Active and passive immunotherapy for neurodegenerative disorders

Abstract

Immunotherapeutic strategies to combat neurodegenerative disorders have galvanized the scientific community since the first dramatic successes in mouse models recreating aspects of Alzheimer disease (AD) were reported. However, initial human trials of active amyloid-beta (Abeta) vaccination were halted early because of a serious safety issue: meningoencephalitis in 6% of subjects. Nonetheless, some encouraging preliminary data were obtained, and rapid progress has been made toward developing alternative, possibly safer active and passive immunotherapeutic approaches for several neurodegenerative conditions. Many of these are currently in human trials for AD. Despite these advances, our understanding of the essential mechanisms underlying the effects seen in preclinical models and human subjects is still incomplete. Antibody-induced phagocytosis of pathological protein deposits, direct antibody-mediated disruption of aggregates, neutralization of toxic soluble proteins, a shift in equilibrium toward efflux of specific proteins from the brain, cell-mediated immune responses, and other mechanisms may all play roles depending on the specific immunotherapeutic scenario.

Figure 1

Effects of active vaccination in transgenic mice modeling aspects of Alzheimer disease. (a) Reduction in Aβ plaque deposition in the cortex of PDAPP mice following vaccination with aggregated Aβ_1–42 (right) compared with saline-injected mice (left) at the same age. Adapted from figure 4b,c of Schenk et al. (1999). (b) Improved behavioral performance in TgCRND8 mice following vaccination with aggregated Aβ_1–42 (red circles, right panel) compared with TgCRND8 mice vaccinated with the irrelevant islet-associated polypeptide (IAPP, red circles, left panel). Performance of similarly vaccinated nontransgenic mice (gray circles) was mostly unchanged. The figure shows latency to reach the hidden platform in the Morris water maze (Morris et al. 1984); each daily session consisted of four trials per mouse. Adapted from figure 2e of Janus et al. (2000). (c) Improved behavioral performance in Tg2576 mice following vaccination with aggregated Aβ_1–42 (purple triangles) compared with Tg2576 mice vaccinated with the irrelevant keyhole limpet hemocyanin (blue squares). Aβ-vaccinated Tg2576 mice performed nearly as well as nontransgenic mice (green circles). The figure shows number of errors in the radial arm water maze during working memory (trials 1–4) and retention (trial 5) testing on days 10 and 11 of training. Adapted from figure 1b of Morgan et al. (2000). Reprinted by permission of Macmillan Publishers Ltd.

Figure 2

Potential mechanisms underlying effects of immunotherapeutics in models of Alzheimer disease. These represent only a subset of the possibilities and are not meant to be considered mutually exclusive; more than one may be in operation at any given time or several may play important roles at different stages of therapy. (This figure was produced with the assistance of MedPIC at Washington University School of Medicine.) For further explanation, see Supplemental Material online.

Figure 3

Putting the timeline in perspective: immunotherapeutic strategies for neoplastic disorders.