ArticleProceedings of the National Academy of Sciences of the United States of America2018
Structural heterogeneity and intersubject variability of Aβ in familial and sporadic Alzheimer's disease.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 85 papers.
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Who cites it
85 citing papers in PubMed, 142 citations in OpenAlex.
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- Mitochondria as a Therapeutic Target in Neurodegeneration: Strategies for Restoring Cellular Homeostasis.Current neuropharmacology · 2026Review
- The Interplay of Inflammation and Gut-Microbiota Dysbiosis in Alzheimer's Disease: Mechanisms and Therapeutic Potential.International journal of molecular sciences · 2025Review
- Incidental vs. Engineered Nanoparticles in Alzheimer's and Parkinson's Disease: Pathological Pathways and Therapeutic Interventions.Nano research · 2025Article
- Endogenous Aβ and Exogenous Wheat Gluten Nanostructures: Understanding Peptide Self-Assembly in Disease.ACS nano · 2025Review
- Aortic Stiffness and Alzheimer's Disease: The Medin Connection.Biomolecules · 2025Review
- Human and Mouse Alzheimer's Seeds Differentially Affect Amyloid Deposition and Microglia-Dependent Plaque Response in Aged Mice.Aging cell · 2025Article
- Myelin dysfunction in aging and brain disorders: mechanisms and therapeutic opportunities.Molecular neurodegeneration · 2025Review
- The question of strains in AA amyloidosis.Scientific reports · 2025Article
- Brain-derived tau oligomer polymorphs: distinct aggregations, stability profiles, and biological activities.Communications biology · 2025Article
- Interplay of p23 with FKBP51 and their chaperone complex in regulating tau aggregation.Nature communications · 2025Article
- Cryo-EM structure of a novel α-synuclein filament subtype from multiple system atrophy.FEBS letters · 2025Article
- Protein-adaptive differential scanning fluorimetry using conformationally responsive dyes.Nature biotechnology · 2025Article
- Deciphering the Morphological Difference of Amyloid-β Fibrils in Familial and Sporadic Alzheimer's Diseases.Journal of chemical information and modeling · 2024Article
- MAPT mutations associated with familial tauopathies lead to formation of conformationally distinct oligomers that have cross-seeding ability.Protein science : a publication of the Protein Society · 2024Article
- E22G Aβ40 fibril structure and kinetics illuminate how Aβ40 rather than Aβ42 triggers familial Alzheimer's.Nature communications · 2024Article
- Image post-processing for SILMAS: structured illumination light sheet microscopy with axial sweeping.Biomedical optics express · 2024Article
- Structural Variations of Prions and Prion-like Proteins Associated with Neurodegeneration.Current issues in molecular biology · 2024Review
- An electrostatic cluster guides Aβ40 fibril formation in sporadic and Dutch-type cerebral amyloid angiopathy.Journal of structural biology · 2024Article
- "Prion-like" seeding and propagation of oligomeric protein assemblies in neurodegenerative disorders.Frontiers in neuroscience · 2024Review
25 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
18 authors at 6 institutions in 4 countries.
Funding
Abstract
Point mutations in the amyloid-β (Aβ) coding region produce a combination of mutant and WT Aβ isoforms that yield unique clinicopathologies in familial Alzheimer's disease (fAD) and cerebral amyloid angiopathy (fCAA) patients. Here, we report a method to investigate the structural variability of amyloid deposits found in fAD, fCAA, and sporadic AD (sAD). Using this approach, we demonstrate that mutant Aβ determines WT Aβ conformation through prion template-directed misfolding. Using principal component analysis of multiple structure-sensitive fluorescent amyloid-binding dyes, we assessed the conformational variability of Aβ deposits in fAD, fCAA, and sAD patients. Comparing many deposits from a given patient with the overall population, we found that intrapatient variability is much lower than interpatient variability for both disease types. In a given brain, we observed one or two structurally distinct forms. When two forms coexist, they segregate between the parenchyma and cerebrovasculature, particularly in fAD patients. Compared with sAD samples, deposits from fAD patients show less intersubject variability, and little overlap exists between fAD and sAD deposits. Finally, we examined whether E22G (Arctic) or E22Q (Dutch) mutants direct the misfolding of WT Aβ, leading to fAD-like plaques in vivo. Intracerebrally injecting mutant Aβ40 fibrils into transgenic mice expressing only WT Aβ induced the deposition of plaques with many biochemical hallmarks of fAD. Thus, mutant Aβ40 prions induce a conformation of WT Aβ similar to that found in fAD deposits. These findings indicate that diverse AD phenotypes likely arise from one or more initial Aβ prion conformations, which kinetically dominate the spread of prions in the brain.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.