Frenkel Dan, Puckett Lindsay, Petrovic Sanja, Xia Weiming, Chen Guiquan, Vega Jose, Dembinsky-Vaknin Adi, Shen Jie, Plante Martin, Burt David S, Weiner Howard L
Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Ann Neurol. 2008 May;63(5):591-601. doi: 10.1002/ana.21340.
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.
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.
We found reduction in the level of fibrillar amyloid (93%), insoluble beta-amyloid (Abeta; 68%), and soluble Abeta (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 Abeta (1-40) and (1-42) and improved memory function. Activated microglia (CD11b+ cells) colocalized with Abeta fibrils in the 24-month-old animals, and microglial activation correlated with the decrease in Abeta. No microglial activation was observed in 14-month-old mice, suggesting that once Abeta 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.
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.
我们评估了一种已安全应用于人体的基于鼻内蛋白酶体的佐剂（Protollin）对外周小胶质细胞的激活是否能够预防年轻小鼠的淀粉样蛋白沉积，并影响淀粉样蛋白负荷量大的老年小鼠的淀粉样蛋白沉积和记忆功能。
淀粉样前体蛋白（APP）转基因（Tg）J20小鼠在5月龄时开始每周接受一次Protollin鼻内治疗，持续8个月。24月龄的J20小鼠每周接受一次治疗，持续6周。
我们发现，从5月龄开始用Protollin治疗的14月龄小鼠，其纤维状淀粉样蛋白水平降低了93%，不溶性β淀粉样蛋白（Aβ）降低了68%，可溶性Aβ片段降低了45%。用鼻内Protollin治疗6周的24月龄小鼠，其可溶性和不溶性Aβ（1-40）和（1-42）减少，记忆功能改善。在24月龄动物中，活化的小胶质细胞（CD11b+细胞）与Aβ纤维共定位，小胶质细胞活化与Aβ的减少相关。在14月龄小鼠中未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。两组的星形细胞增生均减少。在鼻腔和颈部淋巴结中发现了Protollin，但在大脑中未发现。在血液和颈部淋巴结中发现了活化的CD11b+SRA+（清道夫受体A）细胞，颈部淋巴结中的白细胞介素-10增加。治疗未产生毒性。
我们的结果证明了一种新型的、不依赖抗体的免疫疗法，可用于预防和治疗阿尔茨海默病，该疗法由外周小胶质细胞激活介导，且无明显毒性。
