CD40L disruption enhances Aβ vaccine-mediated reduction of cerebral amyloidosis while minimizing cerebral amyloid angiopathy and inflammation

NEUROBIOLOGY OF DISEASE

卷:29

Article

Obregon, D.¹  Hou, H.¹  Bai, Y.¹  Nikolic, W. V.¹  Mori, T.^1,2  Luo, Deyan¹  Zeng, J.¹  Ehrhart, J.¹  Fernandez, F.¹  Morgan, D.³  Giunta, B.¹  Town, T.¹  Tan, J.^1,2,3 

[1] Univ S Florida, Dept Psychiat & Behav Sci, Neuroimmunol Lab, Tampa, FL 33613 USA

[2] Saitama Med Sch, Inst Med Sci, Kawagoe, Saitama 3508550, Japan

[3] Univ S Florida, Dept Mol Pharmacol & Physiol, Tampa, FL 33613 USA

关键词: Alzheimer's disease;    beta-amyloid;    cerebral amyloid angiopathy;    A beta immunization;    CD40;    CD154;    CD40 ligand;    CD40L;    inflammation;    microglia;   

DOI  :  10.1016/j.nbd.2007.09.009

来源: Elsevier

【 摘 要 】

Amyloid-beta (A beta) immunization efficiently reduces amyloid plaque load and memory impairment in transgenic mouse models of Alzheimer's disease (AD). Active A beta immunization has also yielded favorable results in a subset of AD patients. However, a small percentage of patients developed severe aseptic meningoencephalitis associated with brain inflammation and infiltration of T-cells. We have shown that blocking the CD40-CD40 ligand (L) interaction mitigates A beta-induced inflammatory responses and enhances A beta clearance. Here, we utilized genetic and pharmacologic approaches to test whether CD40-CD40L blockade could enhance the efficacy of A beta(1-42) immunization, while limiting potentially damaging inflammatory responses. We show that genetic or pharmacologic interruption of the CD40-CD40L interaction enhanced A beta(1-42) immunization efficacy to reduce cerebral amyloidosis in the PSAPP and Tg2576 mouse models of AD. Potentially deleterious pro-inflammatory immune responses, cerebral amyloid angiopathy (CAA) and cerebral microhemorrhage were reduced or absent in these combined approaches. Pharmacologic blockade of CD40L decreased T-cell neurotoxicity to A beta-producing neurons. Further reduction of cerebral amyloidosis in A beta-immunized PSAPP mice completely deficient for CD40 occurred in the absence of A beta immunoglobulin G (IgG) antibodies or efflux of A beta from brain to blood, but was rather correlated with anti-inflammatory cytokine profiles and reduced plasma soluble CD40L. These results suggest CD40-CD40L blockade promotes anti-inflammatory cellular immune responses, likely resulting in promotion of microglial phagocytic activity and A beta clearance without generation of neurotoxic A beta-reactive T-cells. Thus, combined approaches of A beta immunotherapy and CD40-CD40L blockade may provide for a safer and more effective A beta vaccine. (C) 2007 Elsevier Inc. All rights reserved.

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