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1.
Front Aging Neurosci ; 16: 1423139, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39076205

RESUMO

Background: Alzheimer's disease (AD) is the predominant cause of dementia on a global scale, significantly impacting the health of the elderly population. The pathogenesis of AD is closely linked to neuroinflammation. The present study employs a bibliometric analysis to examine research pertaining to neuroinflammation and AD within the last decade, with the objective of providing a comprehensive overview of the current research profile, hotspots and trends. Methods: This research conducted a comprehensive review of publications within the Science Citation Index Expanded of the Web of Science Core Collection Database spanning the years 2014 to 2024. Bibliometric analyses were performed using VOSviewer (version 1.6.19) and CiteSpace (version 6.3.R1) software to visualize data on countries, institutions, authors, journals, keywords, and references. Results: A total of 3,833 publications on neuroinflammation and AD were included from January 2014 to January 2024. Publications were mainly from the United States and China. Zetterberg, Henrik emerged as the author with the highest publication output, while Edison, Paul was identified as the most cited author. The most productive journal was Journal of Alzheimers Disease, and the most co-cited was Journal of Neuroinflammation. Research hotspot focused on microglia, mouse models, oxidative stress, and amyloid-beta through keyword analysis. Additionally, keywords such as blood-brain barrier and tau protein exhibited prolonged citation bursts from 2022 to 2024. Conclusion: This study provides a comprehensive review of the last 10 years of research on neuroinflammation and AD, including the number and impact of research findings, research hotspots, and future trends. The quantity of publications in this field is increasing, mainly in the United States and China, and there is a need to further strengthen close cooperation with different countries and institutions worldwide. Presently, research hotspots are primarily concentrated on microglia, with a focus on inhibiting their pro-inflammatory responses and promoting their anti-inflammatory functions as a potential direction for future investigations.

2.
J Alzheimers Dis ; 101(2): 637-649, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39213067

RESUMO

Background: The cholinergic hypothesis is one of the main theories that describe the pathogenesis of Alzheimer's disease (AD). Cholinergic neurons degenerate early and are severely damaged in AD. Despite extensive research, the causes of cholinergic neuron damage and the underlying molecular changes remain unclear. Objective: This study aimed to explore the characteristics and transcriptomic changes in cholinergic neurons derived from human induced pluripotent stem cells (iPSCs) with APP mutation. Methods: Peripheral blood mononuclear cells from patients with AD and healthy individuals were reprogrammed into iPSCs. The iPSCs were differentiated into cholinergic neurons. Cholinergic neurons were stained, neurotoxically tested, and electrophysiologically and transcriptomically analyzed. Results: The iPSCs-derived cholinergic neurons from a patient with AD carrying a mutation in APP displayed enhanced susceptibility to Aß1-42-induced neurotoxicity, characterized by severe neurotoxic effects, such as cell body coagulation and neurite fragmentation. Cholinergic neurons exhibited electrophysiological impairments and neuronal death after 21 days of culture in the AD group. Transcriptome analysis disclosed 883 differentially expressed genes (DEGs, 420 upregulated and 463 downregulated) participating in several signaling pathways implicated in AD pathogenesis. To assess the reliability of RNA sequencing, the expression of 16 target DEGs was validated using qPCR. Finally, the expression of the 8 core genes in different cell types of brain was analyzed by the AlzData database. Conclusions: In this study, iPSCs-derived cholinergic neurons from AD patients with APP mutations exhibit characteristics reminiscent of neurodegenerative disease. Transcriptome analysis revealed the corresponding DEGs and pathways, providing potential biomarkers and therapeutic targets for advancing AD research.


Assuntos
Doença de Alzheimer , Precursor de Proteína beta-Amiloide , Neurônios Colinérgicos , Células-Tronco Pluripotentes Induzidas , Mutação , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/genética , Neurônios Colinérgicos/metabolismo , Neurônios Colinérgicos/patologia , Mutação/genética , Perfilação da Expressão Gênica , Transcriptoma , Peptídeos beta-Amiloides/metabolismo , Diferenciação Celular/genética , Masculino , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Feminino
3.
Stem Cell Res ; 79: 103501, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39029293

RESUMO

Apolipoprotein E (APOE)is the gene with greatest genetic risk for Alzheimer's disease (AD). We successfully established a human induced pluripotent stem cell(iPSC) line from a woman mutated by APOE gene. The cell line was isolated from this woman's peripheral blood mononuclear cells using a non-integrated Sendai virus, which retained the original genotype, showed a normal karyotype, highly expressed pluripotent markers and could differentiate into three germ layers.


Assuntos
Apolipoproteínas E , Células-Tronco Pluripotentes Induzidas , Mutação , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/citologia , Feminino , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Linhagem Celular , Diferenciação Celular , Cariótipo , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/citologia
4.
Stem Cell Res ; 77: 103398, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38552354

RESUMO

Genetic polymorphism of apolipoprotein E (APOE) confers differential susceptibility to Alzheimer's disease (AD), and APOE ɛ4 variants is the most powerful risk factor for this disease. Here, we report the generation of a human induced pluripotent stem cell (iPSC) line carrying the APOE ɛ4/ɛ4 genotype from peripheral blood mononuclear cells (PBMCs) isolated from a male with a family history of AD utilizing non-integrative Sendai virus vector. The iPSC maintains their original genotype, highly express endogenous pluripotency markers, displays a normal karyotype, and retains the ability to differentiate into cells representative of the three germ layers.


Assuntos
Apolipoproteínas E , Células-Tronco Pluripotentes Induzidas , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/citologia , Masculino , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Mutação , Linhagem Celular , Diferenciação Celular , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/citologia
5.
BMJ Open ; 14(7): e082404, 2024 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-39002963

RESUMO

INTRODUCTION: The efficacy of multitarget neuroprotective drug DL-3-n-butylphthalide (NBP) in improving cognitive function has been confirmed in patients with vascular cognitive impairment without dementia. However, its efficacy in patients with symptomatic predementia phase of Alzheimer's disease remains uncertain. This study aims to evaluate the efficacy and safety of NBP in improving cognitive function in patients with mild cognitive impairment (MCI) through a clinical randomised controlled trail. METHODS AND ANALYSIS: This study is a 12-month, randomised, double-blind, placebo-controlled, multicentric trial, involving 270 patients with MCI. Subjects are randomly assigned to receive either NBP soft capsule (200 mg, three times per day) or placebo with an allocation ratio of 1:1. The efficacy and safety of NBP are assessed by comparing the results of neuropsychological, neuroimaging and laboratory tests between the two groups. The primary endpoint is the change in Alzheimer's Disease Assessment Scale-Cognitive Subscale after 12 months. All patients will be monitored for adverse events. ETHICS AND DISSEMINATION: This study involving human participants has been reviewed and approved by Ethics Committee of Xuan Wu Hospital (No.2017058). The participants provide their written informed consent to participate in this study. Results will be published in peer-reviewed medical journals and disseminated to healthcare professionals at local and international conferences. PROTOCOL VERSION: V 3.0, 3 September 2022. TRIAL REGISTRATION NUMBER: ChiCTR1800018362.


Assuntos
Benzofuranos , Disfunção Cognitiva , Fármacos Neuroprotetores , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Benzofuranos/uso terapêutico , Benzofuranos/efeitos adversos , Cognição/efeitos dos fármacos , Disfunção Cognitiva/tratamento farmacológico , Método Duplo-Cego , Estudos Multicêntricos como Assunto , Fármacos Neuroprotetores/uso terapêutico , Fármacos Neuroprotetores/efeitos adversos , Testes Neuropsicológicos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
6.
Mol Oncol ; 16(19): 3509-3532, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35900231

RESUMO

Adenocarcinoma is the most prevalent histological subtype of colorectal cancer (CRC), with mucinous colorectal adenocarcinoma (MCA) being a unique form. Although the mucinous subtype is known to elicit a worse response to chemotherapy and immunotherapy than the nonmucinous subtype, its pathogenesis remains poorly understood. Neurogenic locus notch homolog protein 3 (NOTCH3), a member of the NOTCH subfamilies, is highly expressed in CRC. In the past three decades, many studies have been performed evaluating the biological role of NOTCH3 in CRC. However, the precise activities of NOTCH3 in MCA, as well as the mechanisms involved in its transcriptional control, are yet to be elucidated. Our finding showed that the critical transcriptional regulatory factor transcription activator BRG1 (SMARCA4) directly binds to the intracellular domain of NOTCH3 to control transcriptional regulation. Moreover, RNA-sequencing results indicated a common targeting effect on the transcriptional activity of mucin-5AC (MUC5AC) and mucin-2 (MUC2) in CRC cells by NOTCH3 and SMARCA4. Furthermore, NOTCH3 was found to control the expressions of MUC5AC and MUC2 in a SMARCA4-dependent manner. MUC5AC and MUC2, which encode two secreted mucins, are located on chromosome 11p15.5, and are linked to the development of MCA. This finding suggests that the interaction between NOTCH3 and SMARCA4 may be involved in MCA differentiation by jointly targeting MUC5AC and MUC2. Patients with MCA are often treated in accordance with CRC guidelines. Determining the relationship between NOTCH3 and SMARCA4 by demonstrating their interactions in the pathophysiology of MCA could provide novel therapeutic targets and help identify potential prognostic markers for MCA.


Assuntos
Adenocarcinoma , Neoplasias Colorretais , Adenocarcinoma/patologia , Neoplasias Colorretais/patologia , DNA Helicases/genética , Humanos , Mucina-5AC , Mucina-2/genética , Mucina-2/metabolismo , Proteínas Nucleares/genética , RNA , Receptor Notch3 , Fatores de Transcrição/genética
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