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1.
CEN Case Rep ; 2019 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-31520251

RESUMO

In individuals treated with immunosuppressive therapies, the varicella-zoster virus (VZV) infection can become disseminated and lead to a life-threatening condition. There is currently no established treatment strategy for this life-threatening condition. Here, we describe a case where plasma exchange (PE) with a high dose of acyclovir (ACV) ameliorated the severe effects, including VZV-hemophagocytic lymphohistiocytosis (VZV-HLH) and disseminated intravascular coagulation (DIC), in a 9-year-old girl with steroid-dependent nephrotic syndrome. This 9-year-old girl experienced frequent relapse steroid-dependent nephrotic syndrome. She had been treated with steroids, tacrolimus, mizoribine, and rituximab. She had not previously received a varicella vaccine. She was admitted with only one vesicular rash. At admission, a serum test revealed 1.6 × 106 copies/mL of VZV DNA. The patient rapidly developed VZV-HLH and DIC. A combination of a high dose of ACV, immunoglobulin, and steroid pulse therapy could not improve these severe complications. Therefore, PE was applied. PE with a high dose of ACV successfully reduced serum VZV DNA from 7.5 × 106 to 2.8 × 104 copies/mL. This reduction in the VZV DNA copy number suggested that the combination of PE and a high dose of ACV was effective in treating a disseminated VZV infection. To the best of our knowledge, this is the first report showing that PE with a high dose of ACV ameliorated the severe complications of disseminated VZV by reducing the VZV DNA copy number.

2.
Neuropediatrics ; 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31486053

RESUMO

The complication of anarthria in hereditary spastic paraplegia (HSP) patients has been reported to result from mutations in either ALS2 or FA2H. Here, we present a case of a 12-year-old boy with hereditary spastic paralysis and anarthria associated with a SPAST mutation. Initial presentation was at 14 months of age, when the patient experienced leg stiffness. At 3 years of age, he could speak well using sentences. At 9 years of age, he was found to have dysarthria and had difficulty writing. At 12 years of age, the ability to speak was lost. The patient could not vocalize any words, despite contraction of his neck and respiratory muscles during attempted vocalization. Additionally, the patient has never walked independently in his life. Considering these symptoms, we diagnosed him as having infantile onset ascending hereditary spastic paralysis (IAHSP) complicated with anarthria. By whole-exome sequencing, we discovered a heterozygous SPAST mutation c.1496G > A (p.Arg499His), which was not found in the parents and is probably de novo. This mutation was already repeatedly described with similar phenotype. Our results suggest that the p.Arg499His mutation in SPAST should be considered as a differential diagnosis in IAHSP.

3.
Neurobiol Dis ; : 104603, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31494281

RESUMO

Alzheimer's disease (AD) is an incurable neurodegenerative disease characterized by memory loss and neurotoxic amyloid beta (Aß) plaques accumulation. Numerous pharmacological interventions targeting Aß plaques accumulation have failed to alleviate AD. Also, the pathological alterations in AD start years before the onset of clinical symptoms. To identify proteins at play during the early stage of AD, we conducted proteomic analysis of the hippocampus of young AppNL-F mice model of AD at the preclinical phase of the disease. This was followed by interactome ranking of the proteome into hubs that were further validated in vivo using immunoblot analysis. We also performed double-immunolabeling of these hub proteins and Aß to quantify colocalization. Behavioral analysis revealed no significant difference in memory performance between 8-month-old AppNL-F and control mice. The upregulation and downregulation of several proteins were observed in the AppNL-F mice compared to control. These proteins corresponded to pathways and processes related to Aß clearance, inflammatory-immune response, transport, mitochondrial metabolism, and glial cell proliferation. Interactome analysis revealed several proteins including DLGP5, DDX49, CCDC85A, ADCY6, HEPACAM, HCN3, PPT1 and TNPO1 as essential proteins in the AppNL-F interactome. Validation by immunoblot confirmed the over-expression of these proteins except HCN3 in the early-stage AD mice hippocampus. Immunolabeling revealed a significant increase in ADCY6/Aß and HEPACAM/Aß colocalized puncta in AppNL-F mice compared to WT. These data suggest that these proteins may be involved in the early stage of AD. Our work suggests new targets and biomarkers for AD diagnosis and therapeutic intervention.

4.
Eur J Pharmacol ; 863: 172681, 2019 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-31542482

RESUMO

Recombinant thrombomodulin (rTM) is a novel anticoagulant and anti-inflammatory agent that inhibits secretion of high-mobility group box 1 (HMGB1) from liver. We evaluated the protective effects of rTM on hepatic ischemia-reperfusion injury in rats. Ischemia was induced by clamping the portal vein and hepatic artery of left lateral and median lobes of the liver. At 30 min before ischemia and at 6 h after reperfusion, 0.3 ml of saline (IR group) or 0.3 ml of saline containing 6 mg/kg body weight of rTM (IR-rTM group) was injected into the liver through inferior vena cava or caudate vein. Blood flow was restored at 60 min of ischemia. Blood was collected 30 min prior to induction of ischemia and before restoration of blood flow, and at 6, 12, and 24 h after reperfusion. All the animals were euthanized at 24 h after reperfusion and the livers were harvested and subjected to biochemical and pathological evaluations. Serum levels of ALT, AST, and HMGB1 were significantly lower after reperfusion in the IR-rTM group compared to IR group. Marked hepatic necrosis was present in the IR group, while necrosis was almost absent in IR-rTM group. Treatment with rTM significantly reduced the expression of TNF-α and formation of 4-hydroxynonenal in the IR-rTM group compared to IR group. The results of the present study indicate that rTM could be used as a potent therapeutic agent to prevent IR-induced hepatic injury and the related adverse events.

5.
J Neuroinflammation ; 16(1): 173, 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31470863

RESUMO

BACKGROUND: Disturbances in clock genes affect almost all patients with Alzheimer's disease (AD), as evidenced by their altered sleep/wake cycle, thermoregulation, and exacerbation of cognitive impairment. As microglia-mediated neuroinflammation proved to be a driver of AD rather than a result of the disease, in this study, we evaluated the relationship between clock gene disturbance and neuroinflammation in microglia and their contribution to the onset of AD. METHODS: In this study, the expression of clock genes and inflammatory-related genes was examined in MACS microglia isolated from 2-month-old amyloid precursor protein knock-in (APP-KI) and wild-type (WT) mice using cap analysis gene expression (CAGE) deep sequencing and RT-PCR. The effects of clock gene disturbance on neuroinflammation and relevant memory changes were examined in 2-month-old APP-KI and WT mice after injection with SR9009 (a synthetic agonist for REV-ERB). The microglia morphology was studied by staining, neuroinflammation was examined by Western blotting, and cognitive changes were examined by Y-maze and novel object recognition tests. RESULTS: CLOCK/BMAL1-driven transcriptional negative feedback loops were impaired in the microglia from 2-month-old APP-KI mice. Pro-inflammatory genes in microglia isolated from APP-KI mice were significantly higher than those isolated from WT mice at Zeitgeber time 14. The expression of pro-inflammatory genes was positively associated with NF-κB activation and negatively associated with the BMAL1 expression. SR9009 induced the activation of microglia, the increased expression of pro-inflammatory genes, and cognitive decline in 2-month-old APP-KI mice. CONCLUSION: Clock gene disturbance in microglia is involved in the early onset of AD through the induction of chronic neuroinflammation, which may be a new target for preventing or slowing AD.

6.
Brain Behav ; : e01392, 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31469254

RESUMO

OBJECTIVE: The diagnosis of childhood-onset cerebellar ataxia (CA) is often challenging due to variations in symptoms and etiologies. Despite the known regional differences in the prevalence of etiologies underlying CA, the frequency and characteristics of CA in Japan remain unclear. We conducted a questionnaire-based survey to identify the clinical characteristics of childhood-onset CA in the Japanese population. MATERIALS AND METHODS: Questionnaires were sent to 1,103 board-certified pediatric neurologists in Japan from 2016 to 2017. The primary survey requested the number of patients with CA under care, and the follow-up secondary questionnaire requested additional clinical characteristics of the patients. RESULTS: The primary survey obtained 578 responses (response rate, 52.4%) on 385 patients with CA, including 171 diagnosed and 214 undiagnosed cases (diagnostic rate, 44.4%). The most frequent etiology was dentatorubropallidoluysian atrophy (DRPLA), followed by mitochondrial disorders and encephalitis. The secondary survey obtained the clinical characteristics of 252 cases (119 diagnosed and 133 undiagnosed cases). Multiple logistic regression analysis revealed that a younger age at onset, hearing issues, and short stature were associated with a higher risk of remaining undiagnosed with CA in Japan. CONCLUSIONS: The diagnostic rate of childhood-onset CA in the current study was comparable to those reported in other countries. The high prevalence of autosomal dominant ataxia, especially DRPLA, was a signature of CA in Japan. These data offer insights into the characteristics of childhood-onset CA in the Japanese population.

7.
Artigo em Inglês | MEDLINE | ID: mdl-31449498

RESUMO

Neuroblastoma (NB) predominantly presents as high-risk disease, requiring intensive multimodal therapy. Proton beam therpy (PBT) is a promising option for many childhood cancers, but is not widely available. Patients with NB hoping to receive PBT may therefore need to be transferred between institutions during intensive multimodal therapy, risking undesirable effects. We evaluated patients with high-risk NB who received PBT at our institute as part of first-line therapy, mainly focusing on the safety and feasibility of mid-treatment patient transfer. Eighteen patients with newly diagnosed high-risk NB who received PBT between April 2010 and June 2016 were retrospectively analyzed for local control, outcomes, and toxicity. Survival (3-y overall survival 71%±11%; 3-y event-free survival 44%±12%) and local control rate (100%) were comparable with previous studies. Few acute adverse events were recorded, and all patients completed PBT without treatment delay. PBT for high-risk NB was safe and feasible for patients requiring mid-treatment interinstitutional transfer.

8.
Neuropediatrics ; 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31370080

RESUMO

BACKGROUND: Leukoencephalopathy associated with dysmorphic features may be attributed to chromosomal abnormalities such as 17p13.3 microdeletion syndrome. CASE: A 19-year-old female patient was referred to our hospital for diagnostic evaluation of her leukoencephalopathy. She demonstrated moderate intellectual disability, minor dysmorphic features, and short stature. Serial brain magnetic resonance images obtained within a 16-year interval revealed prolonged T2 signals in the deep cerebral white matter with enlarged Virchow-Robin spaces. A nonsymptomatic atlas anomaly was also noted. Using microarray-based comparative genomic hybridization, we identified a 2.2-Mb terminal deletion at 17p13.3, encompassing YWHAE, CRK, and RTN4RL1 but not PAFAH1B1. CONCLUSION: Except for atlas anomaly, the patient's clinical and imaging findings were compatible with the diagnosis of 17p13.3 microdeletion syndrome. The white matter abnormality was static and nonprogressive. The association between the atlas abnormality and this deletion remains elusive. We note the importance of exploring submicroscopic chromosomal imbalance when patients show prominent but static white matter abnormalities with discrepantly mild and stable neurological signs.

9.
Nutrients ; 11(8)2019 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-31426549

RESUMO

The biological effects of insulin signaling are regulated by the phosphorylation of insulin receptor substrate 1 (IRS1) at serine (Ser) residues. In the brain, phosphorylation of IRS1 at specific Ser sites increases in patients with Alzheimer's disease (AD) and its animal models. However, whether the activation of Ser sites on neural IRS1 is related to any type of memory decline remains unclear. Here, we show the modifications of IRS1 through its phosphorylation at etiology-specific Ser sites in various animal models of memory decline, such as diabetic, aged, and amyloid precursor protein (APP) knock-in NL-G-F (APPKINL-G-F) mice. Substantial phosphorylation of IRS1 at specific Ser sites occurs in type 2 diabetes- or age-related memory deficits independently of amyloid-ß (Aß). Furthermore, we present the first evidence that, in APPKINL-G-F mice showing Aß42 elevation, the increased phosphorylation of IRS1 at multiple Ser sites occurs without memory impairment. Our findings suggest that the phosphorylation of IRS1 at specific Ser sites is a potential marker of Aß-unrelated memory deficits caused by type 2 diabetes and aging; however, in Aß-related memory decline, the modifications of IRS1 may be a marker of early detection of Aß42 elevation prior to the onset of memory decline in AD.

11.
Nanomedicine (Lond) ; 14(18): 2409-2422, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31456488

RESUMO

Aim: To determine whether a p38 MAPK inhibitor incorporated into nanoemulsion-based chitosan nanocapsules can reduce the activity of this kinase in the brain through their nasal administration in mice. Materials & methods: We selected the p38 MAPK inhibitor PH797804, an ATP-competitive inhibitor of p38α encapsulated in nanoemulsion-based chitosan nanocapsules. Biological effect was evaluated in microglial and neuronal cells in vitro and in ex vivo and in vivo systems, in a mouse model of Alzheimer's disease. Results: Encapsulated inhibitor retains enzymatic inhibitory activity and tissue penetration capacity in vitro, ex vivo and in vivo. Conclusion: Nasal administration of chitosan nanocapsules can be an effective approach for brain-restricted reduction of p38 MAPK activity, thus reducing the side effects of systemic administration.

12.
Dis Model Mech ; 12(9)2019 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-31439589

RESUMO

We studied a new amyloid-beta precursor protein (App) knock-in mouse model of Alzheimer's disease (AppNL-G-F ), containing the Swedish KM670/671NL mutation, the Iberian I716F mutation and the Artic E693G mutation, which generates elevated levels of amyloid beta (Aß)40 and Aß42 without the confounds associated with APP overexpression. This enabled us to assess changes in anxiety-related and social behaviours, and neural alterations potentially underlying such changes, driven specifically by Aß accumulation. AppNL-G-F knock-in mice exhibited subtle deficits in tasks assessing social olfaction, but not in social motivation tasks. In anxiety-assessing tasks, AppNL-G-F knock-in mice exhibited: (1) increased thigmotaxis in the open field (OF), yet; (2) reduced closed-arm, and increased open-arm, time in the elevated plus maze (EPM). Their ostensibly anxiogenic OF profile, yet ostensibly anxiolytic EPM profile, could hint at altered cortical mechanisms affecting decision-making (e.g. 'disinhibition'), rather than simple core deficits in emotional motivation. Consistent with this possibility, alterations in microstructure, glutamatergic-dependent gamma oscillations and glutamatergic gene expression were all observed in the prefrontal cortex, but not the amygdala, of AppNL-G-F knock-in mice. Thus, insoluble Aß overexpression drives prefrontal cortical alterations, potentially underlying changes in social and anxiety-related behavioural tasks.This article has an associated First Person interview with the first author of the paper.

13.
J Biol Chem ; 294(34): 12754-12765, 2019 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-31273083

RESUMO

In cortical regions of brains from individuals with preclinical or clinical Alzheimer's disease (AD), extracellular ß-amyloid (Aß) deposition precedes the aggregation of pathological intracellular tau (the product of the gene microtubule-associated protein tau (MAPT)). To our knowledge, current mouse models of tauopathy reconstitute tau pathology by overexpressing mutant human tau protein. Here, through a homologous recombination approach that replaced the entire murine Mapt gene with the human ortholog, we developed knock-in mice with humanized Mapt to create an in vivo platform for studying human tauopathy. Of note, the humanized Mapt expressed all six tau isoforms present in humans. We next cross-bred the MAPT knock-in mice with single amyloid precursor protein (App) knock-in mice to investigate the Aß-tau axis in AD etiology. The double-knock-in mice exhibited higher tau phosphorylation than did single MAPT knock-in mice but initially lacked apparent tauopathy and neurodegeneration, as observed in the single App knock-in mice. We further observed that tau humanization significantly accelerates cell-to-cell propagation of AD brain-derived pathological tau both in the absence and presence of Aß-amyloidosis. In the presence of Aß-amyloidosis, tau accumulation was intensified and closely associated with dystrophic neurites, consistently showing that Aß-amyloidosis affects tau pathology. Our results also indicated that the pathological human tau interacts better with human tau than with murine tau, suggesting species-specific differences between these orthologous pathogenic proteins. We propose that the MAPT knock-in mice will make it feasible to investigate the behaviors and characteristics of human tau in an animal model.

14.
Pediatr Int ; 2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31298773

RESUMO

BACKGROUND: We previously reported that the top-down approach (TDA) for infants with febrile urinary tract infections (fUTIs) could prevent recurrent fUTIs (r-fUTIs) but produced a high number of false positive result of acute -phase 99m Tc dimercaptosuccinic acid (DMSA) scintigraphy. Therefore we compared the ultrasonography-oriented approach (USOA) with TDA from the viewpoint of the preventive ability of r-fUTIs. METHODS: The TDA was applied between July 2010 and February 2014 and the USOA was applied between March 2014 and April 2017 for the infants with first fUTIs. In the USOA group, voiding cystourethrography (VCUG) was performed in cases with abnormalities on acute-phase renal-bladder ultrasonography (RBUS) or on chronic- phase DMSA which were performed in all cases. A frequency of r-fUTIs was compared between TDA group and USOA group retrospectively. RESULTS: 74 (52 males) and 79 (60 males) received TDA or USOA, respectively. No significant differences were found between the TDA and USOA groups in the male-to-female ratio, age in months at initial onset of fUTIs, observation period, and number of cases of r-fUTIs (4 cases in the TDA group and 5 cases in the USOA group, respectively). Seventy-four DMSA and 25 VCUG in USOA, and 111 DMSA and 34 VCUG in TDA were performed respectively. CONCLUSIONS: This study showed that both USOA and TDA were found to be valid for prevention of r-fUTIs, but from the perspective which the number of cases that underwent VCUG and DMSA could be reduced, USOA was found to be superior to TDA. This article is protected by copyright. All rights reserved.

15.
Brain Dev ; 2019 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-31288946

RESUMO

INTRODUCTION: A loss-of-function mutation in CACNA1A, which encodes P/Q-type Ca channels, causes various diseases. As most of the Ca channels at neuromuscular junctions are of the P/Q type, patients with loss-of-function CACNA1A mutations exhibit disturbed neuromuscular transmission. The associated jitters and blocking in such patients can be detected by single-fiber electromyography (SFEMG). CASES: We report two cases with different phenotypes, which were predicted to harbor loss-of-function mutations of CACNA1A, by using axonal stimulation SFEMG. One case involved a 2-year-old boy with episodic ataxia type 2. The other case involved a 7-year-old girl diagnosed with epileptic encephalopathy. SFEMG results revealed jitters and blocking in both cases. Moreover, whole exome sequencing (WES) revealed a heterozygous CACNA1A mutation, c.5251C>T, p.Arg1751Trp, in the former case and a novel de novo CACNA1A mutation, c.2122G>A, p.Val708Met, in the latter. CONCLUSIONS: Our cases indicate that SFEMG is a potentially useful diagnostic tool for patients with CACNA1A mutation, especially in pediatric cases where trio analysis is difficult or novel mutations are present.

16.
Nat Commun ; 10(1): 2964, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31263162

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

17.
Neurobiol Aging ; 81: 166-176, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31284126

RESUMO

The amyloid beta (Aß) peptide is associated with the neurodegenerative and inflammatory changes in brains affected by Alzheimer's disease (AD). We hypothesized that the enteric nervous system also produces Aß in an intestinal component of disease. To test this idea, we compared C57BL/6 wild-type (WT) male and female mice to two models of Alzheimer's disease, amyloid precursor protein (APP)/presenilin 1 (PS1) mice and amyloid precursor protein NL-G-F (AppNL-G-F) mice, at 3, 6, and 12 months of age. Brain Aß plaque deposition in AppNL-G-F mice preceded that in the APP/PS1 mice, observable by 3 months. Three-month-old female AppNL-G-F mice had decreased intestinal motility compared with WT and APP/PS1 mice. However, 3-month-old female APP/PS1 mice demonstrated increased intestinal permeability compared with WT and AppNL-G-F mice. Both sexes of APP/PS1 and AppNL-G-F mice demonstrated increased colon lipocalin 2 mRNA and insoluble Aß 1-42 levels at 3 months. These data demonstrate an unrecognized enteric aspect of disease in 2 different mouse models correlating with the earliest brain changes.

18.
J Nucl Med ; 2019 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-31302633

RESUMO

Aim: Non-physiological overexpression of ß-amyloid (Aß) precursor protein in common transgenic Aß mouse models of Alzheimer's disease (AD) likely hampers their translational potential. The novel AppNL-G-F mouse incorporates a mutated knock-in, potentially presenting an improved model of AD for Aß-targeting treatment trials. We aimed to establish serial small animal positron-emission-tomography (µPET) of amyloidosis and neuroinflammation in AppNL-G-F mice as a tool for therapy monitoring. Methods: AppNL-G-F mice (homozygous n = 20; heterozygous n = 21) and age-matched wild-type mice (n = 12) were investigated longitudinally from 2.5 to 10 months of age with 18F-florbetaben Aß-µPET and 18F-GE-180 18kDa translocator protein (TSPO)-µPET. Voxel-wise analysis of standardized-uptake-value-ratios (SUVR) images was performed using statistical parametric mapping. All mice underwent a Morris water maze test of spatial learning after their final µPET scan. Quantification of fibrillar Aß and activated microglia by immunohistochemistry and biochemistry served for validation of µPET results. Results: The periaqueductal gray emerged as a suitable pseudo-reference tissue for both tracers. Homozygous AppNL-G-F mice had rising SUVR in cortex and hippocampus for Aß- (+9.1%, +3.8%) and TSPO- (+19.8%, +14.2%) µPET from 2.5 to 10 months of age (all P < 0.05), whereas heterozygous AppNL-G-F mice did not show significant changes with age. Significant voxel-wise clusters of Aß deposition and microglial activation in homozygous mice appeared at five months of age. Immunohistochemical and biochemical findings correlated strongly with µPET data. Water maze escape latency was significantly elevated in homozygous AppNL-G-F mice compared to wild-type at ten months of age and was associated with high TSPO binding. Conclusion: Longitudinal µPET in AppNL-G-F knock-in mice enables monitoring of amyloidogenesis and neuroinflammation in homozygous mice, but is insensitive to minor changes in heterozygous animals. The combination of µPET with behavioral tasks in AppNL-G-F treatment trails is poised to provide important insights in preclinical drug development.

19.
Pediatr Dev Pathol ; : 1093526619855488, 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-31166880

RESUMO

BACKGROUND: Hippocampal sclerosis (HS) is one of the major causes of intractable epilepsy. Astrogliosis in epileptic brain is a peculiar condition showing epileptogenesis and is thought to be different from the other pathological conditions. The aim of this study is to investigate the altered expression of astrocytic receptors, which contribute to neurotransmission in the synapse, and channels in HS lesions. METHODS: We performed immunohistochemical and immunoblotting analyses of the P2RY1, P2RY2, P2RY4, Kir4.1, Kv4.2, mGluR1, and mGluR5 receptors and channels with the brain samples of 20 HS patients and 4 controls and evaluated the ratio of immunopositive cells and those expression levels. RESULTS: The ratio of each immunopositive cell per glial fibrillary acidic protein-positive astrocytes and the expression levels of all 7 astrocytic receptors and channels in HS lesions were significantly increased. We previously described unique astrogliosis in epileptic lesions similar to what was observed in this study. CONCLUSION: This phenomenon is considered to trigger activation of the related signaling pathways and then contribute to epileptogenesis. Thus, astrocytes in epileptic lesion may show self-hyperexcitability and contribute to epileptogenesis through the endogenous astrocytic receptors and channels. These findings may suggest novel astrocytic receptor-related targets for the pharmacological treatment of epilepsy.

20.
Science ; 365(6450)2019 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-31221773

RESUMO

Cerebral blood flow is reduced early in the onset of Alzheimer's disease (AD). Because most of the vascular resistance within the brain is in capillaries, this could reflect dysfunction of contractile pericytes on capillary walls. We used live and rapidly fixed biopsied human tissue to establish disease relevance, and rodent experiments to define mechanism. We found that in humans with cognitive decline, amyloid ß (Aß) constricts brain capillaries at pericyte locations. This was caused by Aß generating reactive oxygen species, which evoked the release of endothelin-1 (ET) that activated pericyte ETA receptors. Capillary, but not arteriole, constriction also occurred in vivo in a mouse model of AD. Thus, inhibiting the capillary constriction caused by Aß could potentially reduce energy lack and neurodegeneration in AD.

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