High-Mobility Group Box-1 Protein and β-Amyloid Oligomers Promote Neuronal Differentiation of Adult Hippocampal Neural Progenitors via Receptor for Advanced Glycation End Products/Nuclear Factor-κB Axis: Relevance for Alzheimer's Disease
High-Mobility Group Box-1 Protein and β-Amyloid Oligomers Promote Neuronal Differentiation of Adult Hippocampal Neural Progenitors via Receptor for Advanced Glycation End Products/Nuclear Factor-κB Axis: Relevance for Alzheimer's Disease
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DOI：
10.1523/jneurosci.2052-12.2013
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发表时间：
2013-04-03
影响因子：
5.3
通讯作者：
Grilli, Mariagrazia
中科院分区：
文献类型：
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作者：
Meneghini, Vasco;Bortolotto, Valeria;Grilli, Mariagrazia
海马神经发生失调与神经退行性疾病有关，包括阿尔茨海默病（AD），其中它可能代表一种自我修复机制，可以抵消神经元丢失和认知障碍。我们评估了TgCRND 8小鼠海马神经发生，并报告说，在32周龄时，对应于晚期AD样神经病理学阶段，与野生型（WT）同窝仔相比，增殖细胞、表达双皮质素的祖细胞/成神经细胞和早期有丝分裂后表达钙视黄蛋白的神经元数量增加。从TgCRND 8小鼠分离海马神经前体细胞（nerve progenitor cells，NPCs），结果表明：（1）NPCs的神经分化潜能高于WT NPCs，（2）TgCRND 8 NPCs条件培养液促进WT NPCs向神经元分化;阻断晚期糖基化终末产物受体（receptor for advanced glycation end products，ERK）/核因子-κ B可抑制TgCRND 8条件培养液的促神经发生作用（NF-κ B）轴。此外，我们发现β-淀粉样蛋白1-42（A β（1-42））寡聚体，而不是单体和原纤维，以及高迁移率族蛋白1（HMGB-1）中的警报可以通过激活β-淀粉样蛋白/NF-κ B轴促进NPC的神经元分化。总之，这些数据表明，在AD脑中，内源性前神经原性反应可能被潜在触发，并涉及也有助于神经炎症/神经毒性的信号（A β（1-42）寡聚体和HMGB-1）和途径（A β/NF-κ B激活）。更详细的分析证实，与WT小鼠相比，TgCRND 8的海马中新的成熟神经元没有显著增加，表明新生神经元的存活和/或整合减少。AD的治疗策略应该理想地结合联合收割机维持海马神经发生的能力以及抵消不利的脑微环境的能力，以促进脆弱细胞群（包括成体产生的神经元）的存活。
Dysregulated hippocampal neurogenesis has been associated with neurodegenerative disorders, including Alzheimer's disease (AD), in which it may potentially represent an auto-reparatory mechanism that could counteract neuronal loss and cognitive impairment. We evaluated hippocampal neurogenesis in TgCRND8 mice and reported that, at 32 weeks of age, corresponding to an advanced AD-like neuropathology stage, increased numbers of proliferating cells, doublecortin-expressing progenitors/neuroblasts, and early postmitotic calretinin-expressing neurons were present compared with wild-type (WT) littermates. When hippocampal neural progenitor cells (NPCs) were isolated from TgCRND8 mice, we demonstrated that (1) their neurogenic potential was higher compared with WTNPCs; (2) medium conditioned by TgCRND8 NPC promoted neuronal differentiation of WT NPCs; and (3) the proneurogenic effect of TgCRND8-conditioned medium was counteracted by blockade of the receptor for advanced glycation end products (RAGE)/nuclear factor-kappa B (NF-kappa B) axis. Furthermore, we showed that beta-amyloid 1-42 (A beta(1-42)) oligomers, but not monomers and fibrils, and the alarm in high-mobility group box-1 protein (HMGB-1) could promote neuronal differentiation of NPCs via activation of the RAGE/NF-kappa B axis. Altogether, these data suggest that, in AD brain, an endogenous proneurogenic response could be potentially triggered and involve signals (A beta(1-42) oligomers and HMGB-1) and pathways (RAGE/NF-kappa B activation) that also contribute to neuroinflammation/neurotoxicity. A more detailed analysis confirmed no significant increase of new mature neurons in hippocampi of TgCRND8 compared with WT mice, suggesting reduced survival and/or integration of newborn neurons. Therapeutic strategies in AD should ideally combine the ability of sustaining hippocampal neurogenesis as well as of counteracting an hostile brain microenvironment so to promote survival of vulnerable cell populations, including adult generated neurons.