TY - JOUR
T1 - APP/Aβ structural diversity and Alzheimer's disease pathogenesis
AU - Roher, Alex E.
AU - Kokjohn, Tyler A.
AU - Clarke, Steven G.
AU - Sierks, Michael
AU - Maarouf, Chera L.
AU - Serrano, Geidy E.
AU - Sabbagh, Marwan S.
AU - Beach, Thomas G.
N1 - Funding Information:
This study was supported by: The National Institute on Aging grants R01 AG019795 (AER), Midwestern University, Glendale , AZ (TAK), The Life Extension Foundation, Inc . and the Elizabeth and Thomas Plott Chair in Gerontology of the UCLA Longevity Center (SGC), and the Arizona Alzheimer's Disease Consortium and from the Department of Defense ( W81XWH-14-1-0467 ) (MRS). Detailed Abeta studies were made possible by the Brain and Body Donation Program at Banner Sun Health Research Institute, which has been supported by the National Institute of Neurological Disorders and Stroke ( U24 NS072026 National Brain and Tissue Resource for Parkinson's Disease and Related Disorders), the National Institute on Aging ( P30 AG19610 Arizona Alzheimer's Disease Core Center), the Arizona Department of Health Services (contract 211002 , Arizona Alzheimer's Research Center), the Arizona Biomedical Research Commission (contracts 4001 , 0011 , 05-901 and 1001 to the Arizona Parkinson's Disease Consortium) and the Michael J. Fox Foundation for Parkinson's Research . The funders had no role in study design, data collection, analysis or interpretation of data, decision to publish or preparation of the manuscript.
Funding Information:
Roher AE, Clarke SG, Kokjohn TA, Maarouf CL, Sierks MR and Serrano G, have no conflicts of interest to declare. Sabbagh MS is a consultant for: Axovant, Biogen, Grifols, Humana, Lilly pharmaceuticals, Sanofi and vTv Therapeutics. He receives research grant support from: Astra Seneca , Avid Pharmaceuticals , Axovant , Genentech Inc. , Lilly Pharmaceuticals , Merck and Co. , Pfizer , Roche Diagnostics Corp. , vTv Therapeutics and Piramal Imaging . He is a stock shareholder of Brain Health, Muses Labs., and Versanum. Beach TG is an advisory board member for Genentech, consultant for Avid Radiopharmaceuticals and GE Healthcare, has research contracts with Avid Radiopharmaceuticals and Navidea Biopharmaceuticals, and receives grant support from the National Institutes of Health , the Michael J. Fox Foundation for Parkinson's Research and the State of Arizona .
Publisher Copyright:
© 2017 Elsevier Ltd
PY - 2017/11
Y1 - 2017/11
N2 - 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.
AB - 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.
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U2 - 10.1016/j.neuint.2017.08.007
DO - 10.1016/j.neuint.2017.08.007
M3 - Review article
C2 - 28811267
AN - SCOPUS:85028061875
SN - 0197-0186
VL - 110
SP - 1
EP - 13
JO - Neurochemistry International
JF - Neurochemistry International
ER -