Amyloid-beta immunotherapy for Alzheimer's disease

Abstract

Alzheimer's disease (AD) is a progressive, degenerative disorder of the brain and the most common form of dementia among the elderly. As the population grows and lifespan is extended, the number of AD patients will continue to rise. Current clinical therapies for AD provide partial symptomatic benefits for some patients; however, none of them modify disease progression. Amyloid-beta (Abeta) peptide, the major component of senile plaques in AD patients, is considered to play a crucial role in the pathogenesis of AD thereby leading to Abeta as a target for treatment. Abeta immunotherapy has been shown to induce a marked reduction in amyloid burden and an improvement in cognitive function in animal models. Although preclinical studies were successful, the initial human clinical trial of an active Abeta vaccine was halted due to the development of meningoencephalitis in approximately 6% of the vaccinated AD patients. Some encouraging outcomes, including signs of cognitive stabilization and apparent plaque clearance, were obtained in subset of patients who generated antibody titers. These promising preliminary data support further efforts to refine Abeta immunotherapy to produce highly effective and safer active and passive vaccines for AD. Furthermore, some new human clinical trials for both active and passive Abeta immunotherapy are underway. In this review, we will provide an update of Abeta immunotherapy in animal models and in human beings, as well as discuss the possible mechanisms underlying Abeta immunotherapy for AD.

Fig (1). Immunization with full-length Aβ dramatically reduced cerebral Aβ plaque burden in J20 hAPP transgenic mice, a mouse model of Alzheimer's disease

In this study, 1 mo-old mice were primed by giving an intraperitoneal injection of 100 μg Aβ_1–40/42 synthetic peptide plus 50 μg Complete Freund's adjuvant. The mice were then boosted weekly by intranasal application of 100 μg Aβ_1–40/42 plus 5 μg adjuvant LT(R192G) for a total of 11 months and euthanized at 12 months, an age in which these mice typically accumulate many plaques in cortex and hippocampus (left panel). Immunohistochemical analysis with an Aβ-specific polyclonal antibody, R1282 (gift of Dennis Selkoe, CND, Boston, MA), revealed a significant reduction in plaque burden in cortex and hippocampus (shown in right panel). Scale bar: 100 μm. [Reprinted with permission from Lemere, C.A., Maier, M., Jiang, L., Peng, Y., Seabrook, T.J. Amyloid-beta immunotherapy for the prevention and treatment of Alzheimer's disease: Lessons from mice, monkeys and men. Rejuvenation Research 9:77–84, 2006.]

Fig (2). Potential mechanisms underlying Aβ immunotherapy in AD models

Antibody-mediated microglial FcR-dependent and FcR-independent clearance of plaques by phagocytosis; antibody-mediated direct disassembly of plaques; prevention of Aβ aggregation and neutralization of oligomer toxicity; peripheral sink effect by clearance of circulating Aβ; intracerebral sequestration of Aβ in a monomeric state; hydrolysis of Aβ by IgM; and antibody-independent, cell mediated plaque clearance have all proposed to play roles in the removal of Aβ from the brain by Aβ immunotherapy in AD models. These potential mechanisms may act concomitantly or sequentially and play independent roles depending on the stage of AD pathogenesis and type of antibody, as well as the specific animal model used.