17 results on '"Parker, Michael"'
Search Results
2. Support groups for Alzheimer’s caregivers: Creating our own space in uncertain times.
- Author
-
Simpson, Gaynell M., Pressley, Tracy, Parker, Michael, Stansbury, Kim, Wilks, Scott E., and McDougall, Graham J.
- Subjects
- *
PSYCHOLOGICAL adaptation , *ALZHEIMER'S disease , *PSYCHOLOGY of caregivers , *SUPPORT groups , *SEX distribution , *JUDGMENT sampling , *SOCIAL support , *THEMATIC analysis , *BURDEN of care - Abstract
Older men are often excluded from family caregiving research despite the steady increase in the number of husbands assuming primary caregiving roles. We explored perceptions of older, male caregivers’ experiences with caring for a wife with Alzheimer’s Disease (AD) and examined what aspects of the support group were beneficial. Our qualitative research methods invited six caregivers ranging in age from 74 to 85 years to narratively construct their perspectives on caring for their wives with Alzheimer’s Disease and benefits of participation in an all-male support group. Thematic analyses revealed caregivers faced several transitions. “Losses related to their personal relationships with their wife, family, and self,” captured as loss of golden years. The second area, benefits and improvements of support groups, were captured in the following theme: “creating our own space,” which included two sub-themes: “releasing our frustration” and “developing coping strategies.” There was also “Gendered experience of caregiving.” This study revealed that male caregivers benefited from the support and company of other men in similar caregiving situations. Results from this study have implications for health care professionals for the development of psychosocial educational groups aimed at providing support to male caregivers. [ABSTRACT FROM PUBLISHER]
- Published
- 2018
- Full Text
- View/download PDF
3. Abeta targets of the biosimilar antibodies of Bapineuzumab, Crenezumab, Solanezumab in comparison to an antibody against N-truncated Abeta in sporadic Alzheimer disease cases and mouse models.
- Author
-
Bouter, Yvonne, Noguerola, Jose, Tucholla, Petra, Crespi, Gabriela, Parker, Michael, Wiltfang, Jens, Miles, Luke, and Bayer, Thomas
- Subjects
- *
IMMUNOGLOBULINS , *AMYLOID beta-protein , *ALZHEIMER'S disease research , *IMMUNOSTAINING , *FROZEN tissue sections - Abstract
Solanezumab and Crenezumab are two humanized antibodies targeting Amyloid-β (Aβ) which are currently tested in multiple clinical trials for the prevention of Alzheimer's disease. However, there is a scientific discussion ongoing about the target engagement of these antibodies. Here, we report the immunohistochemical staining profiles of biosimilar antibodies of Solanezumab, Crenezumab and Bapineuzumab in human formalin-fixed, paraffin-embedded tissue and human fresh frozen tissue. Furthermore, we performed a direct comparative immunohistochemistry analysis of the biosimilar versions of the humanized antibodies in different mouse models including 5XFAD, Tg4-42, TBA42, APP/PS1KI, 3xTg. The staining pattern with these humanized antibodies revealed a surprisingly similar profile. All three antibodies detected plaques, cerebral amyloid angiopathy and intraneuronal Aβ in a similar fashion. Remarkably, Solanezumab showed a strong binding affinity to plaques. We also reaffirmed that Bapineuzumab does not recognize N-truncated or modified Aβ, while Solanezumab and Crenezumab do detect N-terminally modified Aβ peptides Aβ4-42 and pyroglutamate Aβ3-42. In addition, we compared the results with the staining pattern of the mouse NT4X antibody that recognizes specifically Aβ4-42 and pyroglutamate Aβ3-42, but not full-length Aβ1-42. In contrast to the biosimilar antibodies of Solanezumab, Crenezumab and Bapineuzumab, the murine NT4X antibody shows a unique target engagement. NT4X does barely cross-react with amyloid plaques in human tissue. It does, however, detect cerebral amyloid angiopathy in human tissue. In Alzheimer mouse models, NT4X detects intraneuronal Aβ and plaques comparable to the humanized antibodies. In conclusion, the biosimilar antibodies Solanezumab, Crenezumab and Bapineuzumab strongly react with amyloid plaques, which are in contrast to the NT4X antibody that hardly recognizes plaques in human tissue. Therefore, NT4X is the first of a new class of therapeutic antibodies. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
4. Anti-Aβ antibody target engagement: a response to Siemers et al.
- Author
-
Watt, Andrew, Crespi, Gabriela, Down, Russell, Ascher, David, Gunn, Adam, Perez, Keyla, McLean, Catriona, Villemagne, Victor, Parker, Michael, Barnham, Kevin, and Miles, Luke
- Subjects
- *
IMMUNOGLOBULINS , *ALZHEIMER'S disease - Abstract
A response from the author of the article "Anti-A#x03B2 antibody target engagement" is presented.
- Published
- 2014
- Full Text
- View/download PDF
5. Do current therapeutic anti-Aβ antibodies for Alzheimer's disease engage the target?
- Author
-
Watt, Andrew, Crespi, Gabriela, Down, Russell, Ascher, David, Gunn, Adam, Perez, Keyla, McLean, Catriona, Villemagne, Victor, Parker, Michael, Barnham, Kevin, and Miles, Luke
- Subjects
- *
AMYLOID , *ALZHEIMER'S disease , *BIOMOLECULES , *CLINICAL trials , *IMMUNOGLOBULINS - Abstract
Reducing amyloid-β peptide (Aβ) burden at the pre-symptomatic stages of Alzheimer's disease (AD) is currently the advocated clinical strategy for treating this disease. The most developed method for targeting Aβ is the use of monoclonal antibodies including bapineuzumab, solanezumab and crenezumab. We have synthesized these antibodies and used surface plasmon resonance (SPR) and mass spectrometry to characterize and compare the ability of these antibodies to target Aβ in transgenic mouse tissue as well as human AD tissue. SPR analysis showed that the antibodies were able to bind Aβ with high affinity. All of the antibodies were able to bind Aβ in mouse tissue. However, significant differences were observed in human brain tissue. While bapineuzumab was able to capture a variety of N-terminally truncated Aβ species, the Aβ detected using solanezumab was barely above detection limits while crenezumab did not detect any Aβ. None of the antibodies were able to detect any Aβ species in human blood. Immunoprecipitation experiments using plasma from AD subjects showed that both solanezumab and crenezumab have extensive cross-reactivity with non-Aβ related proteins. Bapineuzumab demonstrated target engagement with brain Aβ, consistent with published clinical data. Solanezumab and crenezumab did not, most likely as a result of a lack of specificity due to cross-reactivity with other proteins containing epitope overlap. This lack of target engagement raises questions as to whether solanezumab and crenezumab are suitable drug candidates for the preventative clinical trials for AD. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
6. Regulation of Insulin-Regulated Membrane Aminopeptidase Activity by Its C-Terminal Domain.
- Author
-
Ascher, David B., Cromer, Brett A., Morton, Craig J., Volitakis, Irene, Cherny, Robert A., Albiston, Anthony L., Siew Yeen Chai, and Parker, Michael W.
- Subjects
- *
AMINOPEPTIDASES , *PHARMACEUTICAL research , *MEMORY loss , *ALZHEIMER'S disease , *PROTEOLYSIS , *MASS spectrometry , *OLIGOMERS , *HYPOGLYCEMIC agents - Abstract
The development of inhibitors of insulin-regulated aminopeptidase (IRAP), a membrane-bound zinc metallopeptidase, is a promising approach for the discovery of drugs for the treatment of memory loss such as that associated with Alzheimer's disease. There is, however, no consensus in the literature about the mechanism by which inhibition occurs. Sequence alignments, secondary structure predictions, and homology models based on the structures of recently determined related metallopeptidases suggest that the extracellular region consists of four domains. Partial proteolysis and mass spectrometry reported here confirm some of the domain boundaries. We have produced purified recombinant fragments of human IRAP on the basis of these data and examined their kinetic and biochemical properties. Full-length extracellular constructs assemble as dimers with different nonoverlapping fragments dimerizing as well, suggesting an extended dimer interface. Only recombinant fragments containing domains 1 and 2 possess aminopeptidase activity and bind the radiolabeled hexapeptide inhibitor, angiotensin IV (Ang IV). However, fragments lacking domains 3 and 4 possess reduced activity, although they still bind a range of inhibitors with the same affinity as longer fragments. In the presence of Ang IV, IRAP is resistant to proteolysis, suggesting significant conformational changes occur upon binding of the inhibitor. We show that IRAP has a second Zn2+ binding site, not associated with the catalytic region, which is lost upon binding Ang IV. Modulation of activity caused by domains 3 and 4 is consistent with a conformational change regulating access to the active site of IRAP. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
7. Synthesis and SAR of indole-and 7-azaindole-1,3-dicarboxamide hydroxyethylamine inhibitors of BACE-1
- Author
-
Marcin, Lawrence R., Higgins, Mendi A., Zusi, F. Christopher, Zhang, Yunhui, Dee, Michael F., Parker, Michael F., Muckelbauer, Jodi K., Camac, Daniel M., Morin, Paul E., Ramamurthy, Vidhyashankar, Tebben, Andrew J., Lentz, Kimberley A., Grace, James E., Marcinkeviciene, Jovita A., Kopcho, Lisa M., Burton, Catherine R., Barten, Donna M., Toyn, Jeremy H., Meredith, Jere E., and Albright, Charles F.
- Subjects
- *
INDOLE , *ETHYLAMINES , *ENZYME inhibitors , *AMYLOID , *ALZHEIMER'S disease , *GLYCOPROTEINS , *STRUCTURE-activity relationships , *ORGANIC synthesis - Abstract
Abstract: Heterocyclic replacement of the isophthalamide phenyl ring in hydroxyethylamine (HEA) BACE-1 inhibitors was explored. A variety of indole-1,3-dicarboxamide HEAs exhibited potent BACE-1 enzyme inhibition, but displayed poor cellular activity. Improvements in cellular activity and aspartic protease selectivity were observed for 7-azaindole-1,3-dicarboxamide HEAs. A methylprolinol-bearing derivative (10n) demonstrated robust reductions in rat plasma Aβ levels, but did not lower rat brain Aβ due to poor central exposure. The same analog exhibited a high efflux ratio in a bidirectional Caco-2 assay and was likely a substrate of the efflux transporter P-glycoprotein. X-ray crystal structures are reported for two indole HEAs in complex with BACE-1. [Copyright &y& Elsevier]
- Published
- 2011
- Full Text
- View/download PDF
8. Amyloid-β–Anti-Amyloid-β Complex Structure Reveals an Extended Conformation in the Immunodominant B-Cell Epitope
- Author
-
Miles, Luke A., Wun, Kwok S., Crespi, Gabriela A.N., Fodero-Tavoletti, Michelle T., Galatis, Denise, Bagley, Christopher J., Beyreuther, Konrad, Masters, Colin L., Cappai, Roberto, McKinstry, William J., Barnham, Kevin J., and Parker, Michael W.
- Subjects
- *
MULTIPLE sclerosis , *NUCLEAR magnetic resonance , *ALZHEIMER'S disease , *MASS spectrometry - Abstract
Abstract: Alzheimer''s disease (AD) is the most common form of dementia. Amyloid-β (Aβ) peptide, generated by proteolytic cleavage of the amyloid precursor protein, is central to AD pathogenesis. Most pharmaceutical activity in AD research has focused on Aβ, its generation and clearance from the brain. In particular, there is much interest in immunotherapy approaches with a number of anti-Aβ antibodies in clinical trials. We have developed a monoclonal antibody, called WO2, which recognises the Aβ peptide. To this end, we have determined the three-dimensional structure, to near atomic resolution, of both the antibody and the complex with its antigen, the Aβ peptide. The structures reveal the molecular basis for WO2 recognition and binding of Aβ. The Aβ peptide adopts an extended, coil-like conformation across its major immunodominant B-cell epitope between residues 2 and 8. We have also studied the antibody-bound Aβ peptide in the presence of metals known to affect its aggregation state and show that WO2 inhibits these interactions. Thus, antibodies that target the N-terminal region of Aβ, such as WO2, hold promise for therapeutic development. [Copyright &y& Elsevier]
- Published
- 2008
- Full Text
- View/download PDF
9. Copper binding to the Alzheimer’s disease amyloid precursor protein.
- Author
-
Kong, Geoffrey K.-W., Miles, Luke A., Crespi, Gabriela A. N., Morton, Craig J., Hooi Ling Ng, Barnham, Kevin J., McKinstry, William J., Cappai, Roberto, and Parker, Michael W.
- Subjects
- *
COPPER , *ALZHEIMER'S disease , *PROTEIN precursors , *AMYLOID beta-protein precursor , *OLIGOMERS - Abstract
Alzheimer’s disease is the fourth biggest killer in developed countries. Amyloid precursor protein (APP) plays a central role in the development of the disease, through the generation of a peptide called Aβ by proteolysis of the precursor protein. APP can function as a metalloprotein and modulate copper transport via its extracellular copper binding domain (CuBD). Copper binding to this domain has been shown to reduce Aβ levels and hence a molecular understanding of the interaction between metal and protein could lead to the development of novel therapeutics to treat the disease. We have recently determined the three-dimensional structures of apo and copper bound forms of CuBD. The structures provide a mechanism by which CuBD could readily transfer copper ions to other proteins. Importantly, the lack of significant conformational changes to CuBD on copper binding suggests a model in which copper binding affects the dimerisation state of APP leading to reduction in Aβ production. We thus predict that disruption of APP dimers may be a novel therapeutic approach to treat Alzheimer’s disease. [ABSTRACT FROM AUTHOR]
- Published
- 2008
- Full Text
- View/download PDF
10. Nitrogen-appended N-alkylsulfonamides as inhibitors of γ-secretase
- Author
-
Bergstrom, Carl P., Sloan, Charles P., Wang, Henry H., Parker, Michael F., Smith, David W., Zheng, Ming, Hansel, Steven B., Polson, Craig T., Barber, Lauren E., Bursuker, Isia, Guss, Valerie L., Corsa, Jason A., Barten, Donna M., Felsenstein, Kevin M., and Roberts, Susan B.
- Subjects
- *
CHEMICAL inhibitors , *TRANSGENIC mice , *NITROGEN , *NONMETALS - Abstract
Abstract: The synthesis and γ-secretase inhibition data for a series of nitrogen-appended N-alkylsulfonamides (11–47) are described. Inhibition of brain Aβ in transgenic mice was demonstrated by two of these compounds (23 and 44). [Copyright &y& Elsevier]
- Published
- 2008
- Full Text
- View/download PDF
11. Structure of Alzheimer's disease amyloid precursor protein copper-binding domain at atomic resolution.
- Author
-
Kwai-Wai Kong, Geoffrey, Adams, Julian J., Cappai, Roberto, and Parker, Michael W.
- Subjects
- *
ALZHEIMER'S disease , *PROTEIN precursors , *AMYLOID , *PEPTIDES , *LABORATORY mice - Abstract
Amyloid precursor protein (APP) plays a central role in the pathogenesis of Alzheimer's disease, as its cleavage generates the Aβ peptide that is toxic to cells. APP is able to bind Cu2+ and reduce it to Cu+ through its copper-binding domain (CuBD). The interaction between Cu2+ and APP leads to a decrease in Aβ production and to alleviation of the symptoms of the disease in mouse models. Structural studies of CuBD have been undertaken in order to better understand the mechanism behind the process. Here, the crystal structure of CuBD in the metal-free form determined to ultrahigh resolution (0.85 Å) is reported. The structure shows that the copper-binding residues of CuBD are rather rigid but that Met170, which is thought to be the electron source for Cu2+ reduction, adopts two different side-chain conformations. These observations shed light on the copper-binding and redox mechanisms of CuBD. The structure of CuBD at atomic resolution provides an accurate framework for structure-based design of molecules that will deplete Aβ production. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
12. Structural Studies of the Alzheimer’s Amyloid Precursor Protein Copper-binding Domain Reveal How it Binds Copper Ions
- Author
-
Kong, Geoffrey K.-W., Adams, Julian J., Harris, Hugh H., Boas, John F., Curtain, Cyril C., Galatis, Denise, Masters, Colin L., Barnham, Kevin J., McKinstry, William J., Cappai, Roberto, and Parker, Michael W.
- Subjects
- *
ALZHEIMER'S disease , *AMYLOID , *GLYCOPROTEINS , *COPPER ions - Abstract
Abstract: Alzheimer''s disease (AD) is the major cause of dementia. Amyloid β peptide (Aβ), generated by proteolytic cleavage of the amyloid precursor protein (APP), is central to AD pathogenesis. APP can function as a metalloprotein and modulate copper (Cu) transport, presumably via its extracellular Cu-binding domain (CuBD). Cu binding to the CuBD reduces Aβ levels, suggesting that a Cu mimetic may have therapeutic potential. We describe here the atomic structures of apo CuBD from three crystal forms and found they have identical Cu-binding sites despite the different crystal lattices. The structure of Cu2+-bound CuBD reveals that the metal ligands are His147, His151, Tyr168 and two water molecules, which are arranged in a square pyramidal geometry. The site resembles a Type 2 non-blue Cu center and is supported by electron paramagnetic resonance and extended X-ray absorption fine structure studies. A previous study suggested that Met170 might be a ligand but we suggest that this residue plays a critical role as an electron donor in CuBDs ability to reduce Cu ions. The structure of Cu+-bound CuBD is almost identical to the Cu2+-bound structure except for the loss of one of the water ligands. The geometry of the site is unfavorable for Cu+, thus providing a mechanism by which CuBD could readily transfer Cu ions to other proteins. [Copyright &y& Elsevier]
- Published
- 2007
- Full Text
- View/download PDF
13. Molecular Dissection of the Interaction between Amyloid Precursor Protein and Its Neuronal Trafficking Receptor SorLA/LR11.
- Author
-
Andersen, Olav M., Schmidt, Vanessa, Spoelgen, Robert, Gliemann, Jørgen, Behlke, Joachim, Galatis, Denise, McKinstry, William J., Parker, Michael W., Masters, Colin L., Hyman, Bradley T., Cappai, Roberto, and Willnow, Thomas E.
- Subjects
- *
PROTEIN precursors , *AMYLOID , *CELL receptors , *CARRIER proteins , *ALZHEIMER'S disease , *NEURONS - Abstract
SorLA/LR11 is a sorting receptor that regulates the intracellular transport and processing of the amyloid precursor protein (APP) in neurons. SorLA/LR11-mediated binding results in sequestration of APP in the Golgi and in protection from processing into the amyloid-fl peptide (Aft), the principal component of senile plaques in Alzheimer's disease (AD). To gain insight into the molecular mechanisms governing sorLA and APP interaction, we have dissected the respective protein interacting domains. Using a fluorescence resonance energy transfer (FRET) based assay of protein proximity, we identified binding sites in the extracellular regions of both proteins. Fine mapping by surface plasmon resonance analysis and analytical ultracentrifugation of recombinant APP and sorLA fragments further narrowed down the binding domains to the cluster of complement-type repeats in sorLA that forms a 1:1 stoichiometric complex with the carbohydrate-linked domain of APP. These data shed new light on the molecular determinants of neuronal APP trafficking and processing and on possible targets for intervention with senile plaque formation in patients with AD. [ABSTRACT FROM AUTHOR]
- Published
- 2006
- Full Text
- View/download PDF
14. Structure of the Alzheimer's Disease Amyloid Precursor Protein Copper Binding Domain.
- Author
-
Barnham, Kevin J., McKinstry, William J., Multhaup, Gerd, Galatis, Denise, Morton, Craig J., Curtain, Cyril C., Williamson, Nicholas A., White, Anthony R., Hinds, Mark G., Norton, Raymond S., Beyreuther, Konrad, Masters, Colin L., Parker, Michael W., and Cappai, Roberto
- Subjects
- *
ALZHEIMER'S disease , *AMYLOID beta-protein precursor , *GENE expression - Abstract
Examines the structure of the Alzheimer's disease amyloid precursor protein (APP) copper binding domain (CuBD). Evidence that it contains a novel copper bindign site that favors CU(I) coordination; Expression and purification; Importance of copper to Alzheimer's disease.
- Published
- 2003
- Full Text
- View/download PDF
15. Crystal structure of the N-terminal, growth factor-like domain of Alzheimer amyloid precursor protein.
- Author
-
Rossjohn, Jamie, Cappai, Roberto, Feil, Susanne C., Henry, Anna, McKinstry, William J., Galatis, Denise, Hesse, Lars, Multhaup, Gerd, Beyreuther, Konrad, Masters, Colin L., and Parker, Michael W.
- Subjects
- *
AMYLOID beta-protein precursor , *PROTEINS , *ALZHEIMER'S disease - Abstract
Amyloid precursor protein (APP) plays a central role in Alzheimer disease. A proteolytic-breakdown product of APP, called β-amyloid, is a major component of the diffuse and fibrillar deposits found in Alzheimer diseased brains. The normal physiological role of APP remains largely unknown despite much work. A knowledge of its function will not only provide insights into the genesis of the disease but may also prove vital in the development of an effective therapy. Here we describe the 1.8 Å resolution crystal structure of the N-terminal, heparin-binding domain of APP (residues 28?123), which is responsible, among other things, for stimulation of neurite outgrowth. The structure reveals a highly charged basic surface that may interact with glycosaminoglycans in the brain and an abutting hydrophobic surface that is proposed to play an important functional role such as dimerization or ligand binding. Structural similarities with cysteine-rich growth factors, taken together with its known growth-promoting properties, suggests the APP N-terminal domain could function as a growth factor in vivo. [ABSTRACT FROM AUTHOR]
- Published
- 1999
16. Macrocyclic BACE inhibitors: Optimization of a micromolar hit to nanomolar leads
- Author
-
Huang, Yifang, Strobel, Eric D., Ho, Chih Y., Reynolds, Charles H., Conway, Kelly A., Piesvaux, Jennifer A., Brenneman, Douglas E., Yohrling, George J., Moore Arnold, H., Rosenthal, Daniel, Alexander, Richard S., Tounge, Brett A., Mercken, Marc, Vandermeeren, Marc, Parker, Michael H., Reitz, Allen B., and Baxter, Ellen W.
- Subjects
- *
PROTEASE inhibitors , *MACROCYCLIC compounds , *ETIOLOGY of diseases , *ALZHEIMER'S disease treatment , *MOLECULAR structure , *BINDING sites - Abstract
Abstract: We have identified macrocyclic inhibitors of the aspartic protease BACE, implicated in the etiology of Alzheimer’s disease. An X-ray structure of screening hit 1 in the BACE active site revealed a hairpin conformation suggesting that constrained macrocyclic derivatives may also bind there. Several of the analogs we prepared were >100× more potent than 1, such as 7 (5nM K i). [Copyright &y& Elsevier]
- Published
- 2010
- Full Text
- View/download PDF
17. Crystallization and preliminary crystallographic studies of the copper-binding domain of the amyloid precursor protein of Alzheimer's disease.
- Author
-
Kong, Geoffrey K.-W., Galatis, Denise, Barnham, Kevin J., Polekhina, Galina, Adams, Julian J., Masters, Colin L., Cappai, Roberto, Parker, Michael W., and McKinstry, William J.
- Subjects
- *
CRYSTALLIZATION , *CHEMICAL bonds , *COPPER , *AMYLOID , *GLYCOPROTEINS , *ALZHEIMER'S disease - Abstract
Alzheimer's disease is thought to be triggered by production of the amyloid β (Aβ) peptide through proteolytic cleavage of the amyloid precursor protein (APP). The binding of Cu2+ to the copper-binding domain (CuBD) of APP reduces the production of Aβ in cell-culture and animal studies. It is expected that structural studies of the CuBD will lead to a better understanding of how copper binding causes Aβ depletion and will define a potential drug target. The crystallization of CuBD in two different forms suitable for structure determination is reported here. [ABSTRACT FROM AUTHOR]
- Published
- 2005
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.