Weiner H L, Lemere C A, Maron R, Spooner E T, Grenfell T J, Mori C, Issazadeh S, Hancock W W, Selkoe D J
Department of Neurology, Harvard Medical School, and Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA.
Ann Neurol. 2000 Oct;48(4):567-79.
Progressive cerebral deposition of amyloid-beta (Abeta) peptide, an early and essential feature of Alzheimer's disease (AD), is accompanied by an inflammatory reaction marked by microgliosis, astrocytosis, and the release of proinflammatory cytokines. Mucosal administration of disease-implicated proteins can induce antigen-specific anti-inflammatory immune responses in mucosal lymphoid tissue which then act systemically. We hypothesized that chronic mucosal administration of Abeta peptide might induce an anti-inflammatory process in AD brain tissue that could beneficially affect the neuropathological findings. To test this hypothesis, we treated PDAPP mice, a transgenic line displaying numerous neuropathological features of AD, between the ages of approximately 5 and approximately 12 months with human Abeta synthetic peptide mucosally each week. We found significant decreases in the cerebral Abeta plaque burden and Abeta42 levels in mice treated intranasally with Abeta peptide versus controls treated with myelin basic protein or left untreated. This lower Abeta burden was associated with decreased local microglial and astrocytic activation, decreased neuritic dystrophy, serum anti-Abeta antibodies of the IgG1 and IgG2b classes, and mononuclear cells in the brain expressing the anti-inflammatory cytokines interleukin-4, interleukin-10, and tumor growth factor-beta. Our results demonstrate that chronic nasal administration of Abeta peptide can induce an immune response to Abeta that decreases cerebral Abeta deposition, suggesting a novel mucosal immunological approach for the treatment and prevention of AD.
淀粉样β（Aβ）肽在大脑中的进行性沉积是阿尔茨海默病（AD）的早期基本特征，同时伴有以小胶质细胞增生、星形胶质细胞增生和促炎细胞因子释放为特征的炎症反应。对涉及疾病的蛋白质进行黏膜给药可在黏膜淋巴组织中诱导抗原特异性抗炎免疫反应，进而产生全身作用。我们推测，长期经黏膜给予Aβ肽可能会在AD脑组织中诱导抗炎过程，从而对神经病理学发现产生有益影响。为了验证这一假设，我们在约5至约12月龄的携带众多AD神经病理学特征的转基因系PDAPP小鼠中，每周经黏膜给予人Aβ合成肽。我们发现，与用髓鞘碱性蛋白处理或未处理的对照组相比，经鼻给予Aβ肽处理的小鼠脑内Aβ斑块负荷和Aβ42水平显著降低。这种较低的Aβ负荷与局部小胶质细胞和星形胶质细胞激活减少、神经纤维营养不良减少、IgG1和IgG2b类血清抗Aβ抗体以及脑内表达抗炎细胞因子白细胞介素-4、白细胞介素-10和肿瘤生长因子-β的单核细胞有关。我们的结果表明，长期经鼻给予Aβ肽可诱导针对Aβ的免疫反应，从而减少脑内Aβ沉积，提示一种治疗和预防AD的新型黏膜免疫方法。
