Toll-like receptor 4-dependent glial cell activation mediates the impairment in memory establishment induced by beta-amyloid oligomers in an acute mouse model of Alzheimer%26apos;s disease

作者：Balducci Claudia; Frasca Angelisa; Zotti Margherita; La Vitola Pietro; Mhillaj Emanuela; Grigoli Emanuele; Iacobellis Martina; Grandi Federica; Messa Massimo; Colombo Laura; Molteni Monica; Trabace Luigia; Rossetti Carlo; Salmona Mario; Forloni Gianluigi

来源：Brain, Behavior, and Immunity, 2017, 60: 188-197.

DOI：10.1016/j.bbi.2016.10.012

• Alzheimer's disease
• Beta-amyloid oligomers
• Memory impairment
• Novel object recognition test
• Neuroinflammation
• Pro-inflammatory cytokines
• IL-1 beta
• IL-1 beta receptor antagonist
• Indomethacin
• Toll-like receptor 4

Background: Amyloid-beta oligomers (A beta O) are species mainly involved in the synaptic and cognitive dysfunction in Alzheimer's disease. Although their action has been described mainly at neuronal level, it is now clear that glial cells govern synaptic activity in their resting state, contributing to new learning and memory establishment. In contrast, when activated, they may lead to synaptic and cognitive dysfunction. Using a reliable acute A beta O-mediated mouse model of AD, we explored whether the memory alteration A beta Os induce relies on the activation of glial cells, and if Toll-like receptor 4 (TLR4), pivotal in the initiation of an immune response, is involved. Methods: C57 naive mice were given a single intracerebroventricular injection of synthetic A beta O-containing solution (1 mu M), which induces substantial impairment in the establishment of recognition memory. Then, first we assessed glial cell activation at different times post-injection by western blot, immunohistochemistry and ELISA in the hippocampus. After that we explored the efficacy of pre-treatment with anti-inflammatory drugs (indomethacin and an IL-1 beta receptor antagonist) to prevent impairment in the novel object recognition task, and compared A beta O's effects in TLR4 knockout mice. Results: A single A beta O injection rapidly activated glial cells and increased pro-inflammatory cytokine expression. Both anti-inflammatory drugs prevented the A beta O-mediated impairment in memory establishment. A selective TLR4 receptor antagonist abolished A beta O's action on memory, and in TLR4 knockout mice it had no effect on either memory or glial activation. Conclusions: These data provide new information on A beta O's mechanism of action, indicating that besides direct action at the synapses, they also act through the immune system, with TLR4 playing a major role. This suggests that in a potential therapeutic setting inflammation must be considered as well.

• 出版日期2017-2