Active Immunization of Mice with an <i>Aβ-Hsp70</i> Vaccine

Abstract

Heat-shock proteins are highly immunogenic. Complexed with an antigen, they act as adjuvants, inducing a humoral and cellular immune response against both the antigen and the chaperone. In this study, we produced an Hsp70-supported vaccine to induce the generation of antibodies against amyloid-β (Aβ) peptides, the major constituent of β-amyloid plaques in Alzheimer’s disease. The vaccine consisted of synthetic human Aβ₄₂ covalently cross-linked with DnaK, an Hsp70 homolog of Escherichia coli. Active immunization of mice with this vaccine resulted in the generation of antibodies against Aβ, that were detectable in sera after the first booster immunization. Antibody titers varied markedly with the genetic background of the mice. Prophylactic short-term immunization of transgenic mice (APP tg2576) before the onset of plaques, however, did not prevent amyloid plaque deposition. There were no differences in the plaque load and in the level of Triton X-100-soluble Aβ peptides in the brains of immunized and control-treated transgenic mice. Unexpectedly, the level of formic-acid soluble Aβ peptides tended to be higher in immunized mice. The reason for the increase may be an enhanced deposition of Aβ in the small cerebral blood vessels. These data emphasize the need for anti-Aβ antibodies that remove Aβ peptides from the central nervous system without negative side effects.

Quantitative and Mechanistic Studies of A&#946; Immunotherapy

“…Abs present in the sera of humans and mice following immunization with fibrillar A 42 (fA 42) appear to be a mixture of Abs capable of recognizing monomeric A (mA ), naturally secreted oligomers, in vitro formed oligomers, A amyloid or some combination of these [3,4,20,[40][41][42][43][44][45][46][47][48][49]. Thus, active A immunotherapies produce a repertoire of Abs that can mediate a multiplicity of effects, including attenuation of A deposition, improvement of behavioral impairments, and alterations in plaque associated pathologies.…”

Immune Activation in Amyloid-β-Related Angiitis Correlates with Decreased Parenchymal Amyloid-β Plaque Load

“…Interestingly, recent therapeutic trials in AD, with active immunization against Aβ as the mechanistic principle, have drawn attention to ABRA. In patients immunized against Aβ, occurrence of specific antibodies seems to go along with clearance of Aβ from brain parenchyma, immune activation and vascular inflammation [20,21,22], as well as potentially more prominent vessel wall deposition of Aβ [23]. Therefore, in order to explore whether enhanced clearance of parenchymal Aβ occurs in ABRA and to assess whether enhanced clearance of Aβ correlates with parenchymal immune activation, we carried out a case control study.…”

Detergent‐Insoluble EAAC1/EAAT3 Aberrantly Accumulates in Hippocampal Neurons of Alzheimer's Disease Patients

“…The remaining pelleted detergent-insoluble proteins were subsequently solublized in formic acid (FA) and then analyzed by ELISA to determine the levels of Triton X-100-insoluble but FA-soluble EAAC1. We and others have used this method previously to obtain abnormal tau, Aβ and other proteins from AD cerebrum (17, 18, 29, 44, 54, 58, 68). Detergent-insoluble hippocampal EAAC1 levels were also measured in the same panel of four PD patients examined above (Figure 5).…”