Journal
NEUROBIOLOGY OF DISEASE
Volume 29, Issue 2, Pages 336-353Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2007.09.009
Keywords
Alzheimer's disease; beta-amyloid; cerebral amyloid angiopathy; A beta immunization; CD40; CD154; CD40 ligand; CD40L; inflammation; microglia
Categories
Funding
- NIA NIH HHS [R01 AG032432, K99 AG029726, 1 K99AG029726-01, AG04418, P01 AG004418] Funding Source: Medline
- NINDS NIH HHS [R01 NS048335-04, R01 NS048335-01A1, R01 NS048335-03, R01 NS048335-02S1, R01 NS048335, R01 NS048335-02] Funding Source: Medline
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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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