دورية أكاديمية
APP/Aβ structural diversity and Alzheimer's disease pathogenesis.
| العنوان: | APP/Aβ structural diversity and Alzheimer's disease pathogenesis. |
|---|---|
| المؤلفون: | Roher AE; Division of Neurobiology, Barrow Neurological Institute, Phoenix, AZ 85013, USA; Division of Clinical Education, Midwestern University, Glendale, AZ 85308, USA. Electronic address: aeroher@gmail.com., Kokjohn TA; Department of Microbiology, Midwestern University, Glendale, AZ 85308, USA., Clarke SG; Department of Chemistry and Biochemistry and the Molecular Biology Institute, University of California, Los Angeles, Los Angeles CA 90095-1569, USA., Sierks MR; Department of Chemical Engineering, Arizona State University, Tempe, AZ 85287-6106, USA., Maarouf CL; Laboratory of Neuropathology, Banner Sun Health Research Institute, Sun City, AZ 85351, USA., Serrano GE; Laboratory of Neuropathology, Banner Sun Health Research Institute, Sun City, AZ 85351, USA., Sabbagh MS; Alzheimer's and Memory Disorders Division, Barrow Neurological Institute, Phoenix, AZ 85013, USA., Beach TG; Laboratory of Neuropathology, Banner Sun Health Research Institute, Sun City, AZ 85351, USA. |
| المصدر: | Neurochemistry international [Neurochem Int] 2017 Nov; Vol. 110, pp. 1-13. Date of Electronic Publication: 2017 Aug 12. |
| نوع المنشور: | Journal Article; Review |
| اللغة: | English |
| بيانات الدورية: | Publisher: Pergamon Press Country of Publication: England NLM ID: 8006959 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1872-9754 (Electronic) Linking ISSN: 01970186 NLM ISO Abbreviation: Neurochem Int Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Oxford [Elmsford, N. Y.] Pergamon Press. |
| مواضيع طبية MeSH: | Alzheimer Disease/*diagnostic imaging , Alzheimer Disease/*etiology , Amyloid beta-Peptides/*chemistry , Amyloid beta-Protein Precursor/*chemistry, Alzheimer Disease/metabolism ; Amyloid beta-Peptides/analysis ; Amyloid beta-Peptides/metabolism ; Amyloid beta-Protein Precursor/analysis ; Amyloid beta-Protein Precursor/metabolism ; Animals ; Brain/metabolism ; Brain/pathology ; Humans ; Plaque, Amyloid/complications ; Plaque, Amyloid/diagnostic imaging ; Plaque, Amyloid/metabolism |
| مستخلص: | The amyloid cascade hypothesis of Alzheimer's disease (AD) proposes amyloid- β (Aβ) is a chief pathological element of dementia. AD therapies have targeted monomeric and oligomeric Aβ 1-40 and 1-42 peptides. However, alternative APP proteolytic processing produces a complex roster of Aβ species. In addition, Aβ peptides are subject to extensive posttranslational modification (PTM). We propose that amplified production of some APP/Aβ species, perhaps exacerbated by differential gene expression and reduced peptide degradation, creates a diverse spectrum of modified species which disrupt brain homeostasis and accelerate AD neurodegeneration. We surveyed the literature to catalog Aβ PTM including species with isoAsp at positions 7 and 23 which may phenocopy the Tottori and Iowa Aβ mutations that result in early onset AD. We speculate that accumulation of these alterations induce changes in secondary and tertiary structure of Aβ that favor increased toxicity, and seeding and propagation in sporadic AD. Additionally, amyloid-β peptides with a pyroglutamate modification at position 3 and oxidation of Met35 make up a substantial portion of sporadic AD amyloid deposits. The intrinsic physical properties of these species, including resistance to degradation, an enhanced aggregation rate, increased neurotoxicity, and association with behavioral deficits, suggest their emergence is linked to dementia. The generation of specific 3D-molecular conformations of Aβ impart unique biophysical properties and a capacity to seed the prion-like global transmission of amyloid through the brain. The accumulation of rogue Aβ ultimately contributes to the destruction of vascular walls, neurons and glial cells culminating in dementia. A systematic examination of Aβ PTM and the analysis of the toxicity that they induced may help create essential biomarkers to more precisely stage AD pathology, design countermeasures and gauge the impacts of interventions. (Copyright © 2017 Elsevier Ltd. All rights reserved.) |
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| معلومات مُعتمدة: | P30 AG019610 United States AG NIA NIH HHS; R01 AG019795 United States AG NIA NIH HHS; U24 NS072026 United States NS NINDS NIH HHS |
| المشرفين على المادة: | 0 (Amyloid beta-Peptides) 0 (Amyloid beta-Protein Precursor) |
| تواريخ الأحداث: | Date Created: 20170817 Date Completed: 20180606 Latest Revision: 20240610 |
| رمز التحديث: | 20240610 |
| مُعرف محوري في PubMed: | PMC5688956 |
| DOI: | 10.1016/j.neuint.2017.08.007 |
| PMID: | 28811267 |
| قاعدة البيانات: | MEDLINE |
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