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| neurofibrillary tangles | |
|---|---|
| Name | Neurofibrillary tangles |
| Field | Neuropathology |
neurofibrillary tangles
Neurofibrillary tangles are intracellular aggregates found in the human brain, characterized by filamentous inclusions composed primarily of abnormally modified proteins; they are most prominently associated with degenerative conditions of aging. Research on tangles has involved investigators and institutions across the globe, including laboratories affiliated with Alzheimer's Disease Research Center, National Institutes of Health, Mayo Clinic, Massachusetts General Hospital, and Columbia University. Historical and clinical studies linking tangles to cognitive decline have intersected with work by figures and centers such as Alois Alzheimer, Stanley Prusiner, John Hardy, Dennis Selkoe, and Reisa Sperling.
Neurofibrillary tangles are intracellular filamentous inclusions composed mainly of hyperphosphorylated forms of the microtubule-associated protein tau, a protein studied by groups at University of Cambridge, University College London, Harvard University, Yale University, and University of California, San Francisco. Ultrastructural analyses by teams at Rockefeller University and Max Planck Society revealed paired helical filaments and straight filaments within tangles, findings that were corroborated by researchers at University of Oxford, Karolinska Institutet, University of Toronto, Johns Hopkins University, and Stanford University. Biochemical investigations conducted at institutions including Cold Spring Harbor Laboratory, Scripps Research, University of Pennsylvania, Imperial College London, and University of Melbourne identified post-translational modifications—most notably hyperphosphorylation, truncation, and ubiquitination—contributing to filament assembly.
Molecular models of tangle formation incorporate kinases and phosphatases studied at National Institute of Mental Health, Salk Institute, European Molecular Biology Laboratory, Weizmann Institute of Science, and Rockefeller University; implicated enzymes include glycogen synthase kinase-3β, cyclin-dependent kinase 5, and protein phosphatase 2A, with mechanistic studies reported by laboratories at Massachusetts Institute of Technology, University of Cambridge, Princeton University, Columbia University, and University of California, San Diego. Cellular stressors investigated by teams at University of Tokyo, Peking University, Seoul National University, University of São Paulo, and University of British Columbia—including oxidative stress, impaired proteostasis, and mitochondrial dysfunction—promote pathological tau modifications and aggregation. Genetic modifiers discovered through work at Wellcome Trust Sanger Institute, Broad Institute, McGill University, University of Iceland, and University of Munich (including MAPT haplotypes and risk loci from genome-wide association studies) influence propensity for tangle formation, as do environmental exposures characterized in studies at Karolinska Institutet, University of Glasgow, University of Copenhagen, University of Zurich, and University of Amsterdam.
Neurofibrillary tangles are central pathological features in several neurodegenerative disorders, notably Alzheimer disease, where correlations between tangle distribution and clinical symptoms have been reported by centers such as Mayo Clinic, Memory and Aging Center, National Institute on Aging, Rush University Medical Center, and Mount Sinai Health System. Tangles also appear in frontotemporal lobar degeneration with tauopathy subtypes studied at University College London, Cambridge University Hospitals, University of Pennsylvania, University of Gothenburg, and University of California, Irvine; in progressive supranuclear palsy and corticobasal degeneration investigated at University of California, Los Angeles, University of Sydney, University of Pisa, University of Barcelona, and University of Tokyo; and in chronic traumatic encephalopathy described by groups at Boston University, University of Glasgow, Veterans Affairs Boston Healthcare System, University of Pittsburgh, and Yale University. Comparative pathologic studies linking tangles to clinical phenotypes were advanced by collaborations among Alzheimer's Association, Dementia Research Centre, Canadian Consortium on Neurodegeneration in Aging, European Alzheimer’s Disease Consortium, and Global Brain Health Initiative.
Histopathological identification of tangles utilizes silver staining and immunohistochemistry with tau-specific antibodies developed in laboratories at Stanford University, Harvard Medical School, Scripps Research, University of California, San Diego, and University of Cambridge. In vivo detection strategies using positron emission tomography tracers were pioneered in studies from Mayo Clinic, University of Pittsburgh Medical Center, Karolinska Institutet, University of Michigan, and University of California, Los Angeles, enabling correlation of tracer binding with cognitive measures in cohorts from Alzheimer's Disease Neuroimaging Initiative, Framingham Heart Study, UK Biobank, Baltimore Longitudinal Study of Aging, and Rotterdam Study. Cerebrospinal fluid and plasma biomarkers reflecting tau species have been assayed by teams at University of Gothenburg, Massachusetts General Hospital, Ruhr University Bochum, McGill University, and University of Zurich, supporting diagnostic algorithms used by National Health Service, Centers for Disease Control and Prevention, World Health Organization, European Medicines Agency, and Food and Drug Administration.
Staging systems linking tangle distribution to clinical progression were formalized by researchers at Baylor College of Medicine, Albert Einstein College of Medicine, Columbia University Irving Medical Center, Montreal Neurological Institute, and University of Pittsburgh; Braak staging remains widely used, with extensions and validations published by teams at University of Kiel, University of Vienna, University of Heidelberg, University of Basel, and University College Dublin. Longitudinal neuropathological and neuroimaging cohorts from Alzheimer's Disease Neuroimaging Initiative, Dominantly Inherited Alzheimer Network, Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing, Baltimore Longitudinal Study of Aging, and Rotterdam Study informed models of spread and regional vulnerability, integrating cellular findings from Johns Hopkins University, Yale University, University of California, San Francisco, University of Oxford, and Purdue University.
Therapeutic strategies targeting tangles include small molecules, immunotherapies, antisense oligonucleotides, and kinase modulators developed and trialed by academic centers and companies collaborating with Biogen, Eli Lilly and Company, Roche, AstraZeneca, Merck & Co., Novartis, Amgen, Johnson & Johnson, GlaxoSmithKline, and AbbVie. Clinical trials conducted at National Institutes of Health Clinical Center, Mayo Clinic Phase I Unit, Massachusetts General Hospital Clinical Trials Unit, University College London Hospitals, and University of California San Diego Health evaluate safety and efficacy of tau-directed agents, while preclinical innovations from Salk Institute, Broad Institute, Cold Spring Harbor Laboratory, Howard Hughes Medical Institute, and Wellcome Trust explore mechanisms of propagation, clearance, and neuroprotection. Future directions involve integrative research programs supported by National Institute on Aging, European Commission Horizon 2020, Bill & Melinda Gates Foundation, Chan Zuckerberg Initiative, and Michael J. Fox Foundation to translate mechanistic insights into therapies that modify disease trajectories.
Category:Neuropathology