Activation of matrix metalloproteinases following anti-Ab immunotherapy; implications for microhe... more Activation of matrix metalloproteinases following anti-Ab immunotherapy; implications for microhemorrhage occurrence
660 NATURE | VOL 412 | 9 AUGUST 2001 | www.nature.com 25. Erdjument-Bromage, H. et al. Micro-tip ... more 660 NATURE | VOL 412 | 9 AUGUST 2001 | www.nature.com 25. Erdjument-Bromage, H. et al. Micro-tip reversed-phase liquid chromatographic extraction of peptide pools for mass spectrometry. J. Chromatogr. 826, 157±181 (1998). 26. Geromanos, S., Freckleton, G. & Tempst, P. Tuning of an electrospray ionization source for maximum peptide-ion transmission into a mass spectrometer. Anal. Chem. 72, 779±790 (2000). 27. Mann, M., Hojrup, P. & Roepstorff, P. Use of mass spectrometric molecular weight information to identify proteins in databases. Biol. Mass Spectrom. 22, 338±345 (1993). 28. Mann, M. & Wilm, M. Error-tolerant identi®cation of peptides in sequence databases by peptide sequence tags. Anal. Chem. 66, 4390±4399 (1994). 29. FenyoÈ, D., Qin, J. & Chait, B. T. Protein identi®cation using mass spectrometric information. Electrophoresis 19, 998±1005 (1998).
While the presence of an inflammatory response in AD (Alzheimer's disease) is well known, the... more While the presence of an inflammatory response in AD (Alzheimer's disease) is well known, the data on inflammation are conflicting, suggesting that inflammation either attenuates pathology, exacerbates it or has no effect. Our goal was to more fully characterize the inflammatory response in APP (amyloid precursor protein) transgenic mice with and without disease progression. In addition, we have examined how anti-A β (amyloid β-peptide) immunotherapy alters this inflammatory response. We have used quantitative RT–PCR (reverse transcription–PCR) and protein analysis to measure inflammatory responses ranging from proinflammatory to anti-inflammatory and repair factors in transgenic mice that develop amyloid deposits only (APPSw) and amyloid deposits with progression to tau pathology and neuron loss [APPSw/NOS2–/– (nitric oxide synthase 2–/–)]. We also examined tissues from previously published immunotherapy studies. These studies were a passive immunization study in APPSw mice and...
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2006
Systemic administration of anti-amyloid-beta (Abeta) antibodies results in reduced parenchymal am... more Systemic administration of anti-amyloid-beta (Abeta) antibodies results in reduced parenchymal amyloid but increased vascular amyloid and microhemorrhage in amyloid precursor protein (APP) transgenic mice. Here, we evaluate the effects of reducing effector interactions of the antibody via deglycosylation. Mice aged 20 months were treated weekly for 4 months and tested behaviorally before they were killed. APP transgenic mice receiving either anti-Abeta (2H6) or deglycosylated anti-Abeta (de-2H6) showed significant improvement in radial arm water maze performance compared with mice receiving a control antibody. Both groups receiving anti-Abeta antibodies showed significant reductions in total Abeta immunochemistry and Congo red. Significantly fewer vascular amyloid deposits and microhemorrhages were observed in mice administered the de-2H6 antibody compared with those receiving unmodified 2H6 antibody. Deglycosylated anti-Abeta antibodies may be preferable to unmodified IgG because t...
Alzheimer's disea... more Alzheimer's disease (AD) is a progressive, neurodegenerative disorder that results in severe cognitive decline. Amyloid plaques are a principal pathology found in AD and are composed of aggregated amyloid-beta (Abeta) peptides. According to the amyloid hypothesis, Abeta peptides initiate the other pathologies characteristic for AD including cognitive deficits. Immunotherapy against Abeta is a potential therapeutic for the treatment of humans with AD. While anti-Abeta immunotherapy has been shown to reduce amyloid burden in both mouse models and in humans, immunotherapy also exacerbates vascular pathologies. Cerebral amyloid angiopathy (CAA), that is, the accumulation of amyloid in the cerebrovasculature, is increased with immunotherapy in humans with AD and in mouse models of amyloid deposition. CAA persists in the brains of clinical trial patients that show removal of parenchymal amyloid. Mouse model studies also show that immunotherapy results in multiple small bleeds in the brain, termed microhemorrhages. The neurovascular unit is a term used to describe the cerebrovasculature and its associated cells-astrocytes, neurons, pericytes and microglia. CAA affects brain perfusion and there is now evidence that the neurovascular unit is affected in AD when CAA is present. Understanding the type of damage to the neurovascular unit caused by CAA in AD and the underlying cause of microhemorrhage after immunotherapy is essential to the success of therapeutic vaccines as a treatment for AD.
Activation of matrix metalloproteinases following anti-Ab immunotherapy; implications for microhe... more Activation of matrix metalloproteinases following anti-Ab immunotherapy; implications for microhemorrhage occurrence
660 NATURE | VOL 412 | 9 AUGUST 2001 | www.nature.com 25. Erdjument-Bromage, H. et al. Micro-tip ... more 660 NATURE | VOL 412 | 9 AUGUST 2001 | www.nature.com 25. Erdjument-Bromage, H. et al. Micro-tip reversed-phase liquid chromatographic extraction of peptide pools for mass spectrometry. J. Chromatogr. 826, 157±181 (1998). 26. Geromanos, S., Freckleton, G. & Tempst, P. Tuning of an electrospray ionization source for maximum peptide-ion transmission into a mass spectrometer. Anal. Chem. 72, 779±790 (2000). 27. Mann, M., Hojrup, P. & Roepstorff, P. Use of mass spectrometric molecular weight information to identify proteins in databases. Biol. Mass Spectrom. 22, 338±345 (1993). 28. Mann, M. & Wilm, M. Error-tolerant identi®cation of peptides in sequence databases by peptide sequence tags. Anal. Chem. 66, 4390±4399 (1994). 29. FenyoÈ, D., Qin, J. & Chait, B. T. Protein identi®cation using mass spectrometric information. Electrophoresis 19, 998±1005 (1998).
While the presence of an inflammatory response in AD (Alzheimer's disease) is well known, the... more While the presence of an inflammatory response in AD (Alzheimer's disease) is well known, the data on inflammation are conflicting, suggesting that inflammation either attenuates pathology, exacerbates it or has no effect. Our goal was to more fully characterize the inflammatory response in APP (amyloid precursor protein) transgenic mice with and without disease progression. In addition, we have examined how anti-A β (amyloid β-peptide) immunotherapy alters this inflammatory response. We have used quantitative RT–PCR (reverse transcription–PCR) and protein analysis to measure inflammatory responses ranging from proinflammatory to anti-inflammatory and repair factors in transgenic mice that develop amyloid deposits only (APPSw) and amyloid deposits with progression to tau pathology and neuron loss [APPSw/NOS2–/– (nitric oxide synthase 2–/–)]. We also examined tissues from previously published immunotherapy studies. These studies were a passive immunization study in APPSw mice and...
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2006
Systemic administration of anti-amyloid-beta (Abeta) antibodies results in reduced parenchymal am... more Systemic administration of anti-amyloid-beta (Abeta) antibodies results in reduced parenchymal amyloid but increased vascular amyloid and microhemorrhage in amyloid precursor protein (APP) transgenic mice. Here, we evaluate the effects of reducing effector interactions of the antibody via deglycosylation. Mice aged 20 months were treated weekly for 4 months and tested behaviorally before they were killed. APP transgenic mice receiving either anti-Abeta (2H6) or deglycosylated anti-Abeta (de-2H6) showed significant improvement in radial arm water maze performance compared with mice receiving a control antibody. Both groups receiving anti-Abeta antibodies showed significant reductions in total Abeta immunochemistry and Congo red. Significantly fewer vascular amyloid deposits and microhemorrhages were observed in mice administered the de-2H6 antibody compared with those receiving unmodified 2H6 antibody. Deglycosylated anti-Abeta antibodies may be preferable to unmodified IgG because t...
Alzheimer's disea... more Alzheimer's disease (AD) is a progressive, neurodegenerative disorder that results in severe cognitive decline. Amyloid plaques are a principal pathology found in AD and are composed of aggregated amyloid-beta (Abeta) peptides. According to the amyloid hypothesis, Abeta peptides initiate the other pathologies characteristic for AD including cognitive deficits. Immunotherapy against Abeta is a potential therapeutic for the treatment of humans with AD. While anti-Abeta immunotherapy has been shown to reduce amyloid burden in both mouse models and in humans, immunotherapy also exacerbates vascular pathologies. Cerebral amyloid angiopathy (CAA), that is, the accumulation of amyloid in the cerebrovasculature, is increased with immunotherapy in humans with AD and in mouse models of amyloid deposition. CAA persists in the brains of clinical trial patients that show removal of parenchymal amyloid. Mouse model studies also show that immunotherapy results in multiple small bleeds in the brain, termed microhemorrhages. The neurovascular unit is a term used to describe the cerebrovasculature and its associated cells-astrocytes, neurons, pericytes and microglia. CAA affects brain perfusion and there is now evidence that the neurovascular unit is affected in AD when CAA is present. Understanding the type of damage to the neurovascular unit caused by CAA in AD and the underlying cause of microhemorrhage after immunotherapy is essential to the success of therapeutic vaccines as a treatment for AD.
Uploads
Papers by Donna Wilcock