular unit, few studies have investigated the functional impact of astrocyte signaling in cognitive decline and dementia related to vascular pathology. Diet-mediated induction of hyperhomocysteinemia (HHcy) recapitulates numerous features of vascular contributions to cognitive impairment and dementia (VCID). Here, we used astrocyte targeting approaches to evaluate astrocyte Ca2+ dysregulation and the impact of aberrant astrocyte signaling on cerebrovascular dysfunction and synapse impairment in male and female HHcy diet mice. Two-photon imaging conducted in fully awake mice revealed activity-dependent Ca2+ dysregulation in barrel cortex astrocytes under HHcy. Stimulation of contralateral whiskers elicited larger Ca2+ transients in individual astrocytes of HHcy diet mice compared with control diet mice. However, evoked Ca2+ signaling across astrocyte networks was impaired in HHcy mice. HHcy also was associated with increased activation of the Ca2+/calcineurin-dependent transcription factor NFAT4, which has been linked previously to the reactive astrocyte phenotype and synapse dysfunction in amyloid and brain injury models. Targeting the NFAT inhibitor VIVIT to astrocytes, using adeno-associated virus vectors, led to reduced GFAP promoter activity in HHcy diet mice and improved functional hyperemia in arterioles and capillaries. VIVIT expression in astrocytes also preserved CA1 synaptic function and improved spontaneous alternation performance on the Y maze. Together, the results demonstrate that aberrant astrocyte signaling can impair the major functional properties of the neurovascular unit (i.e., cerebral vessel regulation and synaptic regulation) and may therefore represent a promising drug target for treating VCID and possibly Alzheimer's disease and other related dementias.SIGNIFICANCE STATEMENT The impact of reactive astrocytes in Alzheimer's disease and related dementias is poorly understood. Here, we evaluated Ca2+ responses and signaling in barrel cortex astrocytes of mice fed with a B-vitamin deficient diet that induces hyperhomocysteinemia (HHcy), cerebral vessel disease, and cognitive decline. Multiphoton imaging in awake mice with HHcy revealed augmented Ca2+ responses in individual astrocytes, but impaired signaling across astrocyte networks. Stimulation-evoked arteriole dilation and elevated red blood cell velocity in capillaries were also impaired in cortex of awake HHcy mice. Astrocyte-specific inhibition of the Ca2+-dependent transcription factor, NFAT, normalized cerebrovascular function in HHcy mice, improved synaptic properties in brain slices, and stabilized cognition. Results suggest that astrocytes are a mechanism and possible therapeutic target for vascular-related dementia.

Nano-Selenium Antagonized Cadmium-Induced Liver Fibrosis in Chicken.

Cadmium is a global ecological toxic pollutant; in animals, hepatotoxic fibrosis is caused by bioaccumulation of Cd through food chains. We determined the path of nano-Se antagonism in Cd-induced hepatocyte pyroptosis by targeting the APJ-AMPK-PGC1α pathway, using an in vivo model of hepatotoxicity. All 1-day-old chicks were treated with Cd (140 mg/kg BW/day) and/or nano-Se (0.3 or 0.6 mg/kg BW/day) for 90 days. The result showed that Cd (1.55 ± 0.148) activated NLRP3 inflammasome 49.903% as compared to the Con group (1.034 ± 0.008) to release the inflammasome as a result of hepatocyte pyroptosis (2.824 ± 0.057). Compared with the Con group (1.010 ± 0.021), Kupffer cells were 219.109% more to activate astrocytes through the APJ-AMPK-PGC1α pathway, resulting in 185.149% more hepatic fibrosis. However, the fibrosis degree of the H-Se + Cd group (1.252 ± 0.056) was 56.5278% (p < 0.001) lower than that of the Cd group (2.880 ± 0.124). Therefore, this study established that pyroptotic hepatocytes and Kupffer cells could be targeted for nano-Se antagonizing Cd toxicity, which reveals a potential new approach targeting astrocytes for the treatment of liver fibrosis triggered by Cd pollution.

Impact of Environmental Pollutants on Alzheimer’s Disease: A Review

Environmental pollution is one of the major concerns as it affects public health and is responsible for various neurological disorders too. Neurological disorders are governed by many different factors - they can be genetic, based on lifestyle, or environmental. In many recent studies, it has been observed that exposure to many environmental pollutants increases the risk of Alzheimer’s disease (AD). Pollutants like PM 10, PM2.5, and some other ultrafine nanoparticles, lipophilic vaporized toxicant (acrolein) can easily reach the brain by crossing the blood-brain barrier after it they can activate the innate immune responses inside the target site like neurons, astrocytes, and microglia by this way they can be neurotoxic. Human epidemiological evidence proves that there is a correlation between environmental pollutants and neurological disorders like dysfunction of mitochondrial, oxidative stress, disruption in the myelin sheath, the blood-brain barrier anatomy alterations, and endoplasmic reticulum stress which direct towards cognitive impairment with lower quality of lifestyle. The review article aims to culminate the correlation between the environmental factors and Alzheimer’s disease, The different sources of pollution and their effect on various stages of human life, developmental neurotoxicity, and neurological disorders also have been discussed.

Gene Enrichment Analysis of Astrocyte Subtypes in Psychiatric Disorders and Psychotropic Medication Datasets.

Astrocytes have many important functions in the brain, but their roles in psychiatric disorders and their responses to psychotropic medications are still being elucidated. Here, we used gene enrichment analysis to assess the relationships between different astrocyte subtypes, psychiatric diseases, and psychotropic medications (antipsychotics, antidepressants and mood stabilizers). We also carried out qPCR analyses and “look-up” studies to assess the chronic effects of these drugs on astrocyte marker gene expression. Our bioinformatic analysis identified gene enrichment of different astrocyte subtypes in psychiatric disorders. The highest level of enrichment was found in schizophrenia, supporting a role for astrocytes in this disorder. We also found differential enrichment of astrocyte subtypes associated with specific biological processes, highlighting the complex responses of astrocytes under pathological conditions. Enrichment of protein phosphorylation in astrocytes and disease was confirmed by biochemical analysis. Analysis of LINCS chemical perturbagen gene signatures also found that kinase inhibitors were highly discordant with astrocyte-SCZ associated gene signatures. However, we found that common gene enrichment of different psychotropic medications and astrocyte subtypes was limited. These results were confirmed by “look-up” studies and qPCR analysis, which also reported little effect of psychotropic medications on common astrocyte marker gene expression, suggesting that astrocytes are not a primary target of these medications. Conversely, antipsychotic medication does affect astrocyte gene marker expression in postmortem schizophrenia brain tissue, supporting specific astrocyte responses in different pathological conditions. Overall, this study provides a unique view of astrocyte subtypes and the effect of medications on astrocytes in disease, which will contribute to our understanding of their role in psychiatric disorders and offers insights into targeting astrocytes therapeutically.

P12.15.B Astrocyte immunometabolic regulation of the glioblastoma microenvironment drives tumor pathogenicity

Abstract Background Malignant brain tumors are the cause of a disproportionate level of morbidity and mortality among cancer patients, an unfortunate statistic that has remained constant for decades. Despite considerable advances in the molecular characterization of these tumors, targeting the cancer cells has yet to produce significant advances in treatment. An alternative strategy is to target cells in the glioblastoma microenvironment, such as tumor associated astrocytes. Astrocytes control multiple processes in health and disease, ranging from maintaining the brain's metabolic homeostasis, to modulating neuroinflammation. However, their role in glioblastoma pathogenicity is not well understood. Material and Methods Immunocompetent mice were implanted with murine glioma cell lines and the role of astrocyte in the tumor pathogenicity was analyzed, and further investigated using in-vitro co-cultures. Results Here we report that depletion of reactive astrocytes regresses glioblastoma and prolongs mouse survival. Analysis of the tumor-associated astrocyte translatome, revealed that astrocytes initiate transcriptional programs that shape the immune and metabolic compartments in the glioma microenvironment. Specifically, their expression of CCL2 and CSF1 governs the recruitment of tumor-associated macrophages and promotes a pro-tumorigenic macrophage phenotype. Concomitantly, we demonstrate that astrocyte-derived cholesterol is key to glioma cell survival, and that targeting astrocytic cholesterol efflux, via ABCA1, halts tumor progression. In summary, astrocytes control glioblastoma pathogenicity by reprogramming the immunological properties of the tumor microenvironment and supporting the non-oncogenic metabolic dependency of glioblastoma on cholesterol. Conclusion These findings suggest that targeting astrocyte immunometabolic signaling may help treat this uniformly lethal brain tumor.

4-Phenylbutyrate Mitigates the Motor Impairment and Dopaminergic Neuronal Death During Parkinson's Disease Pathology via Targeting VDAC1 Mediated Mitochondrial Function and Astrocytes Activation.

Parkinson's disease (PD) is a progressive motor neurodegenerative disorder significantly associated with protein aggregation related neurodegenerative mechanisms. In view of no disease modifying drugs, the present study was targeted to investigate the therapeutic effects of pharmacological agent 4-phenylbutyric acid (4PBA) in PD pathology. 4PBA is an FDA approved monocarboxylic acid with inhibitory activity towards histone deacetylase andclinically treats urea cycle disorder. First, we observed the significant protective effects of 4PBA on PD specific neuromuscular coordination, level of tyrosine hydroxylase, α-synuclein level and neurotransmitter dopamine in both substantia nigra and striatal regions of the experimental rat model of PD. Further results revealed that treatment with 4PBA drug exhibited significant protection against disease related oxidative stress and augmented nitrite levels. The disease pathology-related depletion in mitochondrial membrane potential and augmented level of calcium as well as mitochondrion membrane located VDAC1 protein level and cytochrome-c translocation were also significantly attenuated with 4PBA administration. Inhibited neuronal apoptosis and restored neuronal morphology were also observed with 4PBA treatment as measured by level of pro-apoptotic proteins t-Bid, Bax and cleaved caspase-3 along with cresyl violet staining in both substantia nigra and striatal regions. Lastly, PD-linked astrocyte activation was significantly inhibited with 4PBA treatment. Altogether, our findings suggest that 4PBA exerts broad-spectrum neuroprotective effects in PD animal model.

Astrocyte immunometabolic regulation of the tumour microenvironment drives glioblastoma pathogenicity.

Malignant brain tumours are the cause of a disproportionate level of morbidity and mortality among cancer patients, an unfortunate statistic that has remained constant for decades. Despite considerable advances in the molecular characterization of these tumours, targeting the cancer cells has yet to produce significant advances in treatment. An alternative strategy is to target cells in the glioblastoma microenvironment, such as tumour-associated astrocytes. Astrocytes control multiple processes in health and disease, ranging from maintaining the brain's metabolic homeostasis, to modulating neuroinflammation. However, their role in glioblastoma pathogenicity is not well understood. Here we report that depletion of reactive astrocytes regresses glioblastoma and prolongs mouse survival. Analysis of the tumour-associated astrocyte translatome revealed astrocytes initiate transcriptional programmes that shape the immune and metabolic compartments in the glioma microenvironment. Specifically, their expression of CCL2 and CSF1 governs the recruitment of tumour-associated macrophages and promotes a pro-tumourigenic macrophage phenotype. Concomitantly, we demonstrate that astrocyte-derived cholesterol is key to glioma cell survival, and that targeting astrocytic cholesterol efflux, via ABCA1, halts tumour progression. In summary, astrocytes control glioblastoma pathogenicity by reprogramming the immunological properties of the tumour microenvironment and supporting the non-oncogenic metabolic dependency of glioblastoma on cholesterol. These findings suggest that targeting astrocyte immunometabolic signalling may be useful in treating this uniformly lethal brain tumour.

Sera of Neuromyelitis Optica Patients Increase BID-Mediated Apoptosis in Astrocytes.

Neuromyelitis optica (NMO) is a rare disease usually presenting with bilateral or unilateral optic neuritis with simultaneous or sequential transverse myelitis. Autoantibodies directed against aquaporin-4 (AQP4-IgG) are found in most patients. They are believed to cross the blood–brain barrier, target astrocytes, activate complement, and eventually lead to astrocyte destruction, demyelination, and axonal damage. However, it is still not clear what the primary pathological event is. We hypothesize that the interaction of AQP4-IgG and astrocytes leads to DNA damage and apoptosis. We studied the effect of sera from seropositive NMO patients and healthy controls (HCs) on astrocytes’ immune gene expression and viability. We found that sera from seropositive NMO patients led to higher expression of apoptosis-related genes, including BH3-interacting domain death agonist (BID), which is the most significant differentiating gene (p < 0.0001), and triggered more apoptosis in astrocytes compared to sera from HCs. Furthermore, NMO sera increased DNA damage and led to a higher expression of immunological genes that interact with BID (TLR4 and NOD-1). Our findings suggest that sera of seropositive NMO patients might cause astrocytic DNA damage and apoptosis. It may be one of the mechanisms implicated in the primary pathological event in NMO and provide new avenues for therapeutic intervention.

Glucose Metabolism, Neural Cell Senescence and Alzheimer’s Disease

Alzheimer’s disease (AD), an elderly neurodegenerative disorder with a high incidence and progressive memory decline, is one of the most expensive, lethal, and burdening diseases. To date, the pathogenesis of AD has not been fully illustrated. Emerging studies have revealed that cellular senescence and abnormal glucose metabolism in the brain are the early hallmarks of AD. Moreover, cellular senescence and glucose metabolism disturbance in the brain of AD patients may precede amyloid-β deposition or Tau protein phosphorylation. Thus, metabolic reprogramming targeting senescent microglia and astrocytes may be a novel strategy for AD intervention and treatment. Here, we recapitulate the relationships between neural cell senescence and abnormal glucose metabolism (e.g., insulin signaling, glucose and lactate metabolism) in AD. We then discuss the potential perspective of metabolic reprogramming towards an AD intervention, providing a theoretical basis for the further exploration of the pathogenesis of and therapeutic approach toward AD.

Molecular Signature of Astrocytes for Gene Delivery by the Synthetic Adeno-Associated Viral Vector rAAV9P1.

Astrocytes have crucial functions in the central nervous system (CNS) and are major players in many CNS diseases. Research on astrocyte‐centered diseases requires efficient and well‐characterized gene transfer vectors. Vectors derived from the Adeno‐associated virus serotype 9 (AAV9) target astrocytes in the brains of rodents and nonhuman primates. A recombinant (r) synthetic peptide‐displaying AAV9 variant, rAAV9P1, that efficiently and selectively transduces cultured human astrocytes, has been described previously. Here, it is shown that rAAV9P1 retains astrocyte‐targeting properties upon intravenous injection in mice. Detailed analysis of putative receptors on human astrocytes shows that rAAV9P1 utilizes integrin subunits αv, β8, and either β3 or β5 as well as the AAV receptor AAVR. This receptor pattern is distinct from that of vectors derived from wildtype AAV2 or AAV9. Furthermore, a CRISPR/Cas9 genome‐wide knockout screening revealed the involvement of several astrocyte‐associated intracellular signaling pathways in the transduction of human astrocytes by rAAV9P1. This study delineates the unique receptor and intracellular pathway signatures utilized by rAAV9P1 for targeting human astrocytes. These results enhance the understanding of the transduction biology of synthetic rAAV vectors for astrocytes and can promote the development of advanced astrocyte‐selective gene delivery vehicles for research and clinical applications.

Hemisynapse Formation Between Target Astrocytes and Cortical Neuron Axons in vitro.

One of the most fundamental organizing principles in the mammalian brain is that neurons do not establish synapses with the other major cell type, the astrocytes. However, induced synapse formation between neurons and astrocytes appears conceivable, because astrocytes are well known to express functional ionotropic glutamate receptors. Here, we attempted to trigger synapse formation between co-cultured neurons and astrocytes by overexpressing the strongly synaptogenic adhesion protein LRRTM2 in astrocytes physically contacted by cortical axons. Interestingly, control experiments with immature cortical astrocytes without any overexpression resulted in the induction of synaptic vesicle clustering in contacting axons (hemisynapse formation). This synaptogenic activity correlated with the endogenous expression of the synaptogenic protein Neuroligin1. Hemisynapse formation was further enhanced upon overexpression of LRRTM2 in cortical astrocytes. In contrast, cerebellar astrocytes required overexpression of LRRTM2 for induction of synaptic vesicle clustering in contacting axons. We further addressed, whether hemisynapse formation was accompanied by the appearance of fully functional glutamatergic synapses. We therefore attempted to record AMPA receptor-mediated miniature excitatory postsynaptic currents (mEPSCs) in innervated astrocytes using the whole-cell patch-clamp technique. Despite the endogenous expression of the AMPA receptor subunits GluA2 and to a lesser extent GluA1, we did not reliably observe spontaneous AMPA mEPSCs. In conclusion, overexpression of the synaptogenic protein LRRTM2 induced hemisynapse formation between co-cultured neurons and astrocytes. However, the formation of fully functional synapses appeared to require additional factors critical for nano-alignment of presynaptic vesicles and postsynaptic receptors.

Intelligent lesion blood–brain barrier targeting nano-missiles for Alzheimer's disease treatment by anti-neuroinflammation and neuroprotection

The treatment of Alzheimer's disease (AD) is one of the most difficult challenges in neurodegenerative diseases due to the insufficient blood‒brain barrier (BBB) permeability and unsatisfactory intra-brain distribution of drugs. Therefore, we established an ibuprofen and FK506 encapsulated drug co-delivery system (Ibu&FK@RNPs), which can target the receptor of advanced glycation endproducts (RAGE) and response to the high level of reactive oxygen species (ROS) in AD. RAGE is highly and specifically expressed on the lesion neurovascular unit of AD, this property helps to improve targeting specificity of the system and reduce unselective distribution in normal brain. Meanwhile, these two drugs can be specifically released in astrocytes of AD lesion in response to high levels of ROS. As a result, the cognition of AD mice was significantly improved and the quantity of Aβ plaques was decreased. Neurotoxicity was also alleviated with structural regeneration and functional recovery of neurons. Besides, the neuroinflammation dominated by NF-κB pathway was significantly inhibited with decreased NF-κB and IL-1β in the brain. Overall, Ibu&FK@RNPs can efficiently and successively target diseased BBB and astrocytes in AD lesion. Thus it significantly enhances intracephalic accumulation of drugs and efficiently treats AD by anti-neuroinflammation and neuroprotection.

Astrocyte reactivity in a mouse model of SCN8A epileptic encephalopathy.

Objective SCN8A epileptic encephalopathy is caused predominantly by de novo gain‐of‐function mutations in the voltage‐gated sodium channel Nav1.6. The disorder is characterized by early onset of seizures and developmental delay. Most patients with SCN8A epileptic encephalopathy are refractory to current anti‐seizure medications. Previous studies determining the mechanisms of this disease have focused on neuronal dysfunction as Nav1.6 is expressed by neurons and plays a critical role in controlling neuronal excitability. However, glial dysfunction has been implicated in epilepsy and alterations in glial physiology could contribute to the pathology of SCN8A encephalopathy. In the current study, we examined alterations in astrocyte and microglia physiology in the development of seizures in a mouse model of SCN8A epileptic encephalopathy.MethodsUsing immunohistochemistry, we assessed microglia and astrocyte reactivity before and after the onset of spontaneous seizures. Expression of glutamine synthetase and Nav1.6, and Kir4.1 channel currents were assessed in astrocytes in wild‐type (WT) mice and mice carrying the N1768D SCN8A mutation (D/+).ResultsAstrocytes in spontaneously seizing D/+ mice become reactive and increase expression of glial fibrillary acidic protein (GFAP), a marker of astrocyte reactivity. These same astrocytes exhibited reduced barium‐sensitive Kir4.1 currents compared to age‐matched WT mice and decreased expression of glutamine synthetase. These alterations were only observed in spontaneously seizing mice and not before the onset of seizures. In contrast, microglial morphology remained unchanged before and after the onset of seizures.SignificanceAstrocytes, but not microglia, become reactive only after the onset of spontaneous seizures in a mouse model of SCN8A encephalopathy. Reactive astrocytes have reduced Kir4.1‐mediated currents, which would impair their ability to buffer potassium. Reduced expression of glutamine synthetase would modulate the availability of neurotransmitters to excitatory and inhibitory neurons. These deficits in potassium and glutamate handling by astrocytes could exacerbate seizures in SCN8A epileptic encephalopathy. Targeting astrocytes may provide a new therapeutic approach to seizure suppression.