Schroeter S, Khan K, Barbour R, Doan M, Chen M, Guido T, Gill D, Basi G, Schenk D, Seubert P, Games D.
Immunotherapy reduces vascular amyloid-beta in PDAPP mice.
J Neurosci. 2008 Jul 2;28(27):6787-93.
PubMed.
Roy Weller University of Southampton School of Medicine
Posted:
Prevention Rather Than Cure of CAA May Be the Best Way Forward
Increased severity of cerebral amyloid angiopathy (CAA) has been highlighted as a complication of immunotherapy for Alzheimer disease in both human subjects (1) and in transgenic mouse models (2). In their paper in The Journal of Neuroscience, Sally Schroeter et al. showed that passive immunization of 12-month-old PDAPP transgenic mice with the 3D6 antibody directed against the N-terminal of the Aβ molecule prevented deposition or cleared Aβ from artery walls in a dose-dependent manner. At the moment, however, it is not clear whether Aβ was eliminated from artery walls by macrophages, analogous to the removal of Aβ plaques from brain parenchyma by microglia (1), or by some other mechanism. Perivascular microhemorrhages were increased in animals treated with the higher dose of the antibody. Fewer hemorrhages were detected at lower doses of the 3D6 antibody, although clearance of Aβ was not as complete.
By treating the PDAPP transgenic mice with passive immunization at the relatively early age of 12 months, Schroeter and her colleagues have emphasized the importance of preventing the deposition of Aβ in vessel walls rather than removing it. CAA appears to have two major complications. One is the replacement of smooth muscle cells by Aβ that may result in intracerebral hemorrhage or may interfere with autoregulation of cerebral blood flow. The other complication is the blockage of pathways by which interstitial fluid and solutes drain from the brain. Basement membranes between vascular smooth muscle cells are the perivascular route by which interstitial fluid and solutes, such as Aβ, drain out of the brain (3). In the early stages of CAA, fibrils of insoluble Aβ are deposited within vascular basement membranes and disrupt the structure of the basement membranes involved (4,5). The effects of basement membrane disruption in CAA on the drainage of fluid and solutes from the brain has not been quantified, but it does seem to be associated with deposition of Aβ plaques in gray matter and with increased fluid retention in cerebral white matter (6). It is probable that the elimination of other brain metabolites, in addition to Aβ, is blocked in CAA, leading to a loss of homeostasis of the neuronal environment and possible neuronal malfunction. Thus, it could be vital for normal functioning of the brain to preserve the structure of vascular basement membranes by preventing the deposition of Aβ. In this way, the integrity of the drainage pathways for solutes and fluid from the brain would be maintained. Preserving vascular basement membranes is one reason why the approach of Schroeter et al. in preventing CAA could be so valuable in the management of Alzheimer disease.
References:
Nicoll JA, Wilkinson D, Holmes C, Steart P, Markham H, Weller RO.
Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report.
Nat Med. 2003 Apr;9(4):448-52.
PubMed.
Wilcock DM, Rojiani A, Rosenthal A, Subbarao S, Freeman MJ, Gordon MN, Morgan D.
Passive immunotherapy against Abeta in aged APP-transgenic mice reverses cognitive deficits and depletes parenchymal amyloid deposits in spite of increased vascular amyloid and microhemorrhage.
J Neuroinflammation. 2004 Dec 8;1(1):24.
PubMed.
Carare RO, Bernardes-Silva M, Newman TA, Page AM, Nicoll JA, Perry VH, Weller RO.
Solutes, but not cells, drain from the brain parenchyma along basement membranes of capillaries and arteries: significance for cerebral amyloid angiopathy and neuroimmunology.
Neuropathol Appl Neurobiol. 2008 Apr;34(2):131-44. Epub 2008 Jan 16
PubMed.
Preston SD, Steart PV, Wilkinson A, Nicoll JA, Weller RO.
Capillary and arterial cerebral amyloid angiopathy in Alzheimer's disease: defining the perivascular route for the elimination of amyloid beta from the human brain.
Neuropathol Appl Neurobiol. 2003 Apr;29(2):106-17.
PubMed.
Weller RO, Subash M, Preston SD, Mazanti I, Carare RO.
Perivascular drainage of amyloid-beta peptides from the brain and its failure in cerebral amyloid angiopathy and Alzheimer's disease.
Brain Pathol. 2008 Apr;18(2):253-66.
PubMed.
Roher AE, Kuo YM, Esh C, Knebel C, Weiss N, Kalback W, Luehrs DC, Childress JL, Beach TG, Weller RO, Kokjohn TA.
Cortical and leptomeningeal cerebrovascular amyloid and white matter pathology in Alzheimer's disease.
Mol Med. 2003 Mar-Apr;9(3-4):112-22.
PubMed.
The manuscript by Schroeter et al. demonstrates that even in middle-aged mice, anti-Aβ immunotherapy can cause increased vascular leakage. Importantly, the Schroeter et al. report indicates that high dose antibody treatment can prevent the formation of new vascular deposits and clear the existing deposits when treatment is continued for six months. Critically, they demonstrate that low doses of antibodies do not appear to increase microhemorrhage, although both the highest and the intermediate antibody doses did reduce/prevent the vascular deposits. Unfortunately, it appears from figure 3 and the results mentioned in the text that only the highest antibody dose succeeded in clearing the parenchymal deposits, presumably the target of anti-amyloid therapy. Prior reports showed that older mice harboring significant parenchymal amyloid deposits developed microhemorrhage when treated with one of several different anti-Aβ antibodies (Pfeifer et al., 2002; Wilcock et al., 2004; Racke et al., 2005; Wilcock et al., 2006). In some, but not all instances this modest amount of vascular leakage was associated with increased vascular amyloid deposits.
James Nicoll has mentioned that in autopsy cases from the Phase 1 Elan-Wyeth vaccine trial, both increased vascular amyloid and microhemorrhage were found at one to two years after the vaccine treatment. In fact, these observations were used as evidence that active clearance was occurring in those regions (presentation at New York Academy of Sciences, 24 March 2008). However, two patients coming to autopsy four years or more after the treatments had no apparent hemorrhages and both vascular and parenchymal amyloid deposits were cleared.
A major question regards whether the clearance of pre-existing parenchymal Aβ deposits by immunotherapy will lead to increased vascular deposits and/or microhemorrhage, especially in older individuals where vessels are less compliant. The available data, including those of Shroeter et al., suggest that effective clearance of parenchymal deposits leads initially to localized vascular leakage around vessels, possibly associated with increased vascular amyloid, but ultimately all deposits can be cleared, and the evidence of prior hemorrhage gradually disappears. Shroeter et al. argue that one can titrate the antibody dose to achieve sufficiently slow rates of clearance that the increased vascular leakage does not occur. However, they still do not provide evidence for a dosage that effectively reduces the parenchymal deposits without resulting in microhemorrhage. It would also be of value to have examined shorter survival times to check for an increase in vascular deposits earlier in the therapy.
Given these data, it is commendable that the Elan-Wyeth bapineuzumab trial is using low doses of antibody with infrequent dosing (every 90 days). While they run the risk of insufficient antibody exposure for a therapeutic effect, they also diminish the likelihood of adverse events associated with development of hemorrhage. I believe everyone hopes immunotherapy can be made safe and successful. The procedures to achieve this goal are already underway.
References:
Pfeifer M, Boncristiano S, Bondolfi L, Stalder A, Deller T, Staufenbiel M, Mathews PM, Jucker M.
Cerebral hemorrhage after passive anti-Abeta immunotherapy.
Science. 2002 Nov 15;298(5597):1379.
PubMed.
Racke MM, Boone LI, Hepburn DL, Parsadainian M, Bryan MT, Ness DK, Piroozi KS, Jordan WH, Brown DD, Hoffman WP, Holtzman DM, Bales KR, Gitter BD, May PC, Paul SM, Demattos RB.
Exacerbation of cerebral amyloid angiopathy-associated microhemorrhage in amyloid precursor protein transgenic mice by immunotherapy is dependent on antibody recognition of deposited forms of amyloid beta.
J Neurosci. 2005 Jan 19;25(3):629-36.
PubMed.
Wilcock DM, Rojiani A, Rosenthal A, Subbarao S, Freeman MJ, Gordon MN, Morgan D.
Passive immunotherapy against Abeta in aged APP-transgenic mice reverses cognitive deficits and depletes parenchymal amyloid deposits in spite of increased vascular amyloid and microhemorrhage.
J Neuroinflammation. 2004 Dec 8;1(1):24.
PubMed.
Wilcock DM, Alamed J, Gottschall PE, Grimm J, Rosenthal A, Pons J, Ronan V, Symmonds K, Gordon MN, Morgan D.
Deglycosylated anti-amyloid-beta antibodies eliminate cognitive deficits and reduce parenchymal amyloid with minimal vascular consequences in aged amyloid precursor protein transgenic mice.
J Neurosci. 2006 May 17;26(20):5340-6.
PubMed.
Comments
University of Southampton School of Medicine
Prevention Rather Than Cure of CAA May Be the Best Way Forward
Increased severity of cerebral amyloid angiopathy (CAA) has been highlighted as a complication of immunotherapy for Alzheimer disease in both human subjects (1) and in transgenic mouse models (2). In their paper in The Journal of Neuroscience, Sally Schroeter et al. showed that passive immunization of 12-month-old PDAPP transgenic mice with the 3D6 antibody directed against the N-terminal of the Aβ molecule prevented deposition or cleared Aβ from artery walls in a dose-dependent manner. At the moment, however, it is not clear whether Aβ was eliminated from artery walls by macrophages, analogous to the removal of Aβ plaques from brain parenchyma by microglia (1), or by some other mechanism. Perivascular microhemorrhages were increased in animals treated with the higher dose of the antibody. Fewer hemorrhages were detected at lower doses of the 3D6 antibody, although clearance of Aβ was not as complete.
By treating the PDAPP transgenic mice with passive immunization at the relatively early age of 12 months, Schroeter and her colleagues have emphasized the importance of preventing the deposition of Aβ in vessel walls rather than removing it. CAA appears to have two major complications. One is the replacement of smooth muscle cells by Aβ that may result in intracerebral hemorrhage or may interfere with autoregulation of cerebral blood flow. The other complication is the blockage of pathways by which interstitial fluid and solutes drain from the brain. Basement membranes between vascular smooth muscle cells are the perivascular route by which interstitial fluid and solutes, such as Aβ, drain out of the brain (3). In the early stages of CAA, fibrils of insoluble Aβ are deposited within vascular basement membranes and disrupt the structure of the basement membranes involved (4,5). The effects of basement membrane disruption in CAA on the drainage of fluid and solutes from the brain has not been quantified, but it does seem to be associated with deposition of Aβ plaques in gray matter and with increased fluid retention in cerebral white matter (6). It is probable that the elimination of other brain metabolites, in addition to Aβ, is blocked in CAA, leading to a loss of homeostasis of the neuronal environment and possible neuronal malfunction. Thus, it could be vital for normal functioning of the brain to preserve the structure of vascular basement membranes by preventing the deposition of Aβ. In this way, the integrity of the drainage pathways for solutes and fluid from the brain would be maintained. Preserving vascular basement membranes is one reason why the approach of Schroeter et al. in preventing CAA could be so valuable in the management of Alzheimer disease.
References:
Nicoll JA, Wilkinson D, Holmes C, Steart P, Markham H, Weller RO. Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med. 2003 Apr;9(4):448-52. PubMed.
Wilcock DM, Rojiani A, Rosenthal A, Subbarao S, Freeman MJ, Gordon MN, Morgan D. Passive immunotherapy against Abeta in aged APP-transgenic mice reverses cognitive deficits and depletes parenchymal amyloid deposits in spite of increased vascular amyloid and microhemorrhage. J Neuroinflammation. 2004 Dec 8;1(1):24. PubMed.
Carare RO, Bernardes-Silva M, Newman TA, Page AM, Nicoll JA, Perry VH, Weller RO. Solutes, but not cells, drain from the brain parenchyma along basement membranes of capillaries and arteries: significance for cerebral amyloid angiopathy and neuroimmunology. Neuropathol Appl Neurobiol. 2008 Apr;34(2):131-44. Epub 2008 Jan 16 PubMed.
Preston SD, Steart PV, Wilkinson A, Nicoll JA, Weller RO. Capillary and arterial cerebral amyloid angiopathy in Alzheimer's disease: defining the perivascular route for the elimination of amyloid beta from the human brain. Neuropathol Appl Neurobiol. 2003 Apr;29(2):106-17. PubMed.
Weller RO, Subash M, Preston SD, Mazanti I, Carare RO. Perivascular drainage of amyloid-beta peptides from the brain and its failure in cerebral amyloid angiopathy and Alzheimer's disease. Brain Pathol. 2008 Apr;18(2):253-66. PubMed.
Roher AE, Kuo YM, Esh C, Knebel C, Weiss N, Kalback W, Luehrs DC, Childress JL, Beach TG, Weller RO, Kokjohn TA. Cortical and leptomeningeal cerebrovascular amyloid and white matter pathology in Alzheimer's disease. Mol Med. 2003 Mar-Apr;9(3-4):112-22. PubMed.
Michigan State University
The manuscript by Schroeter et al. demonstrates that even in middle-aged mice, anti-Aβ immunotherapy can cause increased vascular leakage. Importantly, the Schroeter et al. report indicates that high dose antibody treatment can prevent the formation of new vascular deposits and clear the existing deposits when treatment is continued for six months. Critically, they demonstrate that low doses of antibodies do not appear to increase microhemorrhage, although both the highest and the intermediate antibody doses did reduce/prevent the vascular deposits. Unfortunately, it appears from figure 3 and the results mentioned in the text that only the highest antibody dose succeeded in clearing the parenchymal deposits, presumably the target of anti-amyloid therapy. Prior reports showed that older mice harboring significant parenchymal amyloid deposits developed microhemorrhage when treated with one of several different anti-Aβ antibodies (Pfeifer et al., 2002; Wilcock et al., 2004; Racke et al., 2005; Wilcock et al., 2006). In some, but not all instances this modest amount of vascular leakage was associated with increased vascular amyloid deposits.
James Nicoll has mentioned that in autopsy cases from the Phase 1 Elan-Wyeth vaccine trial, both increased vascular amyloid and microhemorrhage were found at one to two years after the vaccine treatment. In fact, these observations were used as evidence that active clearance was occurring in those regions (presentation at New York Academy of Sciences, 24 March 2008). However, two patients coming to autopsy four years or more after the treatments had no apparent hemorrhages and both vascular and parenchymal amyloid deposits were cleared.
A major question regards whether the clearance of pre-existing parenchymal Aβ deposits by immunotherapy will lead to increased vascular deposits and/or microhemorrhage, especially in older individuals where vessels are less compliant. The available data, including those of Shroeter et al., suggest that effective clearance of parenchymal deposits leads initially to localized vascular leakage around vessels, possibly associated with increased vascular amyloid, but ultimately all deposits can be cleared, and the evidence of prior hemorrhage gradually disappears. Shroeter et al. argue that one can titrate the antibody dose to achieve sufficiently slow rates of clearance that the increased vascular leakage does not occur. However, they still do not provide evidence for a dosage that effectively reduces the parenchymal deposits without resulting in microhemorrhage. It would also be of value to have examined shorter survival times to check for an increase in vascular deposits earlier in the therapy.
Given these data, it is commendable that the Elan-Wyeth bapineuzumab trial is using low doses of antibody with infrequent dosing (every 90 days). While they run the risk of insufficient antibody exposure for a therapeutic effect, they also diminish the likelihood of adverse events associated with development of hemorrhage. I believe everyone hopes immunotherapy can be made safe and successful. The procedures to achieve this goal are already underway.
References:
Pfeifer M, Boncristiano S, Bondolfi L, Stalder A, Deller T, Staufenbiel M, Mathews PM, Jucker M. Cerebral hemorrhage after passive anti-Abeta immunotherapy. Science. 2002 Nov 15;298(5597):1379. PubMed.
Racke MM, Boone LI, Hepburn DL, Parsadainian M, Bryan MT, Ness DK, Piroozi KS, Jordan WH, Brown DD, Hoffman WP, Holtzman DM, Bales KR, Gitter BD, May PC, Paul SM, Demattos RB. Exacerbation of cerebral amyloid angiopathy-associated microhemorrhage in amyloid precursor protein transgenic mice by immunotherapy is dependent on antibody recognition of deposited forms of amyloid beta. J Neurosci. 2005 Jan 19;25(3):629-36. PubMed.
Wilcock DM, Rojiani A, Rosenthal A, Subbarao S, Freeman MJ, Gordon MN, Morgan D. Passive immunotherapy against Abeta in aged APP-transgenic mice reverses cognitive deficits and depletes parenchymal amyloid deposits in spite of increased vascular amyloid and microhemorrhage. J Neuroinflammation. 2004 Dec 8;1(1):24. PubMed.
Wilcock DM, Alamed J, Gottschall PE, Grimm J, Rosenthal A, Pons J, Ronan V, Symmonds K, Gordon MN, Morgan D. Deglycosylated anti-amyloid-beta antibodies eliminate cognitive deficits and reduce parenchymal amyloid with minimal vascular consequences in aged amyloid precursor protein transgenic mice. J Neurosci. 2006 May 17;26(20):5340-6. PubMed.
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