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Consequence of Abeta immunization on the vasculature of human Alzheimer's disease brain

Consequence of Abeta immunization on the vasculature of human Alzheimer's disease brain
Consequence of Abeta immunization on the vasculature of human Alzheimer's disease brain
A major feature of Alzheimer's disease is the accumulation of amyloid-beta peptide (Abeta) in the brain both in the form of plaques in the cerebral cortex and in blood vessel as cerebral amyloid angiopathy (CAA). Experimental models and human clinical trials have shown that accumulation of Abeta plaques can be reversed by immunotherapy. In this study, we hypothesized that Abeta in plaques is solubilized by antibodies generated by immunization and drains via the perivascular pathway, detectable as an increase in cerebrovascular Abeta. We have performed a follow up study of Alzheimer's disease patients immunized against Abeta42. Neuropathological examination was performed on nine patients who died between four months and five years after their first immunization. Immunostaining for Abeta40 and Abeta42 was quantified and compared with that in unimmunized Alzheimer's disease controls (n = 11). Overall, compared with these controls, the group of immunized patients had approximately 14 times as many blood vessels containing Abeta42 in the cerebral cortex (P<0.001) and seven times more in the leptomeninges (P = 0.013); among the affected blood vessels in the immunized cases, most of them had full thickness and full circumference involvement of the vessel wall in the cortex (P = 0.001), and in the leptomeninges (P = 0.015). There was also a significantly higher level of cerebrovascular Abeta40 in the immunized cases than in the unimmunized cases (cortex: P = 0.009 and leptomeninges: P = 0.002). In addition, the immunized patients showed a higher density of cortical microhaemorrhages and microvascular lesions than the unimmunized controls, though none had major CAA-related intracerebral haemorrhages. The changes in cerebral vascular Abeta load did not appear to substantially influence the structural proteins of the blood vessels. Unlike most of the immunized patients, two of the longest survivors, four to five years after first immunization, had virtually complete absence of both plaques and CAA, raising the possibility that, given time, Abeta is eventually cleared from the cerebral vasculature. The findings are consistent with the hypothesis that Abeta immunization results in solubilization of plaque Abeta42 which, at least in part, exits the brain via the perivascular pathway, causing a transient increase in the severity of CAA. The extent to which these vascular alterations following Abeta immunization in Alzheimer's disease are reflected in changes in cognitive function remains to be determined
alzheimer’s disease, cerebral amyloid angiopathy, immunotherapy, vasculature
0006-8950
3299-3310
Boche, D.
bdcca10e-6302-4dd0-919f-67218f7e0d61
Zotova, E.
3558dd45-67a7-4e7a-b2ef-a9155ca784e8
Weller, R.O.
4a501831-e38a-4d39-a125-d7141d6c667b
Love, S.
de3ec24d-be42-4ca4-967d-b05436b6adc9
Neal, J.W.
e10f04af-1a50-4aab-a29d-69a5adcaf423
Pickering, R.M.
4a828314-7ddf-4f96-abed-3407017d4c90
Wilkinson, D.
917ddca3-1dba-4e3c-8618-4db1f8b11800
Holmes, C.
ada5abf3-8459-4cf7-be40-3f4e9391cc96
Nicoll, J.A.R.
88c0685f-000e-4eb7-8f72-f36b4985e8ed
Boche, D.
bdcca10e-6302-4dd0-919f-67218f7e0d61
Zotova, E.
3558dd45-67a7-4e7a-b2ef-a9155ca784e8
Weller, R.O.
4a501831-e38a-4d39-a125-d7141d6c667b
Love, S.
de3ec24d-be42-4ca4-967d-b05436b6adc9
Neal, J.W.
e10f04af-1a50-4aab-a29d-69a5adcaf423
Pickering, R.M.
4a828314-7ddf-4f96-abed-3407017d4c90
Wilkinson, D.
917ddca3-1dba-4e3c-8618-4db1f8b11800
Holmes, C.
ada5abf3-8459-4cf7-be40-3f4e9391cc96
Nicoll, J.A.R.
88c0685f-000e-4eb7-8f72-f36b4985e8ed

Boche, D., Zotova, E., Weller, R.O., Love, S., Neal, J.W., Pickering, R.M., Wilkinson, D., Holmes, C. and Nicoll, J.A.R. (2008) Consequence of Abeta immunization on the vasculature of human Alzheimer's disease brain. Brain, 131 (12), 3299-3310. (doi:10.1093/brain/awn261). (PMID:18953056)

Record type: Article

Abstract

A major feature of Alzheimer's disease is the accumulation of amyloid-beta peptide (Abeta) in the brain both in the form of plaques in the cerebral cortex and in blood vessel as cerebral amyloid angiopathy (CAA). Experimental models and human clinical trials have shown that accumulation of Abeta plaques can be reversed by immunotherapy. In this study, we hypothesized that Abeta in plaques is solubilized by antibodies generated by immunization and drains via the perivascular pathway, detectable as an increase in cerebrovascular Abeta. We have performed a follow up study of Alzheimer's disease patients immunized against Abeta42. Neuropathological examination was performed on nine patients who died between four months and five years after their first immunization. Immunostaining for Abeta40 and Abeta42 was quantified and compared with that in unimmunized Alzheimer's disease controls (n = 11). Overall, compared with these controls, the group of immunized patients had approximately 14 times as many blood vessels containing Abeta42 in the cerebral cortex (P<0.001) and seven times more in the leptomeninges (P = 0.013); among the affected blood vessels in the immunized cases, most of them had full thickness and full circumference involvement of the vessel wall in the cortex (P = 0.001), and in the leptomeninges (P = 0.015). There was also a significantly higher level of cerebrovascular Abeta40 in the immunized cases than in the unimmunized cases (cortex: P = 0.009 and leptomeninges: P = 0.002). In addition, the immunized patients showed a higher density of cortical microhaemorrhages and microvascular lesions than the unimmunized controls, though none had major CAA-related intracerebral haemorrhages. The changes in cerebral vascular Abeta load did not appear to substantially influence the structural proteins of the blood vessels. Unlike most of the immunized patients, two of the longest survivors, four to five years after first immunization, had virtually complete absence of both plaques and CAA, raising the possibility that, given time, Abeta is eventually cleared from the cerebral vasculature. The findings are consistent with the hypothesis that Abeta immunization results in solubilization of plaque Abeta42 which, at least in part, exits the brain via the perivascular pathway, causing a transient increase in the severity of CAA. The extent to which these vascular alterations following Abeta immunization in Alzheimer's disease are reflected in changes in cognitive function remains to be determined

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e-pub ahead of print date: 25 October 2008
Published date: December 2008
Keywords: alzheimer’s disease, cerebral amyloid angiopathy, immunotherapy, vasculature
Organisations: Medicine

Identifiers

Local EPrints ID: 69975
URI: https://eprints.soton.ac.uk/id/eprint/69975
ISSN: 0006-8950
PURE UUID: e1b6e6ef-bcd3-49b2-913a-c897918ff9c8
ORCID for D. Boche: ORCID iD orcid.org/0000-0002-5884-130X
ORCID for C. Holmes: ORCID iD orcid.org/0000-0003-1999-6912
ORCID for J.A.R. Nicoll: ORCID iD orcid.org/0000-0002-9444-7246

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Date deposited: 13 Jan 2010
Last modified: 20 Feb 2019 01:36

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