{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,14]],"date-time":"2026-06-14T06:53:49Z","timestamp":1781420029829,"version":"3.54.1"},"reference-count":57,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2022,10,31]],"date-time":"2022-10-31T00:00:00Z","timestamp":1667174400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Senile plaques, which are mostly composed of beta-amyloid peptide, are the main signature of Alzheimer\u2019s disease (AD). Two main forms of beta-amyloid in humans are 40 and 42-amino acid, long; the latter is considered more relevant to AD etiology. The concentration of soluble beta-amyloid-42 (A\u03b242) in cerebrospinal fluid (CSF-A\u03b242) and the density of amyloid depositions have a strong negative correlation. However, AD patients have lower CSF-A\u03b242 levels compared to individuals with normal cognition (NC), even after accounting for this correlation. The goal of this study was to infer deviations of A\u03b242 metabolism parameters that underlie this difference using data from the Alzheimer\u2019s Disease Neuroimaging Initiative cohort. A\u03b242 is released to the interstitial fluid (ISF) by cells and is removed by several processes. First, growth of insoluble fibrils by aggregation decreases the concentration of soluble beta-amyloid in the ISF. Second, A\u03b242 is physically transferred from the brain to the CSF and removed with the CSF flow. Finally, there is an intratissue removal of A\u03b242 ending in proteolysis, which can occur either in the ISF or inside the cells after the peptide is endocytosed. Unlike aggregation, which preserves the peptide in the brain, transfer to the CSF and intratissue proteolysis together represent amyloid removal. Using a kinetic model of A\u03b242 turnover, we found that compared to NC subjects, AD patients had dramatically increased rates of amyloid removal. A group with late-onset mild cognitive impairment (LMCI) also exhibited a higher rate of amyloid removal; however, this was less pronounced than in the AD group. Estimated parameters in the early-onset MCI group did not differ significantly from those in the NC group. We hypothesize that increased amyloid removal is mediated by A\u03b242 cellular uptake; this is because CSF flow is not increased in AD patients, while most proteases are intracellular. A\u03b2 cytotoxicity depends on both the amount of beta-amyloid internalized by cells and its intracellular conversion into toxic products. We speculate that AD and LMCI are associated with increased cellular amyloid uptake, which leads to faster disease progression. The early-onset MCI (EMCI) patients do not differ from the NC participants in terms of cellular amyloid uptake. Therefore, EMCI may be mediated by the increased production of toxic amyloid metabolites.<\/jats:p>","DOI":"10.1371\/journal.pone.0276933","type":"journal-article","created":{"date-parts":[[2022,10,31]],"date-time":"2022-10-31T17:45:49Z","timestamp":1667238349000},"page":"e0276933","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":22,"title":["Patients with Alzheimer\u2019s disease have an increased removal rate of soluble beta-amyloid-42"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2454-8620","authenticated-orcid":true,"given":"Dmitry V.","family":"Zaretsky","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria V.","family":"Zaretskaia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0862-1974","authenticated-orcid":true,"given":"Yaroslav I.","family":"Molkov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"for the Alzheimer\u2019s Disease Neuroimaging Initiative","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,10,31]]},"reference":[{"issue":"3","key":"pone.0276933.ref001","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1007\/PL00014167","article-title":"Reanalysis of the first case of Alzheimer\u2019s disease","volume":"249","author":"M.B. Graeber","year":"1999","journal-title":"European archives of psychiatry and clinical neuroscience"},{"key":"pone.0276933.ref002","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1007\/BF02866241","article-title":"\u00fcber eigenartige Krankheitsf\u00e4lle des sp\u00e4teren Alters","volume":"4","author":"A. Alzheimer","year":"1911","journal-title":"Zeitschrift f\u00fcr die gesamte Neurologie und Psychiatrie"},{"key":"pone.0276933.ref003","doi-asserted-by":"crossref","first-page":"595","DOI":"10.15252\/emmm.201606210","article-title":"The amyloid hypothesis of Alzheimer\u2019s disease at 25 years","volume":"8","author":"D.J. Selkoe","year":"2016","journal-title":"EMBO Mol Med"},{"key":"pone.0276933.ref004","first-page":"131","article-title":"Cerebrospinal fluid and plasma biomarkers in Alzheimer disease, Nature reviews","volume":"6","author":"K. Blennow","year":"2010","journal-title":"Neurology"},{"key":"pone.0276933.ref005","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1002\/ana.410380413","article-title":"Reduction of beta-amyloid peptide42 in the cerebrospinal fluid of patients with Alzheimer\u2019s disease","volume":"38","author":"R. Motter","year":"1995","journal-title":"Annals of neurology"},{"key":"pone.0276933.ref006","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1002\/acn3.81","article-title":"Diagnostic accuracy of CSF Ab42 and florbetapir PET for Alzheimer\u2019s disease","volume":"1","author":"N. Mattsson","year":"2014","journal-title":"Annals of clinical and translational neurology"},{"key":"pone.0276933.ref007","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1136\/jnnp-2014-308094","article-title":"A\u03b2 imaging with 18F-florbetaben in prodromal Alzheimer\u2019s disease: a prospective outcome study","volume":"86","author":"K.T. Ong","year":"2015","journal-title":"Journal of neurology, neurosurgery, and psychiatry"},{"key":"pone.0276933.ref008","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1002\/ana.20730","article-title":"Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Abeta42 in humans","volume":"59","author":"A.M. Fagan","year":"2006","journal-title":"Annals of neurology"},{"key":"pone.0276933.ref009","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1093\/brain\/awu367","article-title":"Independent information from cerebrospinal fluid amyloid-\u03b2 and florbetapir imaging in Alzheimer\u2019s disease","volume":"138","author":"N. 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Sturchio","year":"2021","journal-title":"EClinicalMedicine"},{"key":"pone.0276933.ref012","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.mbs.2014.11.004","article-title":"Analysis of a compartmental model of amyloid beta production, irreversible loss and exchange in humans","volume":"261","author":"D.L. Elbert","year":"2015","journal-title":"Mathematical biosciences"},{"key":"pone.0276933.ref013","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1038\/s42003-022-03037-0","article-title":"Importance of CSF-based A\u03b2 clearance with age in humans increases with declining efficacy of blood-brain barrier\/proteolytic pathways","volume":"5","author":"D.L. Elbert","year":"2022","journal-title":"Communications Biology"},{"key":"pone.0276933.ref014","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1002\/psp4.12249","article-title":"Studying the Progression of Amyloid Pathology and Its Therapy Using Translational Longitudinal Model of Accumulation and Distribution of Amyloid Beta","volume":"6","author":"T. Karelina","year":"2017","journal-title":"CPT Pharmacometrics Syst Pharmacol"},{"key":"pone.0276933.ref015","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1002\/psp4.12211","article-title":"A Translational Systems Pharmacology Model for A\u03b2 Kinetics in Mouse, Monkey, and Human","volume":"6","author":"T. 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Kolibash","journal-title":"Centiloid Level-2 Analysis of [18F]Florbetaben (FBB) and [18F]Florbetapir (FBP) PET Image Data using the ADNI Pipeline"},{"key":"pone.0276933.ref019","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1186\/s13195-020-00587-5","article-title":"Comparison of amyloid PET measured in Centiloid units with neuropathological findings in Alzheimer\u2019s disease","volume":"12","author":"S. Amadoru","year":"2020","journal-title":"Alzheimer\u2019s Research & Therapy"},{"key":"pone.0276933.ref020","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1001\/jama.2010.2008","article-title":"Use of florbetapir-PET for imaging beta-amyloid pathology","volume":"305","author":"C.M. Clark","year":"2011","journal-title":"Jama"},{"key":"pone.0276933.ref021","doi-asserted-by":"crossref","first-page":"1630","DOI":"10.1093\/brain\/awn016","article-title":"Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer\u2019s disease","volume":"131","author":"M.D. Ikonomovic","year":"2008","journal-title":"Brain: a journal of neurology"},{"key":"pone.0276933.ref022","article-title":"Human apoE isoforms differentially regulate brain amyloid-\u03b2 peptide clearance","author":"J.M. Castellano","year":"2011","journal-title":"Science translational medicine"},{"key":"pone.0276933.ref023","first-page":"8844","article-title":"In vivo assessment of brain interstitial fluid with microdialysis reveals plaque-associated changes in amyloid-beta metabolism and half-life, The Journal of neuroscience: the official journal of the","volume":"23","author":"J.R. Cirrito","year":"2003","journal-title":"Society for Neuroscience"},{"key":"pone.0276933.ref024","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1093\/brain\/awu387","article-title":"What does it mean to be \u2018amyloid-positive\u2019?","volume":"138","author":"A.M. Fagan","year":"2015","journal-title":"Brain: a journal of neurology"},{"key":"pone.0276933.ref025","doi-asserted-by":"crossref","first-page":"1866","DOI":"10.1212\/WNL.58.12.1866","article-title":"The cerebrospinal fluid production rate is reduced in dementia of the Alzheimer\u2019s type","volume":"58","author":"R.A. Fishman","year":"2002","journal-title":"Neurology"},{"key":"pone.0276933.ref026","doi-asserted-by":"crossref","first-page":"1763","DOI":"10.1212\/WNL.57.10.1763","article-title":"The cerebrospinal fluid production rate is reduced in dementia of the Alzheimer\u2019s type","volume":"57","author":"G.D. Silverberg","year":"2001","journal-title":"Neurology"},{"key":"pone.0276933.ref027","doi-asserted-by":"crossref","first-page":"1486","DOI":"10.1093\/brain\/awx057","article-title":"Masters, Biochemically-defined pools of amyloid-\u03b2 in sporadic Alzheimer\u2019s disease: correlation with amyloid PET","volume":"140","author":"B.R. Roberts","year":"2017","journal-title":"Brain: a journal of neurology"},{"key":"pone.0276933.ref028","doi-asserted-by":"crossref","first-page":"a006338","DOI":"10.1101\/cshperspect.a006338","article-title":"Neurotoxicity of amyloid \u03b2-protein: synaptic and network dysfunction","volume":"2","author":"L. Mucke","year":"2012","journal-title":"Cold Spring Harb Perspect Med"},{"key":"pone.0276933.ref029","article-title":"Stereotaxic Infusion of Oligomeric Amyloid-beta into the Mouse Hippocampus","author":"Y.Y. Jean","year":"2015","journal-title":"Journal of visualized experiments: JoVE"},{"key":"pone.0276933.ref030","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1111\/j.1460-9568.1997.tb01425.x","article-title":"Serpins inhibit the toxicity of amyloid peptides","volume":"9","author":"D. Schubert","year":"1997","journal-title":"The European journal of neuroscience"},{"key":"pone.0276933.ref031","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1111\/j.1476-5381.2011.01299.x","article-title":"Animal models in the drug discovery pipeline for Alzheimer\u2019s disease","volume":"164","author":"D. Van Dam","year":"2011","journal-title":"British journal of pharmacology"},{"key":"pone.0276933.ref032","doi-asserted-by":"crossref","first-page":"1884","DOI":"10.3390\/ijms19071884","article-title":"Cellular Receptors of Amyloid \u03b2 Oligomers (A\u03b2Os) in Alzheimer\u2019s Disease","volume":"19","author":"B. Mroczko","year":"2018","journal-title":"International journal of molecular sciences"},{"key":"pone.0276933.ref033","doi-asserted-by":"crossref","first-page":"a024075","DOI":"10.1101\/cshperspect.a024075","article-title":"Binding Sites for Amyloid-\u03b2 Oligomers and Synaptic Toxicity","volume":"7","author":"L.M. Smith","year":"2017","journal-title":"Cold Spring Harb Perspect Med"},{"key":"pone.0276933.ref034","doi-asserted-by":"crossref","first-page":"135959","DOI":"10.1016\/j.neulet.2021.135959","article-title":"Mini-review: Amyloid degradation toxicity hypothesis of Alzheimer\u2019s disease","volume":"756","author":"D.V. Zaretsky","year":"2021","journal-title":"Neurosci Lett"},{"key":"pone.0276933.ref035","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.1006\/bbrc.1994.2047","article-title":"Channel formation in planar lipid bilayers by a neurotoxic fragment of the beta-amyloid peptide","volume":"202","author":"T. Mirzabekov","year":"1994","journal-title":"Biochemical and biophysical research communications"},{"key":"pone.0276933.ref036","doi-asserted-by":"crossref","first-page":"869","DOI":"10.2174\/1567205017666201203142103","article-title":"Degradation Products of Amyloid Protein: Are They The Culprits?","volume":"17","author":"D.V. Zaretsky","year":"2020","journal-title":"Current Alzheimer research"},{"key":"pone.0276933.ref037","first-page":"183506","article-title":"Flow cytometry method to quantify the formation of beta-amyloid membrane ion channels","author":"D.V. Zaretsky","year":"2020","journal-title":"Biochimica et biophysica acta. Biomembranes"},{"key":"pone.0276933.ref038","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1111\/j.1749-6632.1994.tb44414.x","article-title":"The ability of amyloid beta-protein [A beta P (1\u201340)] to form Ca2+ channels provides a mechanism for neuronal death in Alzheimer\u2019s disease","volume":"747","author":"N. Arispe","year":"1994","journal-title":"Annals of the New York Academy of Sciences"},{"key":"pone.0276933.ref039","doi-asserted-by":"crossref","first-page":"10573","DOI":"10.1073\/pnas.90.22.10573","article-title":"Giant multilevel cation channels formed by Alzheimer disease amyloid beta-protein [A beta P-(1\u201340)] in bilayer membranes","volume":"90","author":"N. Arispe","year":"1993","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"pone.0276933.ref040","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1016\/S0196-9781(02)00057-8","article-title":"Electrophysiologic properties of channels induced by Abeta25-35 in planar lipid bilayers","volume":"23","author":"M.-c.A Lin","year":"2002","journal-title":"Peptides"},{"key":"pone.0276933.ref041","first-page":"597","article-title":"The amyloid beta ion channel hypothesis of Alzheimer\u2019s disease","volume":"3","author":"N.A. Shirwany","year":"2007","journal-title":"Neuropsychiatric disease and treatment"},{"key":"pone.0276933.ref042","doi-asserted-by":"crossref","first-page":"1952","DOI":"10.1016\/j.bbamem.2007.03.014","article-title":"A\u03b2 ion channels. Prospects for treating Alzheimer\u2019s disease with A\u03b2 channel blockers","volume":"1768","author":"N. Arispe","year":"2007","journal-title":"Biochimica et Biophysica Acta (BBA)\u2014Biomembranes"},{"key":"pone.0276933.ref043","first-page":"1404","volume":"292","author":"D.C. Bode","year":"2017","journal-title":"Ion Channel Formation by Amyloid-\u03b242 Oligomers but Not Amyloid-\u03b240 in Cellular Membranes"},{"key":"pone.0276933.ref044","doi-asserted-by":"crossref","first-page":"7","DOI":"10.15252\/emmm.201708491","article-title":"Could blocking the formation of amyloid channels rescue Alzheimer\u2019s phenotype?","volume":"10","author":"F.X. Guix","year":"2018","journal-title":"EMBO Mol Med"},{"key":"pone.0276933.ref045","doi-asserted-by":"crossref","first-page":"8868","DOI":"10.1039\/c3cp00017f","article-title":"Alzheimer\u2019s disease: which type of amyloid-preventing drug agents to employ?,","volume":"15","author":"H. Jang","year":"2013","journal-title":"Physical chemistry chemical physics: PCCP"},{"key":"pone.0276933.ref046","doi-asserted-by":"crossref","first-page":"102235","DOI":"10.1016\/j.nano.2020.102235","article-title":"Ion channel formation by N-terminally truncated A\u03b2 (4\u201342): relevance for the pathogenesis of Alzheimer\u2019s disease","volume":"29","author":"A.G. Karkisaval","year":"2020","journal-title":"Nanomedicine: nanotechnology, biology, and medicine"},{"key":"pone.0276933.ref047","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1007\/s12192-014-0551-2","article-title":"Single-cell screening of cytosolic [Ca(2+)] reveals cell-selective action by the Alzheimer\u2019s A\u03b2 peptide ion channel","volume":"20","author":"H. Lin","year":"2015","journal-title":"Cell stress & chaperones"},{"key":"pone.0276933.ref048","article-title":"Membrane channel hypothesis of lysosomal permeabilization by beta-amyloid","author":"D.V. Zaretsky","year":"2021","journal-title":"Neurosci Lett"},{"key":"pone.0276933.ref049","doi-asserted-by":"crossref","first-page":"21821","DOI":"10.1074\/jbc.M112109200","article-title":"Apolipoprotein E4 potentiates amyloid beta peptide-induced lysosomal leakage and apoptosis in neuronal cells","volume":"277","author":"Z.S. Ji","year":"2002","journal-title":"The Journal of biological chemistry"},{"key":"pone.0276933.ref050","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1002\/(SICI)1097-4547(19980615)52:6<691::AID-JNR8>3.0.CO;2-3","article-title":"Loss of endosomal\/lysosomal membrane impermeability is an early event in amyloid Abeta1-42 pathogenesis","volume":"52","author":"A.J. Yang","year":"1998","journal-title":"Journal of neuroscience research"},{"key":"pone.0276933.ref051","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.freeradbiomed.2017.10.001","article-title":"Dysfunction of autophagy and endosomal-lysosomal pathways: Roles in pathogenesis of Down syndrome and Alzheimer\u2019s Disease","volume":"114","author":"D.J. Colacurcio","year":"2018","journal-title":"Free radical biology & medicine"},{"key":"pone.0276933.ref052","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1093\/jnen\/64.2.113","article-title":"Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study","volume":"64","author":"R.A. Nixon","year":"2005","journal-title":"Journal of neuropathology and experimental neurology"},{"key":"pone.0276933.ref053","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.nbd.2011.01.021","article-title":"Autophagy failure in Alzheimer\u2019s disease\u2014locating the primary defect","volume":"43","author":"R.A. Nixon","year":"2011","journal-title":"Neurobiology of disease"},{"key":"pone.0276933.ref054","first-page":"119145","article-title":"Intracellular ion changes induced by the exposure to beta-amyloid can be explained by the formation of channels in the lysosomal membranes","author":"D.V. 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