A nasal proteosome adjuvant activates microglia and prevents amyloid deposition
A nasal proteosome adjuvant activates microglia and prevents amyloid deposition
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DOI：
10.1002/ana.21340
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发表时间：
2008-05-01
影响因子：
11.2
通讯作者：
Weiner, Howard L.
中科院分区：
文献类型：
--
作者：
Frenkel, Dan;Puckett, Lindsay;Weiner, Howard L.
目的：我们评估了人类安全使用的基于鼻蛋白酶体的佐剂（Protollin）对小胶质细胞的外周激活是否可以预防年轻小鼠的淀粉样蛋白沉积，并影响淀粉样蛋白负荷较大的老年小鼠的淀粉样蛋白沉积和记忆功能。方法：淀粉样前体蛋白（APP）转基因（Tg）J20小鼠从5个月大开始每周接受Protollin鼻腔治疗，持续8个月。 24 个月大的 J20 小鼠每周接受治疗，持续 6 周。结果：我们发现，从 5 个月大开始接受 Protollin 治疗的 14 个月大小鼠中，纤维状淀粉样蛋白 (93%)、不溶性 β-淀粉样蛋白 (Aβ；68%) 和可溶性 Aβ (45%) 片段的水平降低。 24 个月大的小鼠经鼻 Protollin 治疗 6 周后，可溶性和不溶性 Aβ (1-40) 和 (1-42) 减少，记忆功能得到改善。在 24 个月大的动物中，激活的小胶质细胞（CD11b（+）细胞）与 A β 原纤维共定位，并且小胶质细胞的激活与 A β 的减少相关。在 14 个月大的小鼠中没有观察到小胶质细胞活化，这表明一旦 Aβ 被清除，小胶质细胞活化就会下调。两组的星形细胞增多症都有所减少。在鼻腔和颈部淋巴结中观察到 Protollin，但在大脑中未观察到。血液和颈部淋巴结中发现活化的CD11b(+)SRA(+)（清道夫受体A）细胞，颈部淋巴结中白细胞介素10增加。没有与治疗相关的毒性。解释：我们的结果证明了一种新型的不依赖于抗体的免疫疗法，可用于预防和治疗阿尔茨海默病，该疗法由小胶质细胞的外周激活介导，没有明显的毒性。
Objective: We assessed whether peripheral activation of microglia by a nasal proteosome-based adjuvant (Protollin) that has been given safely to humans can prevent amyloid deposition in young mice and affect amyloid deposition and memory function in old mice with a large amyloid load.Methods: Amyloid precursor protein (APP) transgenic (Tg) J20 mice received nasal treatment with Protollin weekly for 8 months beginning at age 5 months. Twenty-four-month-old J20 mice were treated weekly for 6 weeks.Results: We found reduction in the level of fibrillar amyloid (93%), insoluble beta-amyloid (A beta; 68%), and soluble A beta (45%) fragments in 14-month-old mice treated with Protollin beginning at age 5 months. Twenty-four-month-old mice treated with nasal Protollin for 6 weeks had decreased soluble and insoluble A beta (1-40) and (1-42) and improved memory function. Activated microglia (CD11b(+) cells) colocalized with A beta fibrils in the 24-month-old animals, and microglial activation correlated with the decrease in A beta. No microglial activation was observed in 14-month-old mice, suggesting that once A beta is cleared, there is downregulation of microglial activation. Both groups had reduction in astrocytosis. Protollin was observed in the nasal cavity and cervical lymph node but not in the brain. Activated CD11b(+)SRA(+) (scavenger receptor A) cells were found in blood and cervical lymph node and increased interleukin-10 in cervical lymph node. No toxicity was associated with treatment.Interpretation: Our results demonstrate a novel antibody-independent immunotherapy for both prevention and treatment of Alzheimer's disease that is mediated by peripheral activation of microglia with no apparent toxicity.