Papers by Kelly Johnson-wood
Journal of Neurochemistry, Mar 1, 1991
: One of the major clinical findings in Alzheimer's disease (AD) is the formation of deposits... more : One of the major clinical findings in Alzheimer's disease (AD) is the formation of deposits of β‐amyloid protein in amyloid plaques, derived from the β‐amyloid precursor protein (β‐APP). To determine the possible use of β‐APP as a diagnostic marker for AD in CSF, a monoclonal antibody‐based immunoassay specific for this protein was developed. The assay does not differentiate between β‐APP695 and β‐APP751 forms but does preferentially recognize β‐APP751 complexed with a protease. Of the two sets of CSF samples tested, one set, obtained from living patients, gave a slightly lower level of β‐APP in AD and Parkinson's disease patients relative to controls, whereas the other set, composed of postmortem samples, showed no significant differences between the AD and control groups.
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Vaccine, Jul 1, 2001
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Neurodegenerative Diseases, 2008
Background: In vivo administration of antibodies against the amyloid-β (Aβ) peptide has been show... more Background: In vivo administration of antibodies against the amyloid-β (Aβ) peptide has been shown to reduce and reverse the progressive amyloidosis that develops in a variety of mouse models of Alzheimer’s disease (AD). This work has been extended to clinical trials where subsequent autopsy cases of AD subjects immunized against Aβ showed similar reductions in parenchymal amyloid plaques, suggesting this approach to reduce neuropathology in man is feasible. Objective: Multiple hypotheses have been advanced to explain how anti-Aβ antibodies may lower amyloid burden. In this report, we compare approaches utilizing either plaque-binding or peptide-capturing anti-Aβ antibodies for effectiveness in reducing amyloidosis in a mouse model of AD. Methods: A plaque-binding monoclonal antibody (3D6) and an Aβ peptide-capturing monoclonal antibody (266) were compared in chronic treatment and prevention paradigms using a transgenic mouse model of AD. The effects of antibody therapy on plaque burden and plasma clearance of Aβ were investigated by quantitative imaging and clearance studies of intravenously injected 125I-Aβ. Results: The plaque-binding antibody 3D6 was highly effective in either treatment or prevention of amyloidosis. In these studies, the peptide-capture antibody 266 showed no reduction in amyloidosis in either paradigm and showed trends towards increasing amyloidosis. Antibody 266 was also found to greatly prolong (>180-fold) the normally rapid peripheral clearance of Aβ, in contrast to that found with 3D6 (>24-fold). Conclusion: Reversing and preventing Alzheimer’s type amyloidosis is most effectively accomplished with anti-amyloid antibodies that avidly bind plaque.
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Neurobiology of Aging, 1996
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Biochemical and Biophysical Research Communications, May 1, 1994
ABSTRACT Based upon recent evidence that the secreted form of APP can cause the release of cytoki... more ABSTRACT Based upon recent evidence that the secreted form of APP can cause the release of cytokines and elicit other biological activities, we sought to identify whether a receptor could be identified on the surface of cells. The secreted amyloid precursor protein containing the Kunitz domain (scAPP751) is identical to protease nexin II, a protease inhibitor which has been shown to form complexes with labeled EGF binding protein that subsequently binds to cells. Results of [125I]scAPP751-trypsin complex incubated with intact fibroblast cells show that the complex appears to bind in a saturable time-dependent and reversible manner. The kinetic constants from the binding studies demonstrate a k1 = 2.5 x 10(7) M-1 s-1 and k2 = 4.7 x 10(-4) s-1 and thus a KD (= k2/k1) = 20 pM. Furthermore, the complex formation of [125I]scAPP751 with a protease appears to be a requirement for optimal binding. The binding affinity of secreted APP demonstrated in this study is consistent with its potency in eliminating a range of biological efforts that have been documented.
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Journal of Biological Chemistry, Sep 1, 2007
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The Journal of Neuroscience, Jun 1, 2000
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Proceedings of the National Academy of Sciences of the United States of America, Jul 14, 2004
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Neurobiology of Aging, May 1, 2000
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Neurobiology of Aging, Jul 1, 2004
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Nature, Jul 1, 1999
Amyloid-peptide (A ) seems to have a central role in the neuropathology of Alzheimer's disea... more Amyloid-peptide (A ) seems to have a central role in the neuropathology of Alzheimer's disease (AD) 1 . Familial forms of the disease have been linked to mutations in the amyloid precursor protein (APP) and the presenilin genes 2 , 3 . Disease-linked mutations in these genes ...
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L'invention concerne de maniere generale des methodes et des compositions permettant d'id... more L'invention concerne de maniere generale des methodes et des compositions permettant d'identifier et de quantifier une espece particuliere d'antichymotrypsine α1 dans un echantillon biologique. L'invention concerne plus specifiquement des methodes et des compositions permettant de detecter et de mesurer une espece d'antichymotrypsine α1 cerebrale produite dans le tissu cerebral d'individus presentant des troubles neuropathologiques et qui peut etre detectee dans des echantillons biologiques accessibles. L'invention decrit des tests de detection comme les titrages par liaison de type sandwich, permettant de detecter et de quantifier l'antichymotrypsine α1 cerebrale contenue dans un echantillon biologique comme le sang, l'urine, le liquide cephalo-rachidien ou un tissu. Ces tests de detection permettent de detecter et de diagnostiquer des maladies neuropathologiques et d'identifier des cellules d'une lignee du systeme nerveux central de l...
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Selon divers aspects, l'invention concerne des procedes et des trousses qui permettent de pre... more Selon divers aspects, l'invention concerne des procedes et des trousses qui permettent de predire l'efficacite therapeutique d'un reactif immunologique et/ou d'identifier un reactif immunologique possedant une efficacite therapeutique dans le traitement d'une affection amyloidogene en comparant la quantite de monomere As dans une preparation de As qui lie le reactif immunologique a une quantite d'au moins un oligomere As dans la preparation de As qui lie le reactif immunologique afin de determiner une quantite liee relative, et de predire l'efficacite du reactif immunologique et/ou d'identifier un reactif immunologique possedant une efficacite therapeutique dans le traitement d'une affection amyloidogene au moins sur la base de la quantite liee relative.
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The PDAPP transgenic mouse, which over- expresses human amyloid precursor protein (APP717V3F), ha... more The PDAPP transgenic mouse, which over- expresses human amyloid precursor protein (APP717V3F), has been shown to develop much of the pathology associated with Alzheimer disease. In this report, levels of APP and its amyloidogenic metabolites were measured in brain regions of transgenic mice between 4 and 18 months of age. While absolute levels of APP expression likely contribute to the rate of amyloid b-peptide (Ab) deposition, regionally specific factors also seem important, as homozygotic mice express APP levels in pathologically unaffected regions in excess of that measured in certain amyloid plaque-prone regions of heterozygotic mice. Regional levels of APP and APP-b were nearly constant at all ages, while Ablevels dramatically and predictablyincreasedinbrainregionsundergoinghistochem- ically confirmed amyloidosis, most notably in the cortex and hippocampus. In hippocampus, Ab concentrations increase 17-fold between the ages of 4a nd 8m onths, and by 18 months of age are over 50...
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Journal of Biological Chemistry, 1991
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Proceedings of the National Academy of Sciences, Jul 14, 2004
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Nature, 1999
Amyloid-peptide (A ) seems to have a central role in the neuropathology of Alzheimer's disea... more Amyloid-peptide (A ) seems to have a central role in the neuropathology of Alzheimer's disease (AD) 1 . Familial forms of the disease have been linked to mutations in the amyloid precursor protein (APP) and the presenilin genes 2 , 3 . Disease-linked mutations in these genes ...
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Nature Medicine, 2000
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The Journal of Neuroscience, 2000
Amyloid plaques are a neuropathological hallmark of Alzheimer's disease (AD), but their relat... more Amyloid plaques are a neuropathological hallmark of Alzheimer's disease (AD), but their relationship to neurodegeneration and dementia remains controversial. In contrast, there is a good correlation in AD between cognitive decline and loss of synaptophysin-immunoreactive (SYN-IR) presynaptic terminals in specific brain regions. We used expression-matched transgenic mouse lines to compare the effects of different human amyloid protein precursors (hAPP) and their products on plaque formation and SYN-IR presynaptic terminals. Four distinct minigenes were generated encoding wild-type hAPP or hAPP carrying mutations that alter the production of amyloidogenic Aβ peptides. The platelet-derived growth factor β chain promoter was used to express these constructs in neurons. hAPP mutations associated with familial AD (FAD) increased cerebral Aβ1–42levels, whereas an experimental mutation of the β-secretase cleavage site (671M→I) eliminated production of human Aβ. High levels of Aβ1–42resu...
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Papers by Kelly Johnson-wood