Immunotherapeutic strategies for prevention and treatment of Alzheimer's disease

Pathologic examination in Alzheimer's disease (AD) shows a significant correlation between β-amyloid peptide (AβP) deposition and the clinical severity of dementia. Formation of β-amyloid (Aβ) is a complex kinetic and thermodynamic process, dependent on peptide-peptide interactions that may be modulated by other proteins. We found that site-directed antibodies toward peptide EFRH sequences 3-6 of the N-terminal region of AβP suppress in vitro formation of Aβ and dissolve already-formed fibrillar amyloid. These so-called chaperone-like properties of monoclonal antibodies led to the development of a new immunologic approach to AD treatment. The immunization procedure, based on phages displaying the EFRH epitope as antigen, induced anti-AβP antibodies that recognized the whole AβP and exhibited antiaggregating properties similar to those of antibodies obtained by injection of Aβ fibrils. Production and performance of anti-β-amyloid antibodies in the transgenic mouse model of AD showed that these antibodies may be delivered from the periphery to the central nervous system, preventing the formation of Aβ and dissolving already-present aggregates. Moreover, immunization with Aβ protected transgenic mice from the learning and age-related memory deficits that occur in AD. These data support the hypotheses that Aβ plays a central role in AD and that site-directed antibodies that modulate Aβ conformation may provide immunotherapy of the disease.