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Biochemically-defined pools of amyloid-β in sporadic Alzheimer’s disease: correlation with amyloid PET
Open accessAbstract
We fractionated frontal cortical grey matter from human Alzheimer's disease and control subjects into four biochemically defined pools that represent four distinct compartments: soluble/cytosolic, peripheral membrane/vesicular cargo, integral lipid/membranous pools and aggregated/insoluble debris. Most of the readily extractable amyloid-β remains associated with a lipid/membranous compartment. There is an exchange of amyloid-β between the biochemical pools that was lost for the amyloid-β42 species in Alzheimer's disease, consistent with the peptide being irreversibly trapped in extracellular deposits. The quantitative amyloid-β data, combined with magnetic resonance imaging volumetric analysis of the amount of cortical grey matter in brain, allowed us to estimate the total mass of amyloid-β in Alzheimer's disease (6.5 mg) and control (1.7 mg) brains. The threshold positron emission tomography standard uptake value ratio of 1.4 equates to 5.0 μg amyloid-β/g of grey matter and the mean Alzheimer's disease dementia standard uptake value ratio level of 2.3 equates to 11.20 μg amyloid-β/g of grey matter. It takes 19 years to accumulate amyloid from the threshold positron emission tomography standard uptake value ratio to the mean value observed for Alzheimer's disease dementia. This accumulation time window combined with the difference of 4.8 mg of amyloid-β between Alzheimer's disease and control brain allows for a first approximation of amyloid-β accumulation of 28 ng/h. This equates to an estimated 2-5% of the total amyloid-β production being deposited as insoluble plaques. Understanding these rates of amyloid-β accumulation allows for a more quantitative approach in targeting the failure of amyloid-β clearance in sporadic Alzheimer's disease.
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“The buildup and eventual deposition of Aβ is due to a 2–5% decrease in the clearance of Aβ from the brain [9, 10].”
From Discovery of a Missense Mutation (Q222K) of the APOE Gene from the Australian Imaging, Biomarker and Lifestyle Study (2023) · cites this paper as [10]
Experimental — accuracy not yet measuredIn the citing paper
“The EC50 for the action of Aβ1-42, 4.7 nM, is comparable to the concentration of soluble Aβ found in the human AD brain (6 nM, from Table 1 of ref. (37)”
From Amyloid β oligomers constrict human capillaries in Alzheimer's disease via signaling to pericytes (2019) · cites this paper as [37]
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Stabilization of a Membrane-Associated Amyloid-β Oligomer for Its Validation in Alzheimer's Disease
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Metadata
- Authors
- Roberts, B. R., Lind, M., Wagen, A. Z., Rembach, A., Frugier, T., Li, Q.-X., Ryan, T. M., McLean, C. A., Doecke, J. D., Rowe, C. C., Villemagne, V. L., & Masters, C. L.
- Affiliations
- The University of Melbourne (AU)
- Commonwealth Scientific and Industrial Research Organisation (AU)
- ORCID
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2017-04-05
- Volume
- 140
- Issue
- 5
- Pages
- 1486-1498
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- OpenAlex
- W2604285326
- Cited by
- 143
- References
- 49
- Citations by year
- 2026: 12 · 2025: 14 · 2024: 18 · 2023: 15 · 2022: 19 · 2021: 20 · 2020: 16 · 2019: 11 · 2018: 11 · 2017: 6
- FWCI
- 8.90
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Brain (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Melbourne
- State Government of Victoria (LP140100095)
- Medical Research Council
- National Health and Medical Research Council
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- amyloid-beta, sporadic Alzheimer's disease, amyloid PET, amyloid-beta 42, amyloid plaques, amyloid-beta clearance, frontal cortex, grey matter, standard uptake value ratio
- MeSH terms
- Alzheimer Disease, Frontal Lobe, Humans, Magnetic Resonance Imaging, Time Factors, Case-Control Studies, Amyloid beta-Peptides, Positron-Emission Tomography, Plaque, Amyloid, Neuroimaging, Gray Matter
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