Department of Pharmaceutical Sciences, University of Eastern Piedmont Amedeo Avogadro, Novara 28100, Italy.
J Neurosci. 2013 Apr 3;33(14):6047-59. doi: 10.1523/JNEUROSCI.2052-12.2013.
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 WT NPCs; (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-κB (NF-κB) axis. Furthermore, we showed that β-amyloid 1-42 (Aβ(1-42)) oligomers, but not monomers and fibrils, and the alarmin high-mobility group box-1 protein (HMGB-1) could promote neuronal differentiation of NPCs via activation of the RAGE/NF-κB axis. Altogether, these data suggest that, in AD brain, an endogenous proneurogenic response could be potentially triggered and involve signals (Aβ(1-42) oligomers and HMGB-1) and pathways (RAGE/NF-κB 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.
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），在 AD 中，它可能代表一种自动修复机制，可以抵消神经元丢失和认知障碍。我们评估了 TgCRND8 小鼠的海马神经发生，并报告说，在 32 周龄时，相当于 AD 样神经病理学的晚期阶段，与野生型（WT）同窝仔相比，增殖细胞、双皮质素表达祖细胞/神经母细胞和早期有丝分裂后 calretinin 表达神经元的数量增加。当从小鼠海马神经前体细胞（NPCs）中分离出 NPCs 时，我们证明：（1）与 WT NPCs 相比，它们的神经发生潜力更高；（2）TgCRND8 NPC 条件培养基促进 WT NPCs 的神经元分化；（3）TgCRND8 条件培养基的促神经发生作用被阻断受体的先进糖基化终产物（RAGE）/核因子 - κB（NF-κB）轴。此外，我们还表明，β-淀粉样蛋白 1-42（Aβ（1-42））低聚物，而不是单体和纤维，以及警报素高迁移率族蛋白 B1（HMGB-1）可以通过激活 RAGE/NF-κB 轴促进 NPCs 的神经元分化。总之，这些数据表明，在 AD 大脑中，一种内源性的促神经发生反应可能被触发，涉及信号（Aβ（1-42）低聚物和 HMGB-1）和途径（RAGE/NF-κB 激活）也有助于神经炎症/神经毒性。更详细的分析证实，与 WT 小鼠相比，TgCRND8 小鼠海马中新成熟神经元的数量没有显著增加，这表明新生神经元的存活和/或整合减少。AD 的治疗策略理想情况下应结合维持海马神经发生的能力以及对抗敌对的脑微环境的能力，以促进包括成年产生的神经元在内的脆弱细胞群体的存活。
