Kelly Johnson-wood - Academia.edu (original) (raw)

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.

Vaccine, Jul 1, 2001

Poly(lactide-co-glycolide) (PLG) microspheres were tested as a parenteral delivery system for hum... more Poly(lactide-co-glycolide) (PLG) microspheres were tested as a parenteral delivery system for human b-amyloid (1-42) (Ab), a potential immunotherapeutic undergoing assessment in Phase 1 studies for Alzheimer's disease (AD). Ab was successfully encapsulated in PLG microspheres of average sizes of 3 or 15 mm diameter. Swiss Webster (SW) mice were injected by the sub-cutaneous (s.c.) or intra-peritoneal (i.p.) routes with 3-33 mg Ab. Ab-PLG microparticles (3 mm) induced dose-dependent antibody responses, which were maximal at 33 mg Ab, while Ab in phosphate-buffered saline (PBS) produced weak antibody responses at the same doses by both routes. Significantly increased antibody responses were seen for both small and large particle formulations given by the i.p. route in comparison to the s.c route. It was previously reported that passive immunisation with Ab-specific antibodies cleared amyloid plaques in a mouse model of AD (Bard F, Cannon C, Barbour R, et al. Peripherally administered antibodies against amyloid b-peptide enter the nervous system and reduce pathology in a mouse model of Alzheimer disease. Nature Med 2000;6:916-19), an indication that induction of serum antibody is a prerequisite for efficacy.

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.

Neurobiology of Aging, 1996

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.

Journal of Biological Chemistry, Sep 1, 2007

The Journal of Neuroscience, Jun 1, 2000

Amyloid plaques are a neuropathological hallmark of Alzheimer's disease (AD), but their relations... 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 A␤ peptides. The platelet-derived growth factor ␤ chain promoter was used to express these constructs in neurons. hAPP mutations associated with familial AD (FAD) increased cerebral A␤ 1-42 levels, whereas an experimental mutation of the ␤-secretase cleavage site (671 M3I) eliminated production of human A␤. High levels of A␤ 1-42 resulted in age-dependent formation of amyloid plaques in FAD-mutant hAPP mice but not in expression-matched wild-type hAPP mice. Yet, significant decreases in the density of SYN-IR presynaptic terminals were found in both groups of mice. Across mice from different transgenic lines, the density of SYN-IR presynaptic terminals correlated inversely with A␤ levels but not with hAPP levels or plaque load. We conclude that A␤ is synaptotoxic even in the absence of plaques and that high levels of A␤ 1-42 are insufficient to induce plaque formation in mice expressing wild-type hAPP. Our results support the emerging view that plaque-independent A␤ toxicity plays an important role in the development of synaptic deficits in AD and related conditions.

Proceedings of the National Academy of Sciences of the United States of America, Jul 14, 2004

For the article ''Epitope and isotype specificities of antibodies to ␤-amyloid peptide for protec... more For the article ''Epitope and isotype specificities of antibodies to ␤-amyloid peptide for protection against Alzheimer's disease-like neuropathology,'' by Frédérique Bard,

Neurobiology of Aging, May 1, 2000

Mutations in the presenilins are a major cause of familial early onset AD. The central issues in ... more Mutations in the presenilins are a major cause of familial early onset AD. The central issues in presenilin biology are the function of the wild-type protein and the pathogenic mechanism associated with presenilin mutations. Compelling evidence for a role of PSl in Notch signaling has come from genetic studies in C. elegans and developmental studies of PSI-null mice. PSI facilitates Notch signahng by increasing proteolytic release of the intracellular domain, an essential step in the Notch signaling pathway. PSI may also participate in other signaling pathways, as it has been shown to associate with several other proteins, including APP, p and S-catenin, GSK3, calsenilin and sorcin. For example, PSl may regulate the Wnt signaling pathway through effects on the stabilization and nuclear translocation of p-cat&n, and may also function in the unfolded protein response. A leading hypothesis is that presenilin mutations may cause AD by increasing production of the pathogenic 42 amino acid form of AP. PSI is required for y-sex&are cleavage of APP, and FAD mutations increase AP42 production in several experimental paradigms. The identification of two transmembrane asptiatea in PSI that are required for maximal y-secretase actwity raises the possibility that PSl may be a novel aspartyl protease with y-secretaae activity. However, this hypothesis does not readily account for difference\ in the intracellular localization of PSI and y-secretase cleavage, or effects of PSI on APP processing that are presumably independent of y-secretase activity. Alternative proposals are that PSl functions as a cofactor for y-secretase or affects the trafficking or foldmg of APP. Another Important observation is that PSl mutation\ increase neuronal vulnerability to apoptosis, possibly by impairing the unfolded protein response or altering calcium homeostasis. A novel feature of AD associated with PSI mutations is an unusually early age of onset. An intriguing possibility is that PSI mutations, by increasing AD42 and reducing the threshold for AP toxicity, may effectively lower the age barrier to AD.

Neurobiology of Aging, Jul 1, 2004

preclinical research using such indole and nitrone antioxidants may lead to more safe and effecti... more preclinical research using such indole and nitrone antioxidants may lead to more safe and effective drugs for the prevention and treatment of AD.

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 ...

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&#3...

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.

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...

Journal of Biological Chemistry, 1991

We have expressed two forms of the Alzheimer's Bamyloid precursor protein (BAPP), the 695-amino a... more We have expressed two forms of the Alzheimer's Bamyloid precursor protein (BAPP), the 695-amino acid form (695/3APP), and the 751-amino acid form (751BAPP) in a baculovirus system. Both forms were expressed as full-length precursor, and were subsequently processed in vivo to release extracellular secreted proteins. The secreted forms were cleaved from the full-length BAPP in a manner analogous to the cleavage of BAPP during constitutive secretion in mammalian cells (Weidemann, A

Proceedings of the National Academy of Sciences, Jul 14, 2004

Nature, 1999

Nature Medicine, 2000

One hallmark of Alzheimer disease is the accumulation of amyloid β-peptide in the brain and its d... more One hallmark of Alzheimer disease is the accumulation of amyloid β-peptide in the brain and its deposition as plaques. Mice transgenic for an amyloid β precursor protein (APP) mini-gene driven by a platelet-derived (PD) growth factor promoter (PDAPP mice), which overexpress one of the disease-linked mutant forms of the human amyloid precursor protein, show many of the pathological features of Alzheimer disease, including extensive deposition of extracellular amyloid plaques, astrocytosis and neuritic dystrophy 1,2. Active immunization of PDAPP mice with human amyloid β-peptide reduces plaque burden and its associated pathologies 3. Several hypotheses have been proposed regarding the mechanism of this response 4,5. Here we report that peripheral administration of antibodies against amyloid β-peptide, was sufficient to reduce amyloid burden. Despite their relatively modest serum levels, the passively administered antibodies were able to enter the central nervous system, decorate plaques and induce clearance of preexisting amyloid. When examined in an ex vivo assay with sections of PDAPP or Alzheimer disease brain tissue, antibodies against amyloid β-peptide triggered microglial cells to clear plaques through Fc receptor-mediated phagocytosis and subsequent peptide degradation. These results indicate that antibodies can cross the blood-brain barrier to act directly in the central nervous system and should be considered as a therapeutic approach for the treatment of Alzheimer disease and other neurological disorders.

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...