Anti-amyloid-beta immunotherapy in Alzheimer's disease: relevance of transgenic mouse studies to clinical trials

Abstract

Therapeutic approaches to the treatment of Alzheimer's disease are focused primarily on the amyloid-beta peptide which aggregates to form amyloid deposits in the brain. The amyloid hypothesis states that amyloid is the precipitating factor that results in the other pathologies of Alzheimer's disease. One such therapy that has attracted significant attention is anti-amyloid-beta immunotherapy. First described in 1999, immunotherapy uses anti-amyloid-beta antibodies to lower brain amyloid levels. Active and passive immunization were shown to lower brain amyloid levels and improve cognition in multiple transgenic mouse models. Mechanisms of action were studied in these mice and revealed a complex set of mechanisms that depended on the type of antibody used. When active immunization advanced to clinical trials a subset of patients developed meningoencephalitis, an event not predicted in mouse studies. It was suspected that a T-cell response due to the type of adjuvant used was the cause. Passive immunization has also advanced to Phase III clinical trials on the basis of successful transgenic mouse studies. Reports from the active immunization clinical trial indicated that, similarly to effects observed in mouse studies, amyloid levels in brain were reduced.

Figure 1

The two types of immunotherapy for Alzheimer's disease. Panel A depicts active immunization. Fibrillar Aß1−42 is combined with an adjuvant by emulsification. This mixture is then injected into the mouse. The mouse produces anti-Aß antibodies in response to the vaccination. Panel B depicts passive immunization. In this case, mice are immunized with Aß as with active immunization. Hybridomas are then produced and selected for the correct antibody. This antibody is then harvested, purified and administered to another mouse for treatment.

Figure 2

The three major proposed mechanisms of action for immunotherapy in amyloid reduction. Panel A shows the mechanism of microglial phagocytosis. In this case, amyloid fibers (shown in blue) are opsonized by antibodies (shown in green) entering the brain from the bloodstream. Microglia then recognize the opsonized Aß and phagocytose the amyloid via the Fcγ receptor. Panel B shows the mechanism of catalytic disaggregation. In this case amyloid fibers are bound by antibodies which then disrupt the tertiary structure of the amyloid deposit. This results in solublization of the Aß and efflux out of the brain. Panel C shows the peripheral sink mechanism. In this case monomeric soluble Aß circulating in the bloodstream is bound by the circulating antibodies. This sequestration of circulating Aß produces a shift in the concentration gradient of Aß between the brain and the blood causing an efflux of Aß out of the brain.