Abstract
Active and passive Aβ immunotherapy in Alzheimers disease (AD)-like mouse models lowers cerebral amyloid- β protein (Aβ) levels, especially if given early in the disease process, and improves cognitive deficits. In 2002, a Phase IIa clinical trial was halted due to meningoencephalitis in ∼6% of the AD patients. It is hypothesized that the immunogen, full-length Aβ1-42, may have led to an autoimmune response. Currently, we are developing novel Aβ peptide immunogens for active immunization in amyloid precursor protein transgenic mice (APP Tg) to target Aβ B cell epitopes (within Aβ1-15) and avoid Aβ-specific T cell epitopes (Aβ16-42) so as to generate a safe and effective AD vaccine. Intranasal immunization with dendrimeric Aβ1-15 (16 copies of Aβ1-15 on a lysine core) or a tandem repeat of Aβ1-15 joined by 2 lysines and conjugated to an RGD motif with a mutated form of an E. coli-derived adjuvant generated robust Aβ titers in both wildtype and APP Tg mice. The Aβ antibodies recognized a B cell epitope within Aβ1-7, were mostly T-helper 2 associated immunoglobulin isotypes, bound human AD and APP Tg plaques, and detected Aβ oligomers. Splenic T cells reacted to the immunogens but not full-length Aβ. Six months of intranasal immunization (from 6-to-12 months of age) of J20 mice with each immunogen lowered insoluble Aβ42 by 50%, reduced plaque burden and gliosis, and increased Aβ in plasma. Interestingly, Aβ antibody generation was influenced by route of immunization. Transcutaneous immunization with dβ1-15, but not full-length Abeta, led to high Aβ titers. In summary, our short Aβ immunogens induced robust titers of predominantly Th2 antibodies that were able to clear cerebral Aβ in the absence of Aβ-specific T cell reactivity, indicating the potential for a safer vaccine. We remain optimistic about the potential of such a vaccine for prevention and treatment of AD.
Keywords: Aβ immunotherapy, Alzheimer's disease, vaccination, T cells, B cells
Current Alzheimer Research
Title: Novel Aβ Immunogens: Is Shorter Better?
Volume: 4 Issue: 4
Author(s): Cynthia A. Lemere, Marcel Maier, Ying Peng, Liying Jiang and Timothy J. Seabrook
Affiliation:
Keywords: Aβ immunotherapy, Alzheimer's disease, vaccination, T cells, B cells
Abstract: Active and passive Aβ immunotherapy in Alzheimers disease (AD)-like mouse models lowers cerebral amyloid- β protein (Aβ) levels, especially if given early in the disease process, and improves cognitive deficits. In 2002, a Phase IIa clinical trial was halted due to meningoencephalitis in ∼6% of the AD patients. It is hypothesized that the immunogen, full-length Aβ1-42, may have led to an autoimmune response. Currently, we are developing novel Aβ peptide immunogens for active immunization in amyloid precursor protein transgenic mice (APP Tg) to target Aβ B cell epitopes (within Aβ1-15) and avoid Aβ-specific T cell epitopes (Aβ16-42) so as to generate a safe and effective AD vaccine. Intranasal immunization with dendrimeric Aβ1-15 (16 copies of Aβ1-15 on a lysine core) or a tandem repeat of Aβ1-15 joined by 2 lysines and conjugated to an RGD motif with a mutated form of an E. coli-derived adjuvant generated robust Aβ titers in both wildtype and APP Tg mice. The Aβ antibodies recognized a B cell epitope within Aβ1-7, were mostly T-helper 2 associated immunoglobulin isotypes, bound human AD and APP Tg plaques, and detected Aβ oligomers. Splenic T cells reacted to the immunogens but not full-length Aβ. Six months of intranasal immunization (from 6-to-12 months of age) of J20 mice with each immunogen lowered insoluble Aβ42 by 50%, reduced plaque burden and gliosis, and increased Aβ in plasma. Interestingly, Aβ antibody generation was influenced by route of immunization. Transcutaneous immunization with dβ1-15, but not full-length Abeta, led to high Aβ titers. In summary, our short Aβ immunogens induced robust titers of predominantly Th2 antibodies that were able to clear cerebral Aβ in the absence of Aβ-specific T cell reactivity, indicating the potential for a safer vaccine. We remain optimistic about the potential of such a vaccine for prevention and treatment of AD.
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Cite this article as:
Lemere A. Cynthia, Maier Marcel, Peng Ying, Jiang Liying and Seabrook J. Timothy, Novel Aβ Immunogens: Is Shorter Better?, Current Alzheimer Research 2007; 4 (4) . https://dx.doi.org/10.2174/156720507781788800
DOI https://dx.doi.org/10.2174/156720507781788800 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
Call for Papers in Thematic Issues
New Advances in the Prevention, Diagnosis, Treatment, and Rehabilitation of Alzheimer's Disease
Aims and Scope: Introduction: Alzheimer's disease (AD) poses a significant global health challenge, with an increasing prevalence that demands concerted efforts to advance our understanding and strategies for prevention, diagnosis, treatment, and rehabilitation. This thematic issue aims to bring together cutting-edge research and innovative approaches from multidisciplinary perspectives to address ...read more
Alzheimer's Disease Drug Development
Alzheimer's disease is a progressive neurodegenerative disorder that affects millions of people worldwide. Despite decades of research, no cure or disease-modifying treatment is available yet. Therefore, the need for developing effective therapies to treat Alzheimer's disease is an urgent matter. This special issue aims to provide a comprehensive overview of ...read more
Current updates on the Role of Neuroinflammation in Neurodegenerative Disorders
Neuroinflammation is an invariable hallmark of chronic and acute neurodegenerative disorders and has long been considered a potential drug target for Alzheimer?s disease (AD) and dementia. Significant evidence of inflammatory processes as a feature of AD is provided by the presence of inflammatory markers in plasma, CSF and postmortem brain ...read more
Deep Learning for Advancing Alzheimer's Disease Research
Alzheimer's disease (AD) poses a significant global health challenge, with an increasing number of individuals affected yearly. Deep learning, a subfield of artificial intelligence, has shown immense potential in various domains, including healthcare. This thematic issue of Current Alzheimer Research explores the application of deep learning techniques in advancing our ...read more
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