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Vaccination of Alzheimer's model mice with A? derivative in alum adjuvant reduces A? burden without microhemorrhages

Vaccination of Alzheimer's model mice with A? derivative in alum adjuvant reduces A? burden without microhemorrhages
Vaccination of Alzheimer's model mice with A? derivative in alum adjuvant reduces A? burden without microhemorrhages
Immunotherapy holds great promise for Alzheimer's disease (AD) and other conformational disorders but certain adverse reactions need to be overcome. The meningoencephalitis observed in the first AD vaccination trial was likely related to excessive cell-mediated immunity caused by the immunogen, amyloid-? (A?) 1–42, and the adjuvant, QS?21. To avoid this toxicity, we have been using A? derivatives in alum adjuvant that promotes humoral immunity. Other potential side effects of immunotherapy are increased vascular amyloid and associated microhemorrhages that may be related to rapid clearance of parenchymal amyloid. Here, we determined if our immunization strategy was associated with this form of toxicity, and if the therapeutic effect was age-dependent. Tg2576 mice and wild-type littermates were immunized from 11 or 19 months and their behaviour evaluated prior to killing at 24 months. Subsequently, plaque- and vascular-A? burden, A? levels and associated pathology was assessed. The therapy started at the cusp of amyloidosis reduced cortical A? deposit burden by 31% and A? levels by 30–37%, which was associated with cognitive improvements. In contrast, treatment from 19 months, when pathology is well established, was not immunogenic and therefore did not reduce A? burden or improve cognition. Significantly, the immunotherapy in the 11–24 months treatment group, that reduced A? burden, did not increase cerebral bleeding or vascular A? deposits in contrast to several A? antibody studies. These findings indicate that our approach age-dependently improves cognition and reduces A? burden when used with an adjuvant suitable for humans, without increasing vascular A? deposits or microhemorrhages.
amyloid-?, bleeding, cognition, immunotherapy, microglia
0953-816X
2530-2542
Asuni, Ayodeji A.
b1412b1b-9794-4705-aada-aed5d3da038f
Boutajangout, Allal
4cf05670-651d-413c-a299-175d62186a21
Scholtzova, Henrieta
8a84ac14-35ec-4efc-9557-24b526cc0651
Knudsen, Elin
0fb87703-707f-4939-8c65-5b3073a3e8ba
Li, Yong Sheng
4ce6b61d-f143-48a1-9541-929308bbdbcd
Quartermain, David
b86503e8-f88e-4869-b9bc-971afe498ff9
Frangione, Blas
361865d7-4f64-4112-b269-52932d45d376
Wisniewski, Thomas
2b01413e-928d-4c40-9a02-0c87d90942d0
Sigurdsson, Einar M.
ef6db59b-0d48-4ff6-bf8c-60c067230430
Asuni, Ayodeji A.
b1412b1b-9794-4705-aada-aed5d3da038f
Boutajangout, Allal
4cf05670-651d-413c-a299-175d62186a21
Scholtzova, Henrieta
8a84ac14-35ec-4efc-9557-24b526cc0651
Knudsen, Elin
0fb87703-707f-4939-8c65-5b3073a3e8ba
Li, Yong Sheng
4ce6b61d-f143-48a1-9541-929308bbdbcd
Quartermain, David
b86503e8-f88e-4869-b9bc-971afe498ff9
Frangione, Blas
361865d7-4f64-4112-b269-52932d45d376
Wisniewski, Thomas
2b01413e-928d-4c40-9a02-0c87d90942d0
Sigurdsson, Einar M.
ef6db59b-0d48-4ff6-bf8c-60c067230430

Asuni, Ayodeji A., Boutajangout, Allal, Scholtzova, Henrieta, Knudsen, Elin, Li, Yong Sheng, Quartermain, David, Frangione, Blas, Wisniewski, Thomas and Sigurdsson, Einar M. (2006) Vaccination of Alzheimer's model mice with A? derivative in alum adjuvant reduces A? burden without microhemorrhages. European Journal of Neuroscience, 24 (9), 2530-2542. (doi:10.1111/j.1460-9568.2006.05149.x).

Record type: Article

Abstract

Immunotherapy holds great promise for Alzheimer's disease (AD) and other conformational disorders but certain adverse reactions need to be overcome. The meningoencephalitis observed in the first AD vaccination trial was likely related to excessive cell-mediated immunity caused by the immunogen, amyloid-? (A?) 1–42, and the adjuvant, QS?21. To avoid this toxicity, we have been using A? derivatives in alum adjuvant that promotes humoral immunity. Other potential side effects of immunotherapy are increased vascular amyloid and associated microhemorrhages that may be related to rapid clearance of parenchymal amyloid. Here, we determined if our immunization strategy was associated with this form of toxicity, and if the therapeutic effect was age-dependent. Tg2576 mice and wild-type littermates were immunized from 11 or 19 months and their behaviour evaluated prior to killing at 24 months. Subsequently, plaque- and vascular-A? burden, A? levels and associated pathology was assessed. The therapy started at the cusp of amyloidosis reduced cortical A? deposit burden by 31% and A? levels by 30–37%, which was associated with cognitive improvements. In contrast, treatment from 19 months, when pathology is well established, was not immunogenic and therefore did not reduce A? burden or improve cognition. Significantly, the immunotherapy in the 11–24 months treatment group, that reduced A? burden, did not increase cerebral bleeding or vascular A? deposits in contrast to several A? antibody studies. These findings indicate that our approach age-dependently improves cognition and reduces A? burden when used with an adjuvant suitable for humans, without increasing vascular A? deposits or microhemorrhages.

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More information

Published date: November 2006
Keywords: amyloid-?, bleeding, cognition, immunotherapy, microglia
Organisations: Centre for Biological Sciences

Identifiers

Local EPrints ID: 345521
URI: http://eprints.soton.ac.uk/id/eprint/345521
ISSN: 0953-816X
PURE UUID: 3cc54ed0-88d8-4655-8ea7-dcfe130807f3

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Date deposited: 12 Feb 2013 15:25
Last modified: 16 Jul 2019 21:49

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Contributors

Author: Ayodeji A. Asuni
Author: Allal Boutajangout
Author: Henrieta Scholtzova
Author: Elin Knudsen
Author: Yong Sheng Li
Author: David Quartermain
Author: Blas Frangione
Author: Thomas Wisniewski
Author: Einar M. Sigurdsson

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