Journal
JOURNAL OF NEUROSCIENCE
Volume 27, Issue 46, Pages 12721-12731Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.3201-07.2007
Keywords
immunotherapy; Alzheimer's disease; epitope vaccine; antibody; PADRE; beta-amyloid
Categories
Funding
- NIA NIH HHS [P50 AG16573, P50 AG016573, RF1 AG020241, AG00096, AG20241, R01 AG020241-06, T32 AG000096, R01 AG020241] Funding Source: Medline
- NINDS NIH HHS [R01 NS050895-03, NS50895, R01 NS050895] Funding Source: Medline
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Active vaccination of elderly Alzheimer's disease (AD) patients with fibrillar amyloid-beta peptide (A beta(42)), even in the presence of a potent Th1 adjuvant, induced generally low titers of antibodies in a small fraction (similar to 20% responders) of those that received the AN-1792 vaccine. To improve the immunogenicity and reduce the likelihood of inducing adverse autoreactive T-cells specific for A beta(42), we previously tested in wild-type mice an alternative approach for active immunization: an epitope vaccine that selectively initiate B cell responses toward an immunogenic self-epitope of A beta in the absence of anti-A beta T cell responses. Here, we describe a second generation epitope vaccine composed of two copies of A beta(1-11) fused with the promiscuous nonself T cell epitope, PADRE ( pan human leukocyte antigen DR-binding peptide) that completely eliminates the autoreactive T cell responses and induces humoral immune responses in amyloid precursor protein transgenic 2576 mice with pre-existing AD-like pathology. Based on the titers of anti-A beta(1-11) antibody experimental mice were divided into low, moderate and high responders, and for the first time we report a positive correlation between the concentration of anti-A beta(1-11) antibody and a reduction of insoluble, cerebral A beta plaques. The reduction of insoluble A beta deposition was not associated with adverse events, such as CNS T cell or macrophage infiltration or microhemorrhages. Surprisingly, vaccination did not alter the levels of soluble A beta. Alternatively, early protective immunization before substantial neuropathology, neuronal loss and cognitive deficits have become firmly established may be more beneficial and safer for potential patients, especially if they can be identified in a preclinical stage by the development of antecedent biomarkers of AD.
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