Rescue of Transgenic Alzheimer's Pathophysiology by Polymeric Cellular Prion Protein Antagonists
Rescue of Transgenic Alzheimer's Pathophysiology by Polymeric Cellular Prion Protein Antagonists
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DOI：
10.1016/j.celrep.2018.12.021
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发表时间：
2019-01-02
期刊：
影响因子：
8.8
通讯作者：
Strittmatter, Stephen M.
中科院分区：
文献类型：
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作者：
Gunther, Erik C.;Smith, Levi M.;Strittmatter, Stephen M.
细胞朊病毒蛋白 (PrPC) 结合 PrP (PrPSc) 和寡聚 β-淀粉样肽 (Aβo) 的痒病构象，分别介导传染性海绵状脑病 (TSE) 和阿尔茨海默病 (AD)。我们对阻断 PrPC 与 A beta o 相互作用的化合物进行了细胞和生化筛选。抗生素的聚合降解剂以低纳摩尔亲和力靶向 PrPC 上的 Aβo 结合位点，并防止 Aβo 诱导的病理生理学。然后，我们从生物（黑色素）和合成（聚[4-苯乙烯磺酸-马来酸]，PSCMA）来源鉴定了一系列在低至亚纳摩尔范围内具有特定 PrPC 亲和力的带负电荷的聚合物。 PSCMA 与 PrPC 的结合可防止 A β o/PrPC-水凝胶形成，阻断 A β o 与神经元的结合，并消除 ScN2a 细胞产生的 PrPSc。我们证明口服 PSCMA 可以产生有效的大脑浓度，并可将 APPswe/PS1 Delta E9 转基因小鼠从 AD 相关的突触丧失和记忆缺陷中拯救出来。因此，口服活性的 PrPC 导向的聚合物制剂为解决 AD 和 TSE 的神经退行性疾病提供了一种潜在的治疗方法。
Cellular prion protein (PrPC) binds the scrapie conformation of PrP (PrPSc) and oligomeric beta-amyloid peptide (A beta o) to mediate transmissible spongiform encephalopathy (TSE) and Alzheimer's disease (AD), respectively. We conducted cellular and biochemical screens for compounds blocking PrPC interaction with A beta o. A polymeric degradant of an antibiotic targets A beta o binding sites on PrPC with low nanomolar affinity and prevents A beta o-induced pathophysiology. We then identified a range of negatively charged polymers with specific PrPC affinity in the low to sub-nanomolar range, from both biological (melanin) and synthetic (poly [4-styrenesulfonic acid-co-maleic acid], PSCMA) origin. Association of PSCMA with PrPC prevents A beta o/PrPC-hydrogel formation, blocks A beta o binding to neurons, and abrogates PrPSc production by ScN2a cells. We show that oral PSCMA yields effective brain concentrations and rescues APPswe/PS1 Delta E9 transgenic mice from AD-related synapse loss and memory deficits. Thus, an orally active PrPC-directed polymeric agent provides a potential therapeutic approach to address neurodegeneration in AD and TSE.