期刊
JOURNAL OF NEUROSCIENCE
卷 33, 期 11, 页码 4923-4934出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.4672-12.2013
关键词
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资金
- NIH [NS-50895, NS-065518, AG-20241, NS 057395]
- Alzheimer's Association [IIRG-0728314]
- NIA [AG000096]
- University of California-Irvine Alzheimer's Disease Research Center [P50 AG16573]
The Alzheimer's disease (AD) process is understood to involve the accumulation of amyloid plaques and tau tangles in the brain. However, attempts at targeting the main culprits, neurotoxic A beta peptides, have thus far proven unsuccessful for improving cognitive function. Recent clinical trials with passively administrated anti-A beta antibodies failed to slow cognitive decline in mild to moderate AD patients, but suggest that an immunotherapeutic approach could be effective in patients with mild AD. Using an AD mouse model (Tg2576), we tested the immunogenicity (cellular and humoral immune responses) and efficacy (AD-like pathology) of clinical grade Lu AF20513 vaccine. We found that Lu AF20513 induces robust non-self T-cell responses and the production of anti-A beta antibodies that reduce AD-like pathology in the brains of Tg2576 mice without inducing microglial activation and enhancing astrocytosis or cerebral amyloid angiopathy. A single immunization with Lu AF20513 induced strong humoral immunity in mice with preexisting memory T-helper cells. In addition, Lu AF20513 induced strong humoral responses in guinea pigs and monkeys. These data support the translation of Lu AF20513 to the clinical setting with the aims of: (1) inducing therapeutically potent anti-A beta antibody responses in patients with mild AD, particularly if they have memory T-helper cells generated after immunizations with conventional tetanus toxoid vaccine, and (2) preventing pathological autoreactive T-cell responses.
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