Linear and conformation specific antibodies in aged beagles after prolonged vaccination with aggregated Abeta

Abstract

Previously we showed that anti-Aβ peptide immunotherapy significantly attenuated Alzheimer'slike amyloid deposition in the central nervous system of aged canines. In this report we have characterized the changes that occurred in the humoral immune response over 2.4 years in canines immunized repeatedly with aggregated Aβ 1-42 (AN1792) formulated in alum adjuvant. We observed a rapid and robust induction of anti-Aβ antibody titers, which were associated with an anti-inflammatory T helper type 2 (Th2) response. The initial antibody response was against dominant linear epitope at the N-terminus region of the Aβ 1-42 peptide, which is identical to the one in humans and vervet monkeys. After multiple immunizations the antibody response drifted toward the elevation of antibodies that recognized conformational epitopes of assembled forms of Aβ and other types of amyloid. Our findings indicate that prolonged immunization results in distinctive temporal changes in antibody profiles, which may be important for other experimental and clinical settings.

Rapid Improvement of Canine Cognitive Dysfunction with Immunotherapy designed for Alzheimer's Disease

“…Because of their many common hallmarks, CDS is presently considered a model of choice for Mild Cognitive Impairment (MCI) and AD research [15,20,21], and, in particular, for the development of anti-Aβ immunotherapy [13,22,23]. Diagnosed of graded cognitive dysfunctions by practicing neurology veterinarians, these animals are systematically and easily classified into wellcharacterized homogenous groups with no variation due to their breed (including sex, size and genetic background) or familiar life conditions [24][25][26].…”

Design and Optimization of Anti-amyloid Domain Antibodies Specific for β-Amyloid and Islet Amyloid Polypeptide

“…The most widely used one is immunization, which has yielded a wide range of important antibodies specific for different types of prefibrillar oligomers and amyloid fibrils (17)(18)(19)(20)(25)(26)(27). Another powerful approach that has proven useful is to employ in vitro display methods such as phage and yeast surface display (21-24, 29 -37).…”

“…Given these challenges, antibodies with conformational specificity for prefibrillar oligomers and amyloid fibrils have proven valuable for biochemical characterization (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). An obvious strength of such antibodies is their ability to detect specific types of aggregates formed both in vivo and in vitro.…”

Aptamers

“…A high red fluorescent signal of free DOX molecules could be observed upon binding of the negatively charged complex to the MUC1 positive breast cancer cells but not with MUC1 negative cells. Accordingly, a very high cytotoxicity was observed when MUC1 positive cancer cells were treated with the aptamer-Td conjugate [187].…”

“…Recently, Dai et al developed a DNA tetrahedron (Td) labeled with an aptamer targeting MUC1. In this drug delivery system, the aptamer serves for the targeted delivery to MUC1-positive breast cancer cells while the DNA tetrahedron is instrumental for the intercalation of DOX [187]. A fluorescence-based drug loading experiment showed that each aptamer-Td construct with an average size of 12.4 nM could carry up to 25 DOX molecules.…”