Abeta immunization and anti-Abeta antibodies: potential therapies for the prevention and treatment of Alzheimer's disease.
Amyloid-beta (Abeta) is a normally soluble 39-43 amino peptide. Genetic and biochemical data strongly suggest that the conversion of Abeta from soluble to insoluble forms with high beta-sheet content and its buildup in the brain is a key step in the pathogenesis of Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA). Prevention and/or reversal of this process may serve as a treatment. Methods to prevent or reverse Abeta deposition and its toxic effects would include decreasing its production, preventing its conversion to insoluble forms (e.g. inhibit beta-sheet formation) or in changing the dynamics of extracellular brain Abeta, either locally within the brain or by altering net flux of Abeta between the central nervous system (CNS) and plasma compartment. Transgenic mouse models of AD that develop age-dependent Abeta deposition, damage to the neuropil, and behavioral deficits have enabled researchers to test whether different manipulations can influence these AD-like changes. Recently, active immunization with different forms of the Abeta peptide has been shown to decrease brain Abeta deposition and improve cognitive performance in mouse models of AD. Certain peripherally administered anti-Abeta antibodies have similar effects. The mechanism(s) by which anti-Abeta antibodies result in these effects is just beginning to be elucidated. Abeta-related immune therapies in humans are an exciting new area of AD research. Understanding their detailed mechanism(s) of action and their potential usefulness awaits the results of future animal and human studies.
Holtzman
David M
DM
Center for the Study of Nervous System Injury, Washington University School of Medicine, St Louis, MO 63110, USA. holtzman@neuro.wustl.edu
Bales
Kelly R
KR
Paul
Steven M
SM
DeMattos
Ronald B
RB
D000544:Alzheimer Disease / Q000276:immunology* / Q000517:prevention & control / Q000628:therapy*; D016229:Amyloid beta-Peptides / Q000276:immunology*; D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000627:therapeutic use*; D006801:Humans; D007116:Immunization, Passive / Q000379:methods*; D051379:Mice; D008822:Mice, Transgenic; D014611:Vaccination / Q000379:methods*
D016229:Amyloid beta-Peptides; D000906:Antibodies