Bibliographic
Amyloid-β (Aβ) immunization efficiently reduces amyloid plaque load and memory impairment in transgenic mouse models of Alzheimer’s disease (AD) (Schenk et al., 1999; Morgan et al., 2000). Active Aβ immunization has also yielded favorable results in a subset of AD patients (Hock et al., 2003). However, a small percentage of patients developed severe aseptic meningoencephalitis associated with brain inflammation and infiltration of T-cells (Nicoll et al., 2003; Orgogozo et al., 2003). We and others have shown that blocking the CD40-CD40 ligand (L) interaction mitigates Aβ-induced inflammatory responses and enhances Aβ clearance (Tan et al., 2002b; Townsend et al., 2005). Here, we utilized genetic and pharmacologic approaches to test whether CD40-CD40L blockade could enhance the efficacy of Aβ1–42 immunization, while limiting potentially damaging inflammatory responses. We show that genetic or pharmacologic interruption of CD40-CD40L interaction enhanced Aβ1–42 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 while precluding generation of neurotoxic Aβ-reactive T-cells. Thus, combined approaches of Aβ immunotherapy and CD40-CD40L blockade may provide for safer and more effective Aβ vaccine.