Immune hyporesponsiveness to amyloid β-peptide in amyloid precursor protein transgenic mice:: Implications for the pathogenesis and treatment of Alzheimer's disease

Alzheimer's disease is a dementia that involves progressive deposition of amyloid beta -protein (A beta) in brain regions important for memory and cognition, followed by secondary inflammation that contributes to the neuropathologic process. Immunization with A beta can reduce cerebral A beta burden and consequent neuropathologic changes in the brains of mice transgenic for the beta -amyloid precursor protein (APP). We found that transgenic expression of human APP in B6SJL mice, under the prion promoter, results in immune hyporesponsiveness to human A beta, in terms of both antibody and cellular immune responses. The decreased antibody responses were related not to B cell tolerance but rather to the inability of A beta -specific T cells to provide help for antibody production. The immune hyporesponsiveness could be overcome if T cell help was provided by coupling an A beta B cell epitope to BSA. Our results suggest that expression of APP in transgenic mice is associated with an A beta -specific impaired adaptive immune response that may contribute to the neuropathology. Moreover, humans with lifelong elevation of brain and peripheral A beta (e.g., patients with presenilin mutations or Down syndrome) could have reduced immune responses to A beta vaccination.