Immune hyporesponsiveness to amyloid beta-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 (Abeta) in brain regions important for memory and cognition, followed by secondary inflammation that contributes to the neuropathologic process. Immunization with Abeta can reduce cerebral Abeta 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 Abeta, 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 Abeta-specific T cells to provide help for antibody production. The immune hyporesponsiveness could be overcome if T cell help was provided by coupling an Abeta B cell epitope to BSA. Our results suggest that expression of APP in transgenic mice is associated with an Abeta-specific impaired adaptive immune response that may contribute to the neuropathology. Moreover, humans with life-long elevation of brain and peripheral Abeta (e.g., patients with presenilin mutations or Down syndrome) could have reduced immune responses to Abeta vaccination.
Monsonego
A
A
Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, 77 Avenue Louis Pasteur, HIM 730, Boston, MA 02115, USA.
Maron
R
R
Zota
V
V
Selkoe
D J
DJ
Weiner
H L
HL
D000544:Alzheimer Disease / Q000209:etiology* / Q000276:immunology / Q000628:therapy*; D016229:Amyloid beta-Peptides / Q000097:blood / Q000276:immunology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D000917:Antibody Formation; D015870:Gene Expression; D006801:Humans; D007108:Immune Tolerance; D007111:Immunity, Cellular; D007114:Immunization; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D058225:Plaque, Amyloid / Q000276:immunology
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor