Novel therapeutic approach for the treatment of Alzheimer's disease by peripheral administration of agents with an affinity to beta-amyloid

Abstract

Plaques containing beta-amyloid (Abeta) peptides are one of the pathological features of Alzheimer's disease, and the reduction of Abeta is considered a primary therapeutic target. Amyloid clearance by anti-Abeta antibodies has been reported after immunization, and recent data have shown that the antibodies may act as a peripheral sink for Abeta, thus altering the periphery/brain dynamics. Here we show that peripheral treatment with an agent that has high affinity for Abeta (gelsolin or GM1) but that is unrelated to an antibody or immune modulator reduced the level of Abeta in the brain, most likely because of a peripherally acting effect. We propose that in general, compounds that sequester plasma Abeta could reduce or prevent brain amyloidosis, which would enable the development of new therapeutic agents that are not limited by the need to penetrate the brain or evoke an immune response.

Fig. 1.

Effect of gelsolin (●, G) or vehicle (○, V) administration on brain (A–C) and plasma (D) Aβ levels. Brain Aβ load was examined by ELISA (A) and Aβ histochemistry. Typical Aβ immunostaining in mice treated with vehicle (B) and gelsolin (C) is shown. Scale bar, 1 mm. Values represent the mean ± SEM.

Fig. 2.

Effect of GM1 (●) or vehicle (○,V) administration on brain (A) and plasma (B) Aβ levels determined by ELISA. The level of GM1 in the plasma (C) was measured after a single administration of drug, over a 24 hr period. GM1 levels were also compared in the blood cell fraction (D) of vehicle-treated and GM1-treated mice 2 weeks after treatment initiation and after a 1 week washout period. The upper, augmented band runs concurrent with administered bovine GM1. Values represent the mean ± SEM.