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1.
Prog Neurobiol ; 209: 102212, 2021 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-34958873

RESUMO

ApoE4 is a major genetic risk determinant for Alzheimer's disease (AD) and drives its pathogenesis via Aß-dependent and -independent pathways. C/EBPß, a proinflammatory cytokine-activated transcription factor, is upregulated in AD patients and increases cytokines and δ-secretase expression. Under physiological conditions, ApoE is mainly expressed in glial cells, but its neuronal expression is highly elevated under pathological stresses. However, how neuronal ApoE4 mediates AD pathologies remains incompletely understood. Here we show that ApoE4 activates C/EBPß that subsequently regulates APP, Tau and BACE1 mRNA expression in mouse neurons, driving AD-like pathogenesis. To interrogate the pathological roles of both human ApoE4 and C/EBPß elevation in neurons in the aged brain, we develop neuronal specific Thy1-ApoE4/C/EBPß double transgenic mice. Neuronal ApoE4 strongly activates C/EBPß and augmented δ-secretase subsequently cleaves increased mouse APP and Tau, promoting AD-like pathologies. Notably, Thy1-ApoE4/C/EBPß mice develop amyloid deposits, Tau aggregates and neurodegeneration in an age-dependent manner, leading to synaptic dysfunction and cognitive disorders. Thus, our findings demonstrate that neuronal ApoE4 triggers AD pathogenesis via activating the crucial regulator C/EBPß.

4.
Prog Neurobiol ; 204: 102113, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34166772

RESUMO

Asparagine endopeptidase (AEP), a newly identified delta-secretase, simultaneously cleaves both APP and Tau, promoting Alzheimer's disease (AD) pathologies. However, its pathological role in AD remains incompletely understood. Here we show that delta-secretase cleaves BACE1, a rate-limiting protease in amyloid-ß (Aß) generation, escalating its enzymatic activity and enhancing senile plaques deposit in AD. Delta-secretase binds BACE1 and cuts it at N294 residue in an age-dependent manner and elevates its protease activity. The cleaved N-terminal motif is active even under neutral pH and associates with senile plaques in human AD brains. Subcellular fractionation reveals that delta-secretase and BACE1 reside in the endo-lysosomes. Interestingly, truncated BACE1 enzymatic domain (1-294) augments delta-secretase enzymatic activity and accelerates Aß production, facilitating AD pathologies and cognitive impairments in APP/PS1 AD mouse model. Uncleavable BACE1 (N294A) inhibits delta-secretase activity and Aß production and decreases AD pathologies in 5XFAD mice, ameliorating cognitive dysfunctions. Hence, delta- and beta- secretases' crosstalk aggravates each other's roles in AD pathogenesis.

5.
Prog Neurobiol ; 202: 102032, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33716161

RESUMO

ApoE4, an apolipoprotein implicated in cholesterol transport and amyloid-ß (Aß) metabolism, is a major genetic risk determinant for Alzheimer's Disease (AD) and drives its pathogenesis via Aß-dependent and -independent pathways. C/EBPß, a proinflammatory cytokines-activated transcription factor, is upregulated in AD and mediates cytokines and δ-secretase expression. However, how ApoE4 contributes to AD pathogenesis remains incompletely understood. Here we show that ApoE4 and 27-hydroxycholesterol (27-OHC) co-activate C/EBPß/δ-secretase signaling in neurons, mediating AD pathogenesis, and this effect is dependent on neuronal secreted Aß and inflammatory cytokines. Inhibition of cholesterol metabolism with lovastatin diminishes neuronal ApoE4's stimulatory effects. Furthermore, ApoE4 and 27-OHC also mediate lysosomal δ-secretase leakage, activation, secretion and endocytosis. Notably, 27-OHC strongly activates C/EBPß/δ-secretase pathway in human ApoE4-TR mice and triggers AD pathologies and cognitive deficits, which is blocked by C/EBPß depletion. Hence, our findings demonstrate that ApoE4 and 27-OHC additively trigger AD pathogenesis via activating C/EBPß/δ-secretase pathway. Lowering cholesterol levels with statins should benefit the ApoE4 AD carriers.

6.
Mol Psychiatry ; 26(7): 2943-2963, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32782380

RESUMO

Neurotrophins promote neuronal survival and synaptic plasticity via activating the tropomyosin receptor kinases. BDNF and its high-affinity receptor TrkB are reduced in Alzheimer's disease (AD), contributing to progressive cognitive decline. However, how the signaling mediates AD pathologies remains incompletely understood. Here we show that the TrkB receptor binds and phosphorylates APP, reducing amyloid-ß production, which are abrogated by δ-secretase cleavage of TrkB in AD. Remarkably, BDNF stimulates TrkB to phosphorylate APP Y687 residue that accumulates APP in the TGN (Trans-Golgi Network) and diminishes its amyloidogenic cleavage. Delta-secretase cleaves TrkB at N365 and N486/489 residues and abolishes its neurotrophic activity, decreasing p-APP Y687 and altering its subcellular trafficking. Notably, both TrkB and APP are robustly cleaved by δ-secretase in AD brains, accompanied by mitigated TrkB signaling and reduced p-Y687. Blockade of TrkB cleavage attenuates AD pathologies in 5xFAD mice, rescuing the learning and memory. Viral expression of TrkB 1-486 fragment in the hippocampus of APP/PS1 mice facilitates amyloid pathology and mitigates cognitive functions. Hence, δ-secretase cleaves TrkB and blunts its phosphorylation of APP, facilitating AD pathogenesis.

7.
Mol Psychiatry ; 2020 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-33339957

RESUMO

The apolipoprotein E ε4 (APOE4) allele is a major genetic risk factor for Alzheimer's disease (AD), and its protein product, ApoE4, exerts its deleterious effects mainly by influencing amyloid-ß (Aß) and Tau (neurofibrillary tangles, NFTs) deposition in the brain. However, the molecular mechanism dictating its expression during ageing and in AD remains incompletely clear. Here we show that C/EBPß acts as a pivotal transcription factor for APOE and mediates its mRNA levels in an age-dependent manner. C/EBPß binds the promoter of APOE and escalates its expression in the brain. Knockout of C/EBPß in AD mouse models diminishes ApoE expression and Aß pathologies, whereas overexpression of C/EBPß accelerates AD pathologies, which can be attenuated by anti-ApoE monoclonal antibody or deletion of ApoE via its specific shRNA. Remarkably, C/EBPß selectively promotes more ApoE4 expression versus ApoE3 in human neurons, correlating with higher activation of C/EBPß in human AD brains with ApoE4/4 compared to ApoE3/3. Therefore, our data support that C/EBPß is a crucial transcription factor for temporally regulating APOE gene expression, modulating ApoE4's role in AD pathogenesis.

8.
Sci Rep ; 10(1): 19349, 2020 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-33168948

RESUMO

Chronic granulomatous disease (CGD) is characterized by recurrent infections and granuloma formation in multiple organs, especially the lung. We aimed to investigate pulmonary manifestations by computed tomography (CT). In total, 100 patients with 117 episodes of pulmonary infection were included. Chest CT scans of every episode were analyzed. Random nodules were the most common findings (79.49%), followed by ground-grass opacities (74.36%), focal consolidations (62.39%), and masses (59.83%). Cavities (12.82%) and multiple small abscesses (17.09%) could be found in the consolidations and masses. CT revealed interstitial pneumonia with tree-in-bud opacities (17.09%), interlobular septal thickening (23.08%) and emphysema (35.04%), which were more severe in the bilateral upper lobes. Mediastinal and hilar lymphadenopathy (78.63%) and axillary lymphadenopathy (65.81%) were common. Fungal infection (n = 27) was the most common and presented with multiple nodules and masses. Approximately 1/4 of fungal infections had interstitial pneumonia. In Staphylococcus aureus (n = 6) and Klebsiella pneumoniae (n = 3) infections, large areas of consolidation were common. In tuberculosis infection, the pulmonary infections were more severe and complex. For Bacillus Calmette-Guérin disease, left-sided axillary lymphadenopathy was a characteristic manifestation. CT images of CGD demonstrated variable pulmonary abnormalities. The main infectious organisms have unique imaging features.


Assuntos
Doença Granulomatosa Crônica/diagnóstico por imagem , Doença Granulomatosa Crônica/microbiologia , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Micoses/diagnóstico por imagem , Criança , Pré-Escolar , China/epidemiologia , Enfisema/diagnóstico por imagem , Feminino , Humanos , Lactente , Klebsiella pneumoniae , Masculino , Mycobacterium bovis , Radiografia Torácica , Estudos Retrospectivos , Staphylococcus aureus , Tomografia Computadorizada por Raios X
9.
iScience ; 23(9): 101465, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32861999

RESUMO

In Alzheimer's disease (AD), decreases in the amount and synaptic localization of AMPA receptors (AMPARs) result in weakened synaptic activity and dysfunction in synaptic plasticity, leading to impairments in cognitive functions. We have previously found that AMPARs are subject to lysine acetylation, resulting in higher AMPAR stability and protein accumulation. Here we report that AMPAR acetylation was significantly reduced in AD and neurons with Aß incubation. We identified p300 as the acetyltransferase responsible for AMPAR acetylation and found that enhancing GluA1 acetylation ameliorated Aß-induced reductions in total and cell-surface AMPARs. Importantly, expression of acetylation mimetic GluA1 (GluA1-4KQ) in APP/PS1 mice rescued impairments in synaptic plasticity and memory. These findings indicate that Aß-induced reduction in AMPAR acetylation and stability contributes to synaptopathy and memory deficiency in AD, suggesting that AMPAR acetylation may be an effective molecular target for AD therapeutics.

10.
Redox Biol ; 34: 101578, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32526700

RESUMO

Glioblastoma (GBM) is the most common and most aggressive brain tumor, associated with high levels of reactive oxidative species (ROS) due to metabolic and signaling aberrations. High ROS levels are detrimental to cells, but it remains incompletely understood how cancer cells cope with the adverse effects. Here we show that C/EBPß, a ROS responsive transcription factor, regulates the transcription of NQO1 and GSTP1, two antioxidative reductases, which neutralize ROS in the GBM and mediates their proliferation. C/EBPß is upregulated in EGFR overexpressed GBM cells, inversely correlated with the survival rates of brain tumor patients. Interestingly, C/EBPß binds the promoters of NQO1 and GSTP1 and escalates their expression. Overexpression of C/EBPß selectively decreases the ROS in EGFR-overexpressed U87MG cells and promotes cell proliferation via upregulating NQO1 and GSTP1; whereas knocking down C/EBPß elevates the ROS and reduces proliferation by repressing the reductases. Accordingly, C/EBPß mediates the brain tumor growth in vivo, coupling with NQO1 and GSTP1 expression and ROS levels. Hence, C/EBPß regulates the expression of antioxidative reductases and balances the ROS, promoting brain tumor proliferation.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Neoplasias Encefálicas/genética , Proteína beta Intensificadora de Ligação a CCAAT/genética , Linhagem Celular Tumoral , Proliferação de Células , Glioblastoma/genética , Glutationa S-Transferase pi/genética , Humanos , NAD(P)H Desidrogenase (Quinona)/genética , Oxirredutases
11.
J Clin Neurosci ; 77: 49-54, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32418810

RESUMO

To explore the influence of serum lactate dehydrogenase (LDH) level on remote diffusion-weighted imaging lesions (rDWILs) after spontaneous intracerebral hemorrhage (ICH). A consecutive cohort of 160 patients with spontaneous ICH who had brain MRI within 4 weeks of ICH onset were collected and analyzed retrospectively. rDWILs showed high signal on diffusion-weighted image (DWI) while low signal on apparent diffusion coefficient (ADC), and at least 20 mm away from the hemorrhage focus. The blood samples were obtained within 24 h after ICH onset from all patients. Lactate dehydrogenase (LDH) levels in blood were collected from serum biochemical tests. We use multivariate logistic regression analyses to investigate the association between serum LDH level and rDWILs after ICH. The average serum LDH level was 186.5 ± 35.6 U/L. And this level was higher in patients who presented rDWILs than in those without rDWILs. With the best cut-off value of 191 by using receiver operating characteristic (ROC) analysis, elevated LDH was associated with the presence of rDWILs independently (OR = 1.024, 95%CI = 1.011-1.037, P < 0.001) in the bivariate logistic regression analysis with adjustment for age, sex, previous ischemic stroke/TIA, smoker, SBP on admission, hematoma volume, and intraventricular hemorrhage (IVH). The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) of LDH ≥ 191 U/L for rDWILs were 70.4%, 72.2%, 33.9%, 94.2%, respectively. Our study suggests serum LDH level has a significant correlation with rDWILs after spontaneous ICH. Patients with higher serum LDH level in 24 h after ICH onset may be a useful predictor for rDWILs occurrence.


Assuntos
Hemorragia Cerebral/sangue , Hemorragia Cerebral/diagnóstico por imagem , Imagem de Difusão por Ressonância Magnética/métodos , L-Lactato Desidrogenase/sangue , Idoso , Biomarcadores/sangue , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
12.
Curr Med Sci ; 40(2): 389, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32337701

RESUMO

The article "Protein Phosphatase 2A as a Drug Target in the Treatment of Cancer and Alzheimer's Disease", written by Hui WEI, Hui-liang ZHANG, Jia-zhao XIE, Dong-li MENG, Xiao-chuan WANG, Dan KE, Ji ZENG, Rong LIU, was originally published electronically on the publisher's internet portal on 13 March 2020 without open access. With the author(s)' decision to opt for Open Choice the copyright of the article changed to © The Author(s) 2020 and the article is forthwith distributed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.The original article has been corrected.Corresponding authors: Dan KE, E-mail: kedan@hust.edu.cn; Ji ZENG, E-mail: whzjmicro@163.com.

13.
Curr Med Sci ; 40(1): 1-8, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32166659

RESUMO

Protein phosphatase 2A (PP2A) is a major serine/threonine phosphatase which participates in the regulation of multiple cellular processes. As a confirmed tumor suppressor, PP2A activity is downregulated in tumors and its re-activation can induce apoptosis of cancer cells. In the brains of Alzheimer's disease (AD) patients, decreased PP2A activity also plays a key role in promoting tau hyperphosphorylation and Aß generation. In this review, we discussed compounds aiming at modulating PP2A activity in the treatment of cancer or AD. The upstream factors that inactivate PP2A in diseases have not been fully elucidated and further studies are needed. It will help for the refinement and development of novel and clinically tractable PP2A-targeted compounds or therapies for the treatment of tumor and AD.


Assuntos
Doença de Alzheimer/metabolismo , Neoplasias/metabolismo , Proteína Fosfatase 2/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Doença de Alzheimer/tratamento farmacológico , Encéfalo/metabolismo , Regulação para Baixo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/uso terapêutico
14.
Neurotherapeutics ; 17(3): 1087-1103, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32096091

RESUMO

Alzheimer's disease (AD) is a multifactorial neurodegenerative disease for which there are limited therapeutic strategies. Protein phosphatase 2A (PP2A) activity is decreased in AD brains, which promotes the hyperphosphorylation of Tau and APP, thus participate in the formation of neurofibrillary tangles (NFTs) and ß-amyloid (Aß) overproduction. In this study, the effect of synthetic tricyclic sulfonamide PP2A activators (aka SMAPs) on reducing AD-like pathogenesis was evaluated in AD cell models and AD-like hyperhomocysteinemia (HHcy) rat models. SMAPs effectively increased PP2A activity, and decreased tau phosphorylation and Aß40/42 levels in AD cell models. In HHcy-AD rat models, cognitive impairments induced by HHcy were rescued by SMAP administration. HHcy-induced tau hyperphosphorylation and Aß overproduction were ameliorated through increasing PP2A activity on compound treatment. Importantly, SMAP therapy also prevented neuronal cell spine loss and neuronal synapse impairment in the hippocampus of HHcy-AD rats. In summary, our data reveal that pharmacological PP2A reactivation may be a novel therapeutic strategy for AD treatment, and that the tricyclic sulfonamides constitute a novel candidate class of AD therapeutic.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Modelos Animais de Doenças , Proteína Fosfatase 2/metabolismo , Sulfonamidas/uso terapêutico , Doença de Alzheimer/induzido quimicamente , Animais , Células HEK293 , Homocisteína/toxicidade , Humanos , Masculino , Ratos , Ratos Sprague-Dawley , Sulfonamidas/química , Sulfonamidas/farmacologia
15.
EMBO Rep ; 21(3): e48328, 2020 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-31930681

RESUMO

Overexpressing Tau counteracts apoptosis and increases dephosphorylated ß-catenin levels, but the underlying mechanisms are elusive. Here, we show that Tau can directly and robustly acetylate ß-catenin at K49 in a concentration-, time-, and pH-dependent manner. ß-catenin K49 acetylation inhibits its phosphorylation and its ubiquitination-associated proteolysis, thus increasing ß-catenin protein levels. K49 acetylation further promotes nuclear translocation and the transcriptional activity of ß-catenin, and increases the expression of survival-promoting genes (bcl2 and survivin), counteracting apoptosis. Mutation of Tau's acetyltransferase domain or co-expressing non-acetylatable ß-catenin-K49R prevents increased ß-catenin signaling and abolishes the anti-apoptotic function of Tau. Our data reveal that Tau preserves ß-catenin by acetylating K49, and upregulated ß-catenin/survival signaling in turn mediates the anti-apoptotic effect of Tau.


Assuntos
Transdução de Sinais , beta Catenina , Proteínas tau , Acetilação , Apoptose/genética , Sobrevivência Celular/genética , Humanos , Fosforilação , beta Catenina/genética , beta Catenina/metabolismo
16.
Curr Med Sci ; 40(6): 999-1008, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33428127

RESUMO

Alzheimer's disease (AD) is a chronic neurodegenerative disease that mainly causes dementia. It is a serious threat to the health of the global elderly population. Considerable money and effort has been invested in the development of drug therapy for AD worldwide. Many drug therapies are currently under development or in clinical trials, based on two known mechanisms of AD, namely, Aß toxicity and the abnormal Tau hyperphosphorylation. Numerous drugs are also being developed for other AD associated mechanisms such as neuroinflammation, neurotransmitter imbalance, oxidative damage and mitochondrial dysfunction, neuron loss and degeneration. Even so, the number of drugs that can successfully improve symptoms or delay the progression of the disease remains very limited. However, multi-drug combinations may provide a new avenue for drug therapy for AD. In addition, early diagnosis of AD and timely initiation of treatment may allow drugs that act on the early pathological processes of AD to help improve the symptoms and prevent the progression of the condition.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Precursor de Proteína beta-Amiloide/metabolismo , Proteínas tau/metabolismo , Doença de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/antagonistas & inibidores , Ensaios Clínicos como Assunto , Progressão da Doença , Humanos , Terapia de Alvo Molecular , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Proteínas tau/antagonistas & inibidores
17.
Curr Alzheimer Res ; 16(8): 732-740, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31470788

RESUMO

BACKGROUND: Upregulation of Cancerous Inhibitor of PP2A (CIP2A) plays an important role in disease-related phosphorylation of tau/APP and tau pathology/Aß overproduction through inhibiting PP2A in AD brain. Genistein has been shown to potently reduce CIP2A in experimental cancer treatment research. Whether Genistein can ameliorate AD pathology through targeting CIP2A needs further investigation. METHODS: The inhibitory effects of Genistein on tau/APP phosphorylation and Aß overproduction in AD cell models have been explored. HEK293-T cells were co-transfected with CIP2A and APP plasmids, or CIP2A and tau plasmids, with Genistein incubation at 0, 30, 60 or 120 µM for 48 h, cell viability and PP2A activities were measured. HEK293-T cells with CIP2A/APP overexpression treated with Genistein at 30 µM for 48 h were collected and lyzed for Western blotting detection of CIP2A, PP2Ac, APP-T668, total APP, PS1, BACE1, sAPPα and sAPPß. Aß40 and Aß42 levels in cell supernatant, soluble fraction (RIPA) and insoluble fraction (formic acid soluble) of cell lysates were measured by ELISA. HEK293-T cells with CIP2A/tau overexpression treated with Genistein at 30 µM for 48 h were collected for Western blotting detection of CIP2A, PP2Ac, tau-S396, tau-S404 and total tau. RESULTS: Genistein effectively reduced CIP2A expression, and restored PP2A activities both in CIP2A/APP, CIP2A/tau co-expressed cells. Genistein reduced APP phosphorylation at T668 site and inhibited Aß production. Meantime, Genistein ameliorated tau hyperphosphorylation through repressing the inhibitory effect of CIP2A on PP2A. CONCLUSION: CIP2A is a target of Genistein in AD therapy. Genistein reduces APP/tau hyperphosphorylation and Aß production through inhibiting the effect of CIP2A on PP2A.


Assuntos
Precursor de Proteína beta-Amiloide/metabolismo , Autoantígenos/metabolismo , Genisteína/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas tau/metabolismo , Células HEK293 , Humanos , Fosforilação/efeitos dos fármacos , Proteína Fosfatase 2/metabolismo
18.
R Soc Open Sci ; 6(7): 190144, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31417721

RESUMO

Energy extraction from nuclear materials produces high-level radioactive waste. In geological nuclear waste storage repositories, the decay of radioactive elements generates heat, exposing the reservoir rocks to high-temperature conditions for long periods. To explore the effects of these conditions, this study examines the ability of granite to resist fracturing after thermal treatment for 10 h, 10 days, 30 days and 60 days. The results show that the fracture toughness of the granite remained basically unchanged for up to 10 days of thermal treatment. After thermal treatment for 60 days, the mode I, mode II and mixed-mode (I + II) fracture toughness decreased by 15.39%, 18.09% and 15.17%, respectively, compared with samples heated for 10 h. The change trends of the ability of granite to resist tensile, shear and mixed (tensile + shear) failure with an increased thermal treatment duration were basically consistent. Moreover, there was little change in its brittle fracturing characteristics with an increase in heating duration. Changes caused to the internal microstructure of the granite by high temperature were ongoing even up to 60 days.

19.
J Neurosurg Pediatr ; 23(3): 363-368, 2019 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-30611154

RESUMO

OBJECTIVE Mechanical thrombectomy using a Solitaire stent retriever has been widely applied as a safe and effective method in adult acute ischemic stroke (AIS). However, due to the lack of data, the safety and effectiveness of mechanical thrombectomy using a Solitaire stent in pediatric AIS has not yet been verified. The purpose of this study was to explore the safety and effectiveness of mechanical thrombectomy using a Solitaire stent retriever for pediatric AIS. METHODS Between January 2012 and December 2017, 7 cases of pediatric AIS were treated via mechanical thrombectomy using a Solitaire stent retriever. The clinical practice, imaging, and follow-up results were reviewed, and the data were summarized and analyzed. RESULTS The ages of the 7 patients ranged from 7 to 14 years with an average age of 11.1 years. The preoperative National Institutes of Health Stroke Scale (NIHSS) scores ranged from 9 to 22 with an average of 15.4 points. A Solitaire stent retriever was used in all patients, averaging 1.7 applications of thrombectomy and combined balloon dilation in 2 cases. Grade 3 on the modified Thrombolysis In Cerebral Infarction scale of recanalization was achieved in 5 cases and grade 2b in 2 cases. Six patients improved and 1 patient died after thrombectomy. The average NIHSS score of the 6 cases was 3.67 at discharge. The average modified Rankin Scale score was 1 at the 3-month follow-up. Subarachnoid hemorrhage after thrombectomy occurred in 1 case and that patient died 3 days postoperatively. CONCLUSIONS This study shows that mechanical thrombectomy using a Solitaire stent retriever has a high recanalization rate and excellent clinical prognosis in pediatric AIS. The safety of mechanical thrombectomy in pediatric AIS requires more clinical trials for confirmation. ABBREVIATIONS ACA = anterior cerebral artery; AIS = acute ischemic stroke; CTA = CT angiography; ICA = internal carotid artery; MCA = middle cerebral artery; mRS = modified Rankin Scale; mTICI = modified Thrombolysis In Cerebral Infarction; NIHSS = National Institutes of Health Stroke Scale; rt-PA = recombinant tissue plasminogen activator.


Assuntos
Trombólise Mecânica/métodos , Stents , Acidente Vascular Cerebral/terapia , Trombectomia/métodos , Resultado do Tratamento , Adolescente , Angiografia Digital , Isquemia Encefálica/complicações , Isquemia Encefálica/diagnóstico por imagem , Criança , Feminino , Humanos , Masculino , Estudos Retrospectivos , Índice de Gravidade de Doença , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/etiologia
20.
Neurobiol Aging ; 75: 198-208, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30594047

RESUMO

Reactive astrogliosis and early synaptic degeneration are 2 characteristic hallmarks in Alzheimer's disease (AD) brains, but a direct link between the 2 events has not been established. Here, we show that cancerous inhibitor of PP2A (CIP2A), a cancerous protein with high expression level in astrocytes, is upregulated in patients with AD and 3xTg-AD transgenic mice. Overexpression of CIP2A in astrocytes through adeno-associated virus infection both in cultured cells and in mice brains results in activation of astrocytes, increased production of cytokines and Aß, and synaptic degeneration indicated by decreased levels of synaptic proteins, spine loss, and impairment in long-term potentiation. As a result of synaptic degeneration, CIP2A overexpression in astrocytes in vivo induces significant deficits in visual episodic memory detected by novel objective recognition test and spatial memory detected by Morris water maze. We conclude that CIP2A-promoted astrogliosis induces synaptic degeneration and cognitive deficits in AD.


Assuntos
Doença de Alzheimer/metabolismo , Astrócitos/metabolismo , Autoantígenos/metabolismo , Disfunção Cognitiva/metabolismo , Proteínas de Membrana/metabolismo , Memória Espacial/fisiologia , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Autoantígenos/genética , Cognição , Transtornos Cognitivos/metabolismo , Disfunção Cognitiva/genética , Modelos Animais de Doenças , Hipocampo/metabolismo , Potenciação de Longa Duração/fisiologia , Proteínas de Membrana/genética , Transtornos da Memória/metabolismo , Camundongos Transgênicos
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