Intranasal immunotherapy for the treatment of Alzheimer's disease: Escherichia coli LT and LT(R192G) as mucosal adjuvants.
Alzheimer's disease (AD) is the most common form of dementia worldwide, yet there is currently no effective treatment or cure. Extracellular deposition of amyloid-beta protein (Abeta) in brain is a key neuropathological characteristic of AD. In 1999, Schenk et al. first reported that an injected Abeta vaccine given to PDAPP mice, an AD mouse model displaying Abeta deposition in brain, led to the lowering of Abeta levels in brain. In 2000, we demonstrated that intranasal (i.n.) immunization with human synthetic Abeta1-40 peptide for 7 months led to a 50-60% reduction in cerebral Abeta burden in PDAPP mice; serum Abeta antibody titers were low (approximately 26 microg/ml). More recently, we have optimized our i.n. Abeta immunization protocol in wild-type (WT) mice. When low doses Escherichia coli heat-labile enterotoxin (LT) were given as a mucosal adjuvant with Abeta i.n., there was a dramatic 12-fold increase in Abeta antibody titers in WT B6D2F1 mice treated two times per week for 8 weeks compared to those of mice receiving i.n. Abeta without adjuvant. A non-toxic form of LT, designated LT(R192G), showed even better adjuvanticity; anti-Abeta antibody titers were 16-fold higher than those seen in mice given i.n. Abeta without adjuvant. In both cases, the serum Abeta antibodies recognized epitopes within Abeta1-15 and were of the immunoglobulin (Ig) isotypes IgG2b, IgG1, IgG2a and low levels of IgA. This new and improved Abeta vaccine protocol is now being tested in AD mouse models with the expectation that higher Abeta antibody titers may be more effective in reducing cerebral Abeta levels.
Lemere
Cynthia A
CA
Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. lemere@cnd.bwh.harvard.edu
Spooner
Edward T
ET
Leverone
Jodi F
JF
Mori
Chica
C
Clements
John D
JD
D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000281:Administration, Intranasal; D000544:Alzheimer Disease / Q000276:immunology / Q000517:prevention & control*; D023582:Alzheimer Vaccines / Q000008:administration & dosage*; D016229:Amyloid beta-Peptides / Q000276:immunology*; D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D001427:Bacterial Toxins / Q000008:administration & dosage* / Q000276:immunology; D001921:Brain / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D004768:Enterotoxins / Q000008:administration & dosage* / Q000276:immunology; D004926:Escherichia coli / Q000276:immunology*; D029968:Escherichia coli Proteins; D007167:Immunotherapy / Q000379:methods; D008297:Male; D051379:Mice; D009297:Nasal Mucosa / Q000276:immunology / Q000378:metabolism; D012016:Reference Values; D012680:Sensitivity and Specificity; D013045:Species Specificity
D000276:Adjuvants, Immunologic; D023582:Alzheimer Vaccines; D016229:Amyloid beta-Peptides; D001427:Bacterial Toxins; D004768:Enterotoxins; D029968:Escherichia coli Proteins; C027538:heat-labile enterotoxin, E coli