Amyloid beta

Amyloid beta
Name	Amyloid beta
Other names	Aβ, Abeta

Amyloid beta is a peptide derived from the amyloid precursor protein involved in central nervous system physiology and implicated in neurodegenerative disease. It is generated by proteolytic processing and exists in multiple isoforms that differ in aggregation propensity and biochemical properties. Research spans molecular biology, neuropathology, pharmacology, and clinical trials involving institutions and investigators worldwide.

Structure and Biochemistry

Amyloid beta peptides are 37–43 amino acids long and adopt conformations ranging from random coil to β-sheet that facilitate oligomerization and fibrillogenesis, a process studied by Max Perutz, John Kendrew, Linus Pauling, Dorothy Hodgkin, and laboratories at Massachusetts Institute of Technology, University of Cambridge, California Institute of Technology, and Stanford University using techniques developed by Richard Dickerson, Ada Yonath, Venkatraman Ramakrishnan, and teams associated with the Royal Society. Crystallography, nuclear magnetic resonance, cryo-electron microscopy, and mass spectrometry performed in facilities at European Molecular Biology Laboratory, Cold Spring Harbor Laboratory, Howard Hughes Medical Institute, and National Institutes of Health have resolved structural polymorphs related to pathogenicity observed in studies led by John Hardy, Bart De Strooper, Dennis Selkoe, and groups at King's College London and Harvard University. Post-translational modifications such as N-terminal truncation, pyroglutamylation, phosphorylation, and oxidation alter hydrophobicity and charge, topics pursued by researchers at Max Planck Society, University of Oxford, Yale University, Columbia University, and pharmaceutical divisions of Roche, Eli Lilly and Company, Biogen, and Novartis.

Production and Metabolism

Amyloid beta is produced by sequential proteolysis of the amyloid precursor protein by β-secretase (BACE1) and γ-secretase complexes composed of presenilin and nicastrin subunits, pathways elucidated by teams at GlaxoSmithKline, AstraZeneca, Pfizer, and academic groups at University College London, University of Bonn, Johns Hopkins University, University of Toronto, and Karolinska Institutet. Genetic evidence from familial cases linked to mutations in APP, PSEN1, and PSEN2 was provided by investigators in consortia including Alzheimer's Disease Genetics Consortium, International Genomics of Alzheimer's Project, and clinics at Mayo Clinic, Cleveland Clinic, Mount Sinai Health System, and University of Pittsburgh Medical Center. Clearance mechanisms involve enzymatic degradation by neprilysin, insulin-degrading enzyme, and matrix metalloproteinases, as well as transport across the blood–brain barrier mediated by LRP1 and RAGE receptors studied at Salk Institute, Scripps Research, University of California, San Francisco, and Imperial College London.

Physiological Roles

Physiological activities attributed to amyloid beta include modulation of synaptic transmission, neurotrophic signaling, antimicrobial activity, and regulation of cholesterol and lipid metabolism, observations arising from work in laboratories led by Eric Kandel, Rita Levi-Montalcini, Paul Greengard, Stanley Prusiner, Thomas Südhof, and teams at Princeton University, Rockefeller University, University of California, Los Angeles, and Washington University in St. Louis. Experimental models in rodents, nonhuman primates, and stem-cell derived organoids developed by groups at Salk Institute, Riken, Riken Center for Developmental Biology, Weizmann Institute of Science, and University of Tokyo have been used to dissect synaptic and immune interactions implicating microglial receptors such as TREM2 and complement components characterized by collaborators at Gladstone Institutes, Broad Institute, LA BioMed, and Fred Hutchinson Cancer Center.

Pathology and Disease Associations

Pathological aggregation of amyloid beta into oligomers, protofibrils, and amyloid plaques is a hallmark of Alzheimer disease and is linked epidemiologically and mechanistically to neurodegeneration in studies by Alzheimer's Association, World Health Organization, Centers for Disease Control and Prevention, European Commission, and cohorts from Framingham Heart Study, UK Biobank, Rotterdam Study, Baltimore Longitudinal Study of Aging, and Nurses' Health Study. Genetic, biochemical, and imaging correlations implicate amyloid beta in cerebral amyloid angiopathy, Down syndrome–associated dementia, and mixed dementia syndromes reported by clinics at University of California, San Diego, Mayo Clinic, Massachusetts General Hospital, and long-term studies coordinated by National Institute on Aging. Interactions with tau pathology, neuroinflammation involving microglia and astrocytes, synaptic loss, and vascular dysfunction are active research topics in consortia including Dominantly Inherited Alzheimer Network, Alzheimer's Disease Neuroimaging Initiative, European Prevention of Alzheimer's Dementia consortium, and pharmaceutical R&D at Johnson & Johnson and Merck & Co..

Detection and Measurement

Detection methods for amyloid beta include immunohistochemistry, enzyme-linked immunosorbent assays, mass spectrometry, and positron emission tomography using radioligands developed by teams at GE Healthcare, Siemens Healthineers, Eli Lilly and Company, Avid Radiopharmaceuticals, and academic centers including Brigham and Women's Hospital, Mayo Clinic, Karolinska Institutet, and UCL Institute of Neurology. Cerebrospinal fluid and plasma biomarkers quantifying Aβ42, Aβ40, and Aβ42/Aβ40 ratios are employed in clinical diagnostics and research protocols by Food and Drug Administration, European Medicines Agency, ClinicalTrials.gov, and longitudinal studies at Columbia University Irving Medical Center and University of Pennsylvania. Advanced imaging correlates with cognitive assessments from trials at National Institutes of Health Clinical Center and multi-center initiatives such as Alzheimer's Disease Cooperative Study.

Therapeutic Approaches and Research

Therapeutic strategies targeting amyloid beta include active and passive immunotherapy, secretase inhibitors, aggregation modulators, and clearance enhancement via blood-based and gene-therapy approaches investigated by biotech companies Biogen, Eli Lilly and Company, Roche, AstraZeneca, Novartis, Genentech, Regeneron Pharmaceuticals, and academic spinouts from Massachusetts Institute of Technology, Harvard Medical School, University of Cambridge, and University of Oxford. Landmark clinical trials and regulatory decisions involving monoclonal antibodies, small molecules, and vaccine candidates have engaged regulators such as Food and Drug Administration and European Medicines Agency and been overseen by consortia like Alzheimer's Clinical Trials Consortium and Global Alzheimer Platform Foundation. Translational research leverages CRISPR/Cas technologies, induced pluripotent stem cells, and biomarker-guided adaptive trial designs developed at Broad Institute, Stanford University School of Medicine, MIT Broad Institute, and Salk Institute.

Category:Peptides