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Nature Neuroscience Mar 2019Accumulation of damaged mitochondria is a hallmark of aging and age-related neurodegeneration, including Alzheimer's disease (AD). The molecular mechanisms of impaired...
Accumulation of damaged mitochondria is a hallmark of aging and age-related neurodegeneration, including Alzheimer's disease (AD). The molecular mechanisms of impaired mitochondrial homeostasis in AD are being investigated. Here we provide evidence that mitophagy is impaired in the hippocampus of AD patients, in induced pluripotent stem cell-derived human AD neurons, and in animal AD models. In both amyloid-β (Aβ) and tau Caenorhabditis elegans models of AD, mitophagy stimulation (through NAD supplementation, urolithin A, and actinonin) reverses memory impairment through PINK-1 (PTEN-induced kinase-1)-, PDR-1 (Parkinson's disease-related-1; parkin)-, or DCT-1 (DAF-16/FOXO-controlled germline-tumor affecting-1)-dependent pathways. Mitophagy diminishes insoluble Aβ and Aβ and prevents cognitive impairment in an APP/PS1 mouse model through microglial phagocytosis of extracellular Aβ plaques and suppression of neuroinflammation. Mitophagy enhancement abolishes AD-related tau hyperphosphorylation in human neuronal cells and reverses memory impairment in transgenic tau nematodes and mice. Our findings suggest that impaired removal of defective mitochondria is a pivotal event in AD pathogenesis and that mitophagy represents a potential therapeutic intervention.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Animals, Genetically Modified; Caenorhabditis elegans; Disease Models, Animal; Female; Hippocampus; Induced Pluripotent Stem Cells; Male; Memory; Mice; Mitophagy; Neural Stem Cells; Neurons
PubMed: 30742114
DOI: 10.1038/s41593-018-0332-9 -
Journal of the American College of... Sep 2020Evaluation of coronary artery disease (CAD) using coronary computed tomography angiography (CCTA) has seen a paradigm shift in the last decade. Evidence increasingly... (Review)
Review
Evaluation of coronary artery disease (CAD) using coronary computed tomography angiography (CCTA) has seen a paradigm shift in the last decade. Evidence increasingly supports the clinical utility of CCTA across various stages of CAD, from the detection of early subclinical disease to the assessment of acute chest pain. Additionally, CCTA can be used to noninvasively quantify plaque burden and identify high-risk plaque, aiding in diagnosis, prognosis, and treatment. This is especially important in the evaluation of CAD in immune-driven conditions with increased cardiovascular disease prevalence. Emerging applications of CCTA based on hemodynamic indices and plaque characterization may provide personalized risk assessment, affect disease detection, and further guide therapy. This review provides an update on the evidence, clinical applications, and emerging technologies surrounding CCTA as highlighted at the 2019 National Heart, Lung and Blood Institute CCTA Summit.
Topics: Biomedical Technology; Chest Pain; Computed Tomography Angiography; Coronary Angiography; Coronary Artery Disease; Humans; Review Literature as Topic; Risk Assessment; Vascular Calcification
PubMed: 32883417
DOI: 10.1016/j.jacc.2020.06.076 -
Disease-a-month : DM May 2015Pseudomembranous colitis is an inflammatory condition of the colon characterized by elevated yellow-white plaques that coalesce to form pseudomembranes on the mucosa.... (Review)
Review
Pseudomembranous colitis is an inflammatory condition of the colon characterized by elevated yellow-white plaques that coalesce to form pseudomembranes on the mucosa. Patients with the condition commonly present with abdominal pain, diarrhea, fever, and leukocytosis. Because pseudomembranous colitis is often associated with infection, stool testing and empiric antibiotic treatment should be initiated when suspected. When results of testing are negative and symptoms persist despite escalating empiric treatment, early gastroenterology consultation and lower endoscopy would be the next step in the appropriate clinical setting. If pseudomembranous colitis is confirmed endoscopically, colonic biopsies should be obtained, as histology can offer helpful clues to the underlying diagnosis. The less common non- causes of pseudomembranous colitis should be entertained, as a number of etiologies can result in this condition. Examples include Behcet’s disease, collagenous colitis, inflammatory bowel disease, ischemic colitis, other infections organisms (e.g. bacteria, parasites, viruses), and a handful of drugs and toxins. Pinpointing the correct underlying etiology would better direct patient care and disease management. Surgical specialists would be most helpful in colonic perforation, gangrenous colon, or severe disease.
Topics: Biopsy, Needle; Clostridioides difficile; Colonoscopy; Combined Modality Therapy; Disease Progression; Enterocolitis, Pseudomembranous; Female; Humans; Immunohistochemistry; Male; Prognosis; Risk Assessment; Severity of Illness Index
PubMed: 25769243
DOI: 10.1016/j.disamonth.2015.01.006 -
Immunity Sep 2017Microglia play a pivotal role in the maintenance of brain homeostasis but lose homeostatic function during neurodegenerative disorders. We identified a specific...
Microglia play a pivotal role in the maintenance of brain homeostasis but lose homeostatic function during neurodegenerative disorders. We identified a specific apolipoprotein E (APOE)-dependent molecular signature in microglia from models of amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and Alzheimer's disease (AD) and in microglia surrounding neuritic β-amyloid (Aβ)-plaques in the brains of people with AD. The APOE pathway mediated a switch from a homeostatic to a neurodegenerative microglia phenotype after phagocytosis of apoptotic neurons. TREM2 (triggering receptor expressed on myeloid cells 2) induced APOE signaling, and targeting the TREM2-APOE pathway restored the homeostatic signature of microglia in ALS and AD mouse models and prevented neuronal loss in an acute model of neurodegeneration. APOE-mediated neurodegenerative microglia had lost their tolerogenic function. Our work identifies the TREM2-APOE pathway as a major regulator of microglial functional phenotype in neurodegenerative diseases and serves as a novel target that could aid in the restoration of homeostatic microglia.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Apolipoproteins E; Apoptosis; Cerebral Cortex; Cluster Analysis; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Female; Gene Expression Profiling; Gene Expression Regulation; Gene Targeting; Humans; Immune Tolerance; Membrane Glycoproteins; Mice; Mice, Knockout; Mice, Transgenic; Microglia; Monocytes; Neurodegenerative Diseases; Neurons; Phagocytosis; Phenotype; Plaque, Amyloid; Receptors, Immunologic; Signal Transduction; Superoxide Dismutase-1; Transcriptome; Transforming Growth Factor beta
PubMed: 28930663
DOI: 10.1016/j.immuni.2017.08.008 -
Nature Neuroscience May 2019Neuritic plaques, a pathological hallmark in Alzheimer's disease (AD) brains, comprise extracellular aggregates of amyloid-beta (Aβ) peptide and degenerating neurites...
Neuritic plaques, a pathological hallmark in Alzheimer's disease (AD) brains, comprise extracellular aggregates of amyloid-beta (Aβ) peptide and degenerating neurites that accumulate autolysosomes. We found that, in the brains of patients with AD and in AD mouse models, Aβ plaque-associated Olig2- and NG2-expressing oligodendrocyte progenitor cells (OPCs), but not astrocytes, microglia, or oligodendrocytes, exhibit a senescence-like phenotype characterized by the upregulation of p21/CDKN1A, p16/INK4/CDKN2A proteins, and senescence-associated β-galactosidase activity. Molecular interrogation of the Aβ plaque environment revealed elevated levels of transcripts encoding proteins involved in OPC function, replicative senescence, and inflammation. Direct exposure of cultured OPCs to aggregating Aβ triggered cell senescence. Senolytic treatment of AD mice selectively removed senescent cells from the plaque environment, reduced neuroinflammation, lessened Aβ load, and ameliorated cognitive deficits. Our findings suggest a role for Aβ-induced OPC cell senescence in neuroinflammation and cognitive deficits in AD, and a potential therapeutic benefit of senolytic treatments.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cellular Senescence; Dasatinib; Disease Models, Animal; Female; Male; Maze Learning; Mice, Transgenic; Oligodendrocyte Precursor Cells; Plaque, Amyloid; Prosencephalon; Quercetin
PubMed: 30936558
DOI: 10.1038/s41593-019-0372-9 -
Science (New York, N.Y.) Aug 2008Prokaryotes acquire virus resistance by integrating short fragments of viral nucleic acid into clusters of regularly interspaced short palindromic repeats (CRISPRs)....
Prokaryotes acquire virus resistance by integrating short fragments of viral nucleic acid into clusters of regularly interspaced short palindromic repeats (CRISPRs). Here we show how virus-derived sequences contained in CRISPRs are used by CRISPR-associated (Cas) proteins from the host to mediate an antiviral response that counteracts infection. After transcription of the CRISPR, a complex of Cas proteins termed Cascade cleaves a CRISPR RNA precursor in each repeat and retains the cleavage products containing the virus-derived sequence. Assisted by the helicase Cas3, these mature CRISPR RNAs then serve as small guide RNAs that enable Cascade to interfere with virus proliferation. Our results demonstrate that the formation of mature guide RNAs by the CRISPR RNA endonuclease subunit of Cascade is a mechanistic requirement for antiviral defense.
Topics: Amino Acid Sequence; Bacteriophage lambda; Base Sequence; DNA, Intergenic; DNA, Viral; Escherichia coli; Escherichia coli K12; Escherichia coli Proteins; Genes, Bacterial; Molecular Sequence Data; Repetitive Sequences, Nucleic Acid; RNA Precursors; RNA, Bacterial; Transcription, Genetic; Viral Plaque Assay; RNA, Small Untranslated
PubMed: 18703739
DOI: 10.1126/science.1159689 -
The Journal of Clinical Investigation Jun 2023Senescent vascular smooth muscle cells (VSMCs) accumulate in the vasculature with age and tissue damage and secrete factors that promote atherosclerotic plaque...
Senescent vascular smooth muscle cells (VSMCs) accumulate in the vasculature with age and tissue damage and secrete factors that promote atherosclerotic plaque vulnerability and disease. Here, we report increased levels and activity of dipeptidyl peptidase 4 (DPP4), a serine protease, in senescent VSMCs. Analysis of the conditioned media from senescent VSMCs revealed a unique senescence-associated secretory phenotype (SASP) signature comprising many complement and coagulation factors; silencing or inhibiting DPP4 reduced these factors and increased cell death. Serum samples from persons with high risk for cardiovascular disease contained high levels of DPP4-regulated complement and coagulation factors. Importantly, DPP4 inhibition reduced senescent cell burden and coagulation and improved plaque stability, while single-cell resolution of senescent VSMCs reflected the senomorphic and senolytic effects of DPP4 inhibition in murine atherosclerosis. We propose that DPP4-regulated factors could be exploited therapeutically to reduce senescent cell function, reverse senohemostasis, and improve vascular disease.
Topics: Mice; Animals; Plaque, Atherosclerotic; Dipeptidyl Peptidase 4; Cellular Senescence; Muscle, Smooth, Vascular; Atherosclerosis
PubMed: 37097759
DOI: 10.1172/JCI165933 -
The Journal of Thoracic and... Dec 2010The term acute aortic syndrome refers to a heterogeneous group of conditions that cause a common set of signs and symptoms, the foremost of which is aortic pain. Various... (Review)
Review
The term acute aortic syndrome refers to a heterogeneous group of conditions that cause a common set of signs and symptoms, the foremost of which is aortic pain. Various pathologic entities may give rise to this syndrome, but the topic has come to focus on penetrating aortic ulcer and intramural hematoma and their relation to aortic dissection. Penetrating aortic ulcer is a focal atherosclerotic plaque that corrodes a variable depth through the intima into the media. Intramural hematoma is a blood collection within the aortic wall not freely communicating with the aortic lumen, with restricted flow. It may represent a subcategory of aortic dissection that manifests different behavior by virtue of limited flow in the false lumen. This article reviews the current literature regarding acute aortic syndrome, focusing on management options.
Topics: Acute Disease; Aortic Dissection; Aortic Aneurysm; Aortic Diseases; Blood Vessel Prosthesis Implantation; Endovascular Procedures; Hematoma; Humans; Pain; Syndrome; Treatment Outcome; Ulcer; Vascular Surgical Procedures
PubMed: 21092805
DOI: 10.1016/j.jtcvs.2010.07.062 -
Annals of Cardiothoracic Surgery Jul 2019Acute aortic syndromes include a variety of overlapping clinical and anatomic diseases. Intramural hematoma (IMH), penetrating atherosclerotic ulcer (PAU), and aortic... (Review)
Review
Acute aortic syndromes include a variety of overlapping clinical and anatomic diseases. Intramural hematoma (IMH), penetrating atherosclerotic ulcer (PAU), and aortic dissection can occur as isolated processes or can be found in association. All these entities are potentially life threatening, so prompt diagnosis and treatment is of paramount importance. IMH and PAU affect patients with atherosclerotic risk factors and are located in the descending aorta in 60-70% of cases. IMH diagnosis can be correctly made in most cases. Aortic ulcer is a morphologic entity which comprises several entities-the differential diagnosis includes PAU, focal intimal disruptions (FID) in the context of IMH evolution and ulcerated atherosclerotic plaque. The pathophysiologic mechanism, evolution and prognosis differ somewhat between these entities. However, most PAU are diagnosed incidentally outside the acute phase. Persistent pain despite medical treatment, hemodynamic instability, maximum aortic diameter (MAD) >55 mm, significant periaortic hemorrhage and FID in acute phase of IMH are predictors of acute-phase mortality. In these cases, TEVAR or open surgery should be considered. In non-complicated IMH or PAU, without significant aortic enlargement, strict control of cardiovascular risk factors and frequent follow-up imaging appears to be a safe management strategy.
PubMed: 31463208
DOI: 10.21037/acs.2019.07.05 -
Wiley Interdisciplinary Reviews. RNA Mar 2018Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the main cause of dementia among the elderly worldwide. Despite intense efforts to develop drugs... (Review)
Review
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the main cause of dementia among the elderly worldwide. Despite intense efforts to develop drugs for preventing and treating AD, no effective therapies are available as yet, posing a growing burden at the personal, medical, and socioeconomic levels. AD is characterized by the production and aggregation of amyloid β (Aβ) peptides derived from amyloid precursor protein (APP), the presence of hyperphosphorylated microtubule-associated protein Tau (MAPT), and chronic inflammation leading to neuronal loss. Aβ accumulation and hyperphosphorylated Tau are responsible for the main histopathological features of AD, Aβ plaques, and neurofibrillary tangles (NFTs), respectively. However, the full spectrum of molecular factors that contribute to AD pathogenesis is not known. Noncoding (nc)RNAs, including microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs), regulate gene expression at the transcriptional and posttranscriptional levels in various diseases, serving as biomarkers and potential therapeutic targets. There is rising recognition that ncRNAs have been implicated in both the onset and pathogenesis of AD. Here, we review the ncRNAs implicated posttranscriptionally in the main AD pathways and discuss the growing interest in targeting regulatory ncRNAs therapeutically to combat AD pathology. WIREs RNA 2018, 9:e1463. doi: 10.1002/wrna.1463 This article is categorized under: RNA in Disease and Development > RNA in Disease.
Topics: Alzheimer Disease; Animals; Humans; RNA, Untranslated
PubMed: 29327503
DOI: 10.1002/wrna.1463