Anti-amyloid-beta immunotherapy in Alzheimer's disease: relevance of transgenic mouse studies to clinical trials.
Therapeutic approaches to the treatment of Alzheimer's disease are focused primarily on the amyloid-beta peptide which aggregates to form amyloid deposits in the brain. The amyloid hypothesis states that amyloid is the precipitating factor that results in the other pathologies of Alzheimer's disease. One such therapy that has attracted significant attention is anti-amyloid-beta immunotherapy. First described in 1999, immunotherapy uses anti-amyloid-beta antibodies to lower brain amyloid levels. Active and passive immunization were shown to lower brain amyloid levels and improve cognition in multiple transgenic mouse models. Mechanisms of action were studied in these mice and revealed a complex set of mechanisms that depended on the type of antibody used. When active immunization advanced to clinical trials a subset of patients developed meningoencephalitis, an event not predicted in mouse studies. It was suspected that a T-cell response due to the type of adjuvant used was the cause. Passive immunization has also advanced to Phase III clinical trials on the basis of successful transgenic mouse studies. Reports from the active immunization clinical trial indicated that, similarly to effects observed in mouse studies, amyloid levels in brain were reduced.
Wilcock
Donna M
DM
Duke University Medical Center, Department of Medicine Division of Neurology, Durham, NC 27710, USA. donna.wilcock@duke.edu
Colton
Carol A
CA
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics; D023582:Alzheimer Vaccines / Q000627:therapeutic use; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000276:immunology*; D000818:Animals; D019138:Antibodies, Blocking / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D006801:Humans; D007114:Immunization; D007167:Immunotherapy; D051379:Mice; D008822:Mice, Transgenic
D023582:Alzheimer Vaccines; D016229:Amyloid beta-Peptides; D019138:Antibodies, Blocking