β‐Amyloid immunization approaches for Alzheimer's disease

Abstract

AbstractAlzheimer's disease (AD) represents the third leading cause of death in the U.S. and the leading cause of dementia in the elderly population. Until recently, there was little hope of efficiently combating this devastating disease. The deposition of β‐amyloid (Aβ) is the major pathological hallmark of AD brains. Genetic, biochemical, and pharmacological evidence support the hypothesis that Aβ plays a key role in the development of the disease. Thus, in the last 5 years a number of pharmacological strategies have been developed to interfere with the Aβ cascade. The most revolutionary of these approaches was proposed in 1999 by scientists at Elan Pharmaceuticals, which immunized against Aβ transgenic mice with spontaneously developing Aβ pathology. The immunization was achieved by subcutaneous injections of a preaggregated form of the synthetic human 42‐amino acid Aβ emulsified with Freund's adjuvant, an immune stimulant. The vaccination caused a near complete inhibition of Aβ plaque formation in younger animals and a marked reduction of the Aβ burden in older animals. The effects on Aβ plaques were accompanied by a reduction of Aβ‐associated astrogliosis and neuritic dystrophy. These results were later confirmed by other groups with similar vaccination protocols, which also demonstrated that the Aβ immunization of transgenic animals normalize or reduce the cognitive impairment associated with Aβ pathology. Interestingly, effective removal of brain Aβ plaques was also obtained by peripherally administering Aβ antibodies. The mechanism with which the vaccine increases Aβ clearance is not fully understood. Centrally, the vaccine appears to activate Aβ phagocytosis by microglial monocytes. Peripherally, serum Aβ antibodies bind and sequester Aβ, thus altering its equilibrium between CNS and plasma. The dramatic results obtained in animal models of AD raised unprecedented hopes for both a preventive and a curative intervention for this devastating disorder. A vaccine preparation for human use (AN‐1792) composed of preaggregated human Aβ42 peptide and a highly purified saponin derivative (QS‐21) was developed by Elan Pharmaceuticals and Wyeth Ayerst and tested in AD patients. Unfortunately, a Phase IIa study aimed at evaluating the safety and immunological activity of AN‐1792 in 360 AD patients was discontinued because 15 subjects receiving the vaccine developed serious signs of CNS inflammation. Both central activation of cytotoxic T cells and autoimmune reactions were proposed as potential mechanisms of toxicity. Other therapeutic Aβ vaccination strategies are being pursued, including immuno‐conjugates and monoclonal antibodies. The future of these and other Aβ immunization approaches depend on a clear understanding of the mechanism of Aβ clearance and additional insight into the role of inflammation in the AD brain. Drug Dev. Res. 56:150–162, 2002. © 2002 Wiley‐Liss, Inc.