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ARTICLE, Cellular/Molecular

The Binding of 2-(4′-Methylaminophenyl)Benzothiazole to Postmortem Brain Homogenates Is Dominated by the Amyloid Component

William E. Klunk, Yanming Wang, Guo-feng Huang, Manik L. Debnath, Daniel P. Holt, Li Shao, Ronald L. Hamilton, Milos D. Ikonomovic, Steven T. DeKosky and Chester A. Mathis
Journal of Neuroscience 15 March 2003, 23 (6) 2086-2092; https://doi.org/10.1523/JNEUROSCI.23-06-02086.2003
William E. Klunk
1Laboratory of Molecular Neuropharmacology, Department of Psychiatry, Western Psychiatric Institute and Clinic,
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Yanming Wang
2PET Facility, Department of Radiology,
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Guo-feng Huang
2PET Facility, Department of Radiology,
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Manik L. Debnath
1Laboratory of Molecular Neuropharmacology, Department of Psychiatry, Western Psychiatric Institute and Clinic,
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Daniel P. Holt
2PET Facility, Department of Radiology,
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Li Shao
1Laboratory of Molecular Neuropharmacology, Department of Psychiatry, Western Psychiatric Institute and Clinic,
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Ronald L. Hamilton
3Division of Neuropathology, Department of Pathology, and
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Milos D. Ikonomovic
4Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213
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Steven T. DeKosky
4Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213
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Chester A. Mathis
2PET Facility, Department of Radiology,
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  • Fig. 1.
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    Fig. 1.

    Chemical structures of thioflavin-T and BTA-1. The uncharged compound, BTA-1, differs from thioflavin-T by the lack of three methyl groups, including the methyl group imparting the positive charge to the quaternary heterocyclic nitrogen of thioflavin-T (arrow).

  • Fig. 2.
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    Fig. 2.

    Paraffin sections (8 μm) from AD brain stained with 100 nm BTA-1. Left panel shows plaques and cerebrovascular amyloid in the frontal cortex. Right panel shows plaques and neurofibrillary tangles in the entorhinal cortex. Scale bar, 100 μm. Most smaller bright spots are residual lipofuscin autofluorescence.

  • Fig. 3.
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    Fig. 3.

    A, Comparison of [3H]BTA-1 binding to homogenates from control (open bars, circles), AD (filled bars, squares), and NAD brain (hatched bars, triangles) frontal gray (Fr) or cerebellum (Cb).B, Ratio of [3H]BTA-1 binding to the Fr and Cb for each individual brain. Bars represent the mean, and error bars represent the SD. Also shown are the individual data points.

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    Fig. 4.

    Scatchard plots showing the binding of [3H]BTA-1 to homogenates from AD frontal gray matter (▪) and underlying frontal white matter from the same AD brain (▵). In this AD frontal gray matter homogenate, theKd was 4.4 nm and theBmax was 6.9 pmol/mg wet weight. In the frontal white matter immediately underlying this gray matter sample, the Kd was 111 nm and theBmax was 27 pmol/mg wet weight. Also shown is a Scatchard plot showing the binding of [3H]BTA-1 to a homogenate from control brain frontal gray (○) in which the Kd was 180 nm and the Bmax was 5.9 pmol/mg wet weight.

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    Fig. 5.

    Paraffin sections (8 μm) from the entorhinal cortex (A, B), frontal cortex (C, D), and cerebellum (E,F) of a Braak stage II control brain (A, C, E, Cntl 04) and a Braak stage VI AD brain (B,D, F, AD 01) stained with X-34. X-34 is a highly sensitive, fluorescent Congo red derivative that intensely stains plaques, NFTs, and amyloid deposits in general (Styren et al., 2000). Marked atrophy of AD tissue was notable in all regions. In the entorhinal cortex of the control subject (A), frequent numbers of NFTs were seen, whereas there were no amyloid deposits. In the AD case (B), there also were frequent NFTs along with diffuse amyloid deposits (arrows). X-34-positive NFTs and amyloid plaques were absent from the frontal cortex of the control case (C), whereas they were abundant in AD (D). There was no detectable X-34 staining of plaques or NFT in control (E) and AD (F) cerebellum. Control frontal cortex (C) and cerebellum from both control and AD (E, F) show small stellate cells that stain with X-34. Scale bar, 200 μm.

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    Fig. 6.

    Comparison of the Kivalues of 10 BTA-1 derivatives for inhibition of [3H]BTA-1 binding to Aβ(1–40) fibrils and homogenates of AD frontal gray (filled diamonds,solid line). Also shown is a comparison of the same data for Aβ(1–40) fibrils compared with Kivalues previously determined in a separate, older lot of Aβ(1–40) fibrils (open squares, dashed line).

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    Table 1.

    Demographic and neuropathological characteristics

    Brain no.Primary neuropath DxOther neuropath DxBraak stageCortical NP1-aAgePMI (hr)
    AD 01AD1-aAA (severe)VIFrequent833
    AD 02AD1-aAA (severe)VIFrequent574
    AD 03AD1-aAA (mild)VIFrequent783
    AD 04AD1-aAA (mild), DLB (1/10)1-bVIFrequent804
    AD 05AD1-aAA (moderate)VIFrequent789
    AD 06AD1-aChronic subdural hematomaIVFrequent853
    AD 07AD1-aAA (severe), old infarct right putamenVIFrequent794
    AD 08AD1-aAA (mild), old infarct left basis pontisIVFrequent834
    AD 09AD1-aInfarcts, right putamen (3 old);
    Left thalamus (1 subacute)
    IVFrequent844
    Average:78.64.2
    SD8.51.9
    Cntl 01Normal brain1-aModerate atherosclerosis, circle of Willis0None7218
    Cntl 02Normal brain1-aPersistent posterior fetal circulation, bilaterally
    Incidental choroid plexus cyst
    INone824
    Cntl 03Normal brain1-aModerate congestion of leptomeninges0None758
    Cntl 04Normal brain1-aIncidental focal hypoplasia of corpus callosumIINone823
    Cntl 05Normal brain1-aNoneINone745
    Cntl 06Normal brain1-aAtherosclerosis, circle of Willis
    Old infarcts cerebellar cortex, inferior olivary nucleus
    IIRare724
    Cntl 07Normal brain1-aSubacute infarct right brainstemINone746
    Cntl 08Normal brain1-aNone0None535
    Average:73.06.6
    SD9.04.8
    p = (vs AD)0.210.22
    NAD 01Pure DLB(7/10)1-bNoneINone6910
    NAD 02Huntington'sStatus post evacuation subdural hematoma,
    Atherosclerosis, circle of Willis
    INone647
    NAD 03Pick'sAtherosclerosis, circle of Willis0None664
    NAD 04MND-inclusion
    Dementia
    Severe cortical atrophy, atherosclerosis, circle of Willis0None758
    NAD 05DLDHFMesial temporal sclerosisINone564
    NAD 06DLB(6/10)1-bParkinson's diseaseINone878
    Average:69.56.8
    SD10.62.4
    p= (vs AD)0.110.05
    • NP, Neuritic plaques; PMI, postmortem interval; AD, Alzheimer's disease; AA, amyloid angiopathy; DLB, dementia with Lewy Bodies; SD, standard deviation; p = (vs AD), p values compared with corresponding values for AD cases; Cntl, control; NAD, demented, non-Alzheimer's disease; MND, motor neuron disease-inclusion dementia (Jackson et al., 1996); DLDHF, dementia lacking distinctive histologic features (Mann, 1998); neuropath; Dx, neuropathological diagnosis.

    • ↵F1-a CERAD criteria (Mirra et al., 1991).

    • ↵F1-b Scored according to consensus criteria (McKeith et al., 1996).

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    Table 2.

    [3H]BTA-1 binding to specified areas of a Braak stage II control brain (Cntl 04) and a Braak stage VI AD brain (AD 01)

    Brain areapmol BTA-1/mg wet weight (mean ± SD)p value2-a
    Cntl 04AD 01
    EC0.078  ± 0.0060.082  ± 0.0080.489
    Fr0.093  ± 0.0040.887  ± 0.0110.00001
    Cb0.078  ± 0.00010.043  ± 0.0040.005
    • See Table 1 for details. EC, Entorhinal cortex; Fr, frontal cortex; Cb, cerebellum.

    • ↵F2-a Student's t test comparison of control and AD values.

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The Journal of Neuroscience: 23 (6)
Journal of Neuroscience
Vol. 23, Issue 6
15 Mar 2003
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The Binding of 2-(4′-Methylaminophenyl)Benzothiazole to Postmortem Brain Homogenates Is Dominated by the Amyloid Component
William E. Klunk, Yanming Wang, Guo-feng Huang, Manik L. Debnath, Daniel P. Holt, Li Shao, Ronald L. Hamilton, Milos D. Ikonomovic, Steven T. DeKosky, Chester A. Mathis
Journal of Neuroscience 15 March 2003, 23 (6) 2086-2092; DOI: 10.1523/JNEUROSCI.23-06-02086.2003

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The Binding of 2-(4′-Methylaminophenyl)Benzothiazole to Postmortem Brain Homogenates Is Dominated by the Amyloid Component
William E. Klunk, Yanming Wang, Guo-feng Huang, Manik L. Debnath, Daniel P. Holt, Li Shao, Ronald L. Hamilton, Milos D. Ikonomovic, Steven T. DeKosky, Chester A. Mathis
Journal of Neuroscience 15 March 2003, 23 (6) 2086-2092; DOI: 10.1523/JNEUROSCI.23-06-02086.2003
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Keywords

  • Alzheimer's disease
  • neuroimaging
  • plaques
  • neurofibrillary tangles
  • positron emission tomography
  • PET
  • thioflavin-T
  • benzothiazole
  • postmortem
  • binding

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