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

Abstract

Amyloid-β (Aβ) immunization efficiently reduces amyloid plaque load and memory impairment in transgenic mouse models of Alzheimer's disease (AD). Active Aβ 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 Aβ-induced inflammatory responses and enhances Aβ clearance. Here, we utilized genetic and pharmacologic approaches to test whether CD40–CD40L blockade could enhance the efficacy of Aβ 1–42 immunization, while limiting potentially damaging inflammatory responses. We show that genetic or pharmacologic interruption of the CD40–CD40L interaction enhanced Aβ 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 Aβ-producing neurons. Further reduction of cerebral amyloidosis in Aβ-immunized PSAPP mice completely deficient for CD40 occurred in the absence of Aβ immunoglobulin G (IgG) antibodies or efflux of Aβ 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 Aβ clearance without generation of neurotoxic Aβ-reactive T-cells. Thus, combined approaches of Aβ immunotherapy and CD40–CD40L blockade may provide for a safer and more effective Aβ vaccine.