Peripheral anti-Aβ antibody alters CNS and plasma Aβ clearance and decreases brain Aβ burden in a mouse model of Alzheimer's disease
Peripheral anti-Aβ antibody alters CNS and plasma Aβ clearance and decreases brain Aβ burden in a mouse model of Alzheimer's disease
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DOI：
10.1073/pnas.151261398
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发表时间：
2001-07-17
影响因子：
11.1
通讯作者：
Holtzman, DM
中科院分区：
文献类型：
--
作者：
DeMattos, RB;Bales, KR;Holtzman, DM
在阿尔茨海默病转基因小鼠模型中，β-淀粉样蛋白 (Aβ) 肽的主动免疫已被证明可以减少脑部 Aβ 沉积，并且某些外周施用的抗 Aβ 抗体可以模拟这种效果。在探索改变 Aβ 代谢和清除的因素时，我们发现针对 Aβ 中心结构域的单克隆抗体 (m266) 能够结合并完全隔离血浆 Aβ。对中枢神经系统 (CNS) 内特异产生 Aβ 的 PDAPP 转基因小鼠进行 m266 外周给药，导致血浆 Aβ 迅速增加 1,000 倍，部分原因是 CNS 和血浆之间 Aβ 平衡的变化。尽管对 PDAPP 小鼠进行外周注射 m266 可显着减少 AP 沉积，但 m266 不会与大脑中的 Aβ 沉积物结合。因此，m266 似乎可以通过改变 CNS 和血浆 Aβ 清除率来减少大脑 Aβ 负担。
Active immunization with the amyloid beta (A beta) peptide has been shown to decrease brain A beta deposition in transgenic mouse models of Alzheimer's disease and certain peripherally administered anti-A beta antibodies were shown to mimic this effect. In exploring factors that alter A beta metabolism and clearance, we found that a monoclonal antibody (m266) directed against the central domain of A beta was able to bind and completely sequester plasma A beta, Peripheral administration of m266 to PDAPP transgenic mice, in which A beta is generated specifically within the central nervous system (CNS), results in a rapid 1,000-fold increase in plasma A beta, due, in part, to a change in A beta equilibrium between the CNS and plasma. Although peripheral administration of m266 to PDAPP mice markedly reduces AP deposition, m266 did not bind to A beta deposits in the brain. Thus, m266 appears to reduce brain A beta burden by altering CNS and plasma A beta clearance.