High-mobility group box-1 impairs memory in mice through both toll-like receptor 4 and Receptor for Advanced Glycation End Products.
High-mobility group box-1 impairs memory in mice through both toll-like receptor 4 and Receptor for Advanced Glycation End Products.
复制标题
DOI：
10.1016/j.expneurol.2011.08.012
复制
发表时间：
2011-12
影响因子：
5.3
通讯作者：
Carli, Mirjana
中科院分区：
文献类型：
--
作者：
Mazarati, Andrey;Maroso, Mattia;Iori, Valentina;Vezzani, Annamaria;Carli, Mirjana
关键词：
HMGB1 （High-mobility group box-1）是一种核蛋白，在细胞外释放时具有细胞因子型功能。HMGB1通过刺激多种受体激活炎症通路，主要是toll样受体4 （TLR4）和晚期糖基化终产物受体（RAGE）。TLR4和RAGE的激活与记忆障碍有关，尽管内源性配体支持这些作用尚不清楚。我们使用新的物体识别测试来研究HMGB1是否会引起记忆缺陷，以及这两种受体途径中哪一种参与了这些影响。研究了野生型、TLR4敲除小鼠和RAGE敲除小鼠的非空间长期记忆。重组HMGB1 （10 μg，脑室内，i.c.v）对野生型、TLR4敲除和RAGE敲除动物的记忆编码具有相同的破坏作用，但不影响记忆巩固和检索。TLR4敲除小鼠和RAGE敲除小鼠本身都没有表现出记忆缺陷。用球形红杆菌脂多糖（LPS-Rs; 20 μg, i.c.v）阻断RAGE基因敲除小鼠的TLR4，可阻止HMGB1对记忆的损害作用。这些数据表明，大脑中HMGB1水平的升高会引起记忆异常，这可能是由TLR4或RAGE介导的。这一机制可能导致与HMGB1水平升高相关的各种神经和精神疾病（如癫痫、阿尔茨海默病和中风）的记忆缺陷。
High-mobility group box-1 (HMGB1) is a nuclear protein with cytokine-type functions upon its extracellular release. HMGB1 activates inflammatory pathways by stimulating multiple receptors, chiefly toll-like receptor 4 (TLR4) and Receptor for Advanced Glycation End Products (RAGE). TLR4 and RAGE activation has been implicated in memory impairments, although the endogenous ligand subserving these effects is unknown. We examined whether HMGB1 induced memory deficits using novel object recognition test, and which of the two receptor pathways was involved in these effects. Non-spatial long-term memory was examined in wild type, TLR4 knockout, and RAGE knockout mice. Recombinant HMGB1 (10 μg, intracerebroventricularly, i.c.v.) disrupted memory encoding equipotently in wild type, TLR4 knockout and RAGE knockout animals, but affected neither memory consolidation, nor retrieval. Neither TLR4 knockout nor RAGE knockout mice per se, exhibited memory deficits. Blockade of TLR4 in RAGE knockout mice using Rhodobacter sphaeroides lipopolysaccharide (LPS-Rs; 20 μg, i.c.v.) prevented the detrimental effect of HMGB1 on memory. These data show that elevated brain levels of HMGB1 induce memory abnormalities which may be mediated by either TLR4, or RAGE. This mechanism may contribute to memory deficits under various neurological and psychiatric conditions associated with the increased HMGB1 levels, such as epilepsy, Alzeheimer’s disease and stroke.
登录
查看更多内容
影响因子：
3.1
作者：
Campos, MA;Rosinha, GMS;Oliveira, SC
通讯作者：
Oliveira, SC
影响因子：
2.7
作者：
ENNACEUR, A;DELACOUR, J
通讯作者：
DELACOUR, J
影响因子：
2
作者：
Campos, Tania Fernandes;Miranda Barroso, Marina Tostes;de Lara Menezes, Alexandre Augusto
通讯作者：
de Lara Menezes, Alexandre Augusto
影响因子：
37.8
作者：
Andrassy, Martin;Volz, Hans C.;Bierhaus, Angelika
通讯作者：
Bierhaus, Angelika
影响因子：
56.9
作者：
BIANCHI, ME;BELTRAME, M;PAONESSA, G
通讯作者：
PAONESSA, G