The Amyloid β Peptide (Aβ1 - 40) Is Thermodynamically Soluble at Physiological Concentrations
Precipitation of the 39−43-residue amyloid β peptide (Aβ) is a crucial factor in Alzheimer's disease (AD). In normal as well as in AD-afflicted brain, the Aβ concentration is estimated to be a few nanomolar. Here we show that Aβ1 - 40 precipitates in vitro only if the dissolved concentration is...
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| Veröffentlicht in: | Biochemistry (Easton) 2003-09, Vol.42 (35), p.10506-10513 |
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| creator | Sengupta, Parijat Garai, K Sahoo, B Shi, Yuan Callaway, David J. E Maiti, S |
| description | Precipitation of the 39−43-residue amyloid β peptide (Aβ) is a crucial factor in Alzheimer's disease (AD). In normal as well as in AD-afflicted brain, the Aβ concentration is estimated to be a few nanomolar. Here we show that Aβ1 - 40 precipitates in vitro only if the dissolved concentration is >14 μM. Using fluorescence correlation spectroscopy, we further show that the precipitation is complete in 1 day, after which the size distribution of Aβ monomer/oligomers in the solution phase becomes stationary in time and independent of the starting Aβ concentration. Mass spectra confirm that both the solution phase and the coexisting precipitate contain chemically identical Aβ molecules. Incubation at 68 °C for 1 h reduces the solubility by |
| doi_str_mv | 10.1021/bi0341410 |
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Together, these results show that the thermodynamic saturation concentration (C sat) of Aβ1 - 40 in phosphate-buffered saline (PBS) at pH 7.4 has a well-defined lower limit of 15.5 ± 1 μM. Divalent metal ions (believed to play a role in AD) at near-saturation concentrations in PBS reduce C sat only marginally (2 mM Mg2+ by 6%, 2.5 μM Ca2+ by 7%, and 4 μM Zn2+ by 11%). Given that no precipitation is possible at concentrations below C sat, we infer that coprecipitant(s), and not properties of Aβ1 - 40 alone, are key factors in the in vivo aggregation of Aβ.</description><identifier>ISSN: 0006-2960</identifier><identifier>EISSN: 1520-4995</identifier><identifier>DOI: 10.1021/bi0341410</identifier><identifier>PMID: 12950178</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Alzheimer Disease - metabolism ; Amyloid beta-Peptides - chemistry ; Amyloid beta-Peptides - metabolism ; Animals ; Chemical Precipitation ; Humans ; Mathematics ; Peptide Fragments - chemistry ; Peptide Fragments - metabolism ; Solubility ; Spectrometry, Fluorescence ; Thermodynamics ; Tyrosine - metabolism</subject><ispartof>Biochemistry (Easton), 2003-09, Vol.42 (35), p.10506-10513</ispartof><rights>Copyright © 2003 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a380t-d61589682bec94a49c48804f0463526265f71d93ce95da273925ddb6d3551bb63</citedby><cites>FETCH-LOGICAL-a380t-d61589682bec94a49c48804f0463526265f71d93ce95da273925ddb6d3551bb63</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/bi0341410$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/bi0341410$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12950178$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sengupta, Parijat</creatorcontrib><creatorcontrib>Garai, K</creatorcontrib><creatorcontrib>Sahoo, B</creatorcontrib><creatorcontrib>Shi, Yuan</creatorcontrib><creatorcontrib>Callaway, David J. E</creatorcontrib><creatorcontrib>Maiti, S</creatorcontrib><title>The Amyloid β Peptide (Aβ1 - 40) Is Thermodynamically Soluble at Physiological Concentrations</title><title>Biochemistry (Easton)</title><addtitle>Biochemistry</addtitle><description>Precipitation of the 39−43-residue amyloid β peptide (Aβ) is a crucial factor in Alzheimer's disease (AD). In normal as well as in AD-afflicted brain, the Aβ concentration is estimated to be a few nanomolar. Here we show that Aβ1 - 40 precipitates in vitro only if the dissolved concentration is >14 μM. Using fluorescence correlation spectroscopy, we further show that the precipitation is complete in 1 day, after which the size distribution of Aβ monomer/oligomers in the solution phase becomes stationary in time and independent of the starting Aβ concentration. Mass spectra confirm that both the solution phase and the coexisting precipitate contain chemically identical Aβ molecules. Incubation at 68 °C for 1 h reduces the solubility by <12%. Together, these results show that the thermodynamic saturation concentration (C sat) of Aβ1 - 40 in phosphate-buffered saline (PBS) at pH 7.4 has a well-defined lower limit of 15.5 ± 1 μM. Divalent metal ions (believed to play a role in AD) at near-saturation concentrations in PBS reduce C sat only marginally (2 mM Mg2+ by 6%, 2.5 μM Ca2+ by 7%, and 4 μM Zn2+ by 11%). Given that no precipitation is possible at concentrations below C sat, we infer that coprecipitant(s), and not properties of Aβ1 - 40 alone, are key factors in the in vivo aggregation of Aβ.</description><subject>Alzheimer Disease - metabolism</subject><subject>Amyloid beta-Peptides - chemistry</subject><subject>Amyloid beta-Peptides - metabolism</subject><subject>Animals</subject><subject>Chemical Precipitation</subject><subject>Humans</subject><subject>Mathematics</subject><subject>Peptide Fragments - chemistry</subject><subject>Peptide Fragments - metabolism</subject><subject>Solubility</subject><subject>Spectrometry, Fluorescence</subject><subject>Thermodynamics</subject><subject>Tyrosine - metabolism</subject><issn>0006-2960</issn><issn>1520-4995</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqF0M9qFEEQBvBGDGaNHnwB6YvBHEar_08f10VNIOBC1hy8ND3TvaZjz_TaPQOZ18qD5JmcsEu8CJ6Kon58BR9Cbwh8IEDJxyYA44QTeIYWRFCouNbiOVoAgKyolnCMXpZyO68cFH-BjgnVAoiqF8hsbjxedlNMweGHe7z2uyE4j98vH-4JrjCHM3xR8Kxyl9zU2y60NsYJX6U4NtFjO-D1zVRCiunn4wmvUt_6fsh2CKkvr9DR1sbiXx_mCfr-5fNmdV5dfvt6sVpeVpbVMFROElFrWdPGt5pbrlte18C3wCUTVFIptoo4zVqvhbNUMU2Fc410TAjSNJKdoNN97i6n36Mvg-lCaX2MtvdpLEYxSUBS_l9IlKqJJnqGZ3vY5lRK9luzy6GzeTIEzGPt5qn22b49hI5N591feeh5BtUehDL4u6e7zb-MVEwJs1lfmQ3T1z8-XTNDZ_9u721bzG0acz-X94_HfwCkt5Zl</recordid><startdate>20030909</startdate><enddate>20030909</enddate><creator>Sengupta, Parijat</creator><creator>Garai, K</creator><creator>Sahoo, B</creator><creator>Shi, Yuan</creator><creator>Callaway, David J. 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E</au><au>Maiti, S</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The Amyloid β Peptide (Aβ1 - 40) Is Thermodynamically Soluble at Physiological Concentrations</atitle><jtitle>Biochemistry (Easton)</jtitle><addtitle>Biochemistry</addtitle><date>2003-09-09</date><risdate>2003</risdate><volume>42</volume><issue>35</issue><spage>10506</spage><epage>10513</epage><pages>10506-10513</pages><issn>0006-2960</issn><eissn>1520-4995</eissn><abstract>Precipitation of the 39−43-residue amyloid β peptide (Aβ) is a crucial factor in Alzheimer's disease (AD). In normal as well as in AD-afflicted brain, the Aβ concentration is estimated to be a few nanomolar. Here we show that Aβ1 - 40 precipitates in vitro only if the dissolved concentration is >14 μM. Using fluorescence correlation spectroscopy, we further show that the precipitation is complete in 1 day, after which the size distribution of Aβ monomer/oligomers in the solution phase becomes stationary in time and independent of the starting Aβ concentration. Mass spectra confirm that both the solution phase and the coexisting precipitate contain chemically identical Aβ molecules. Incubation at 68 °C for 1 h reduces the solubility by <12%. Together, these results show that the thermodynamic saturation concentration (C sat) of Aβ1 - 40 in phosphate-buffered saline (PBS) at pH 7.4 has a well-defined lower limit of 15.5 ± 1 μM. Divalent metal ions (believed to play a role in AD) at near-saturation concentrations in PBS reduce C sat only marginally (2 mM Mg2+ by 6%, 2.5 μM Ca2+ by 7%, and 4 μM Zn2+ by 11%). 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| subjects | Alzheimer Disease - metabolism Amyloid beta-Peptides - chemistry Amyloid beta-Peptides - metabolism Animals Chemical Precipitation Humans Mathematics Peptide Fragments - chemistry Peptide Fragments - metabolism Solubility Spectrometry, Fluorescence Thermodynamics Tyrosine - metabolism |
| title | The Amyloid β Peptide (Aβ1 - 40) Is Thermodynamically Soluble at Physiological Concentrations |
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