Abstract
BackgroundAlzheimer's disease, a common dementia of the elder, is characterized by accumulation of protein amyloid deposits in the brain. Immunization to prevent this accumulation has been proposed as a therapeutic possibility, although adverse inflammatory reactions in human trials indicate the need for novel vaccination strategies.MethodHere vaccination with novel amyloid peptide immunogens was assessed in a transgenic mouse model displaying age-related accumulation of fibrillar plaques.ResultsImmunization with any conformation of the amyloid peptide initiated at 12 months of age (at which time fibrillar amyloid has just begun to accumulate) showed significant decrease in total and fibrillar amyloid deposits and in glial reactivity relative to control transgenic animals. In contrast, there was no significant decrease in amyloid deposition or glial activation in mice in which vaccination was initiated at 16 months of age, despite the presence of similar levels anti-Aβ antibodies in young and old animals vaccinated with a given immunogen. Interestingly, immunization with an oligomeric conformation of Aβ was equally as effective as other amyloid peptides at reducing plaque accumulation. However, the antibodies generated by immunization with the oligomeric conformation of Aβ have more limited epitope reactivity than those generated by fAβ, and the microglial response was significantly less robust.ConclusionThese results suggest that a more specific immunogen such as oligomeric Aβ can be designed that achieves the goal of depleting amyloid while reducing potential detrimental inflammatory reactions. In addition, the data show that active immunization of older Tg2576 mice with any amyloid conformation is not as efficient at reducing amyloid accumulation and related pathology as immunization of younger mice, and that serum anti-amyloid antibody levels are not quantitatively related to reduced amyloid-associated pathology.
Highlights
Alzheimer's disease, a common dementia of the elder, is characterized by accumulation of protein amyloid deposits in the brain
Several reports have shown that when mice containing the transgene for human mutant amyloid precursor protein (APP) were immunized with fibrillar Aβ 1– conjugated to colloidal gold (Aβ) peptide prior to the accumulation of amyloid deposits, Aβ deposition observed at later ages was greatly decreased [36]
Immunization initiated at 12 months of age with any Aβ conformation decreased both total and fibrillar Aβ immunostaining in Tg2576 mice In Alzheimer's disease (AD) significant cognitive decline is generally correlated with the appearance of "mature" amyloid plaques [26,30]
Summary
Alzheimer's disease, a common dementia of the elder, is characterized by accumulation of protein amyloid deposits in the brain. When applied to humans, "immunization" with Aβ resulted in the development of an adverse inflammatory reaction in a fraction of the patients [7,8,9], which led to a reevaluation of this strategy for AD in humans, at that stage of the disease when substantial fibrillar amyloid deposits have begun to accumulate [10]. It is this stage of the disease that often correlates with appearance of cognitive deficiencies that is a defined point at which potential therapy may be initiated
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