Intranasal immunotherapy for the treatment of Alzheimer's disease: Escherichia coli LT and LT(R192G) as mucosal adjuvants

• Published in: Neurobiology of aging Vol. 23; no. 6; pp. 991 - 1000
• Main Authors: LEMERE, Cynthia A, SPOONER, Edward T, LEVERONE, Jodi F, MORI, Chica, CLEMENTS, John D
• Format: Conference Proceeding Journal Article
• Language: English
• Published: London Elsevier Science 01.11.2002
• Subjects: Adjuvants, Immunologic - administration & dosage; Administration, Intranasal; Alzheimer Disease - immunology; Alzheimer Disease - prevention & control; Alzheimer Vaccines - administration & dosage; Amyloid beta-Peptides - immunology; Animals; Antibody Formation - drug effects; Bacterial Toxins - administration & dosage; Bacterial Toxins - immunology; Biological and medical sciences; Brain - drug effects; Brain - immunology; Brain - metabolism; Brain - pathology; Cell Line; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Enterotoxins - administration & dosage; Enterotoxins - immunology; Escherichia coli - immunology; Escherichia coli Proteins; Immunotherapy - methods; Male; Medical sciences; Mice; Nasal Mucosa - immunology; Nasal Mucosa - metabolism; Neurology; Reference Values; Sensitivity and Specificity; Species Specificity; Nervous system diseases; Alzheimer disease; Rodentia; AD vaccine; Vaccine; Intranasal administration; PDAPP; E. coli heat-labile enterotoxin (LT); Intranasal (i.n.); Cerebral disorder; Aβ immunization; PSAPP; Vertebrata; Mammalia; Treatment; Mouse; β Amyloid protein; Animal; Immunotherapy; Central nervous system disease; Degenerative disease; Alzheimer's disease; LT(R192G)
• ISSN: 0197-4580; 1558-1497
• DOI: 10.1016/S0197-4580(02)00127-6

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.