Molecular Developmental Neurobiology Group, IRBLleida-UDL Rovira Roure 82, 25198 Lleida, Spain.
Institute of Molecular Psychiatry, Medical Faculty, University of Bonn, 53127 Bonn, Germany.
Int J Mol Sci. 2021 Oct 4;22(19):10744. doi: 10.3390/ijms221910744.
In recent decades, neurogenesis in the adult brain has been well demonstrated in a number of animal species, including humans. Interestingly, work with rodents has shown that adult neurogenesis in the dentate gyrus (DG) of the hippocampus is vital for some cognitive aspects, as increasing neurogenesis improves memory, while its disruption triggers the opposite effect. Adult neurogenesis declines with age and has been suggested to play a role in impaired progressive learning and memory loss seen in Alzheimer's disease (AD). Therefore, therapeutic strategies designed to boost adult hippocampal neurogenesis may be beneficial for the treatment of AD. The precursor forms of neurotrophins, such as pro-NGF, display remarkable increase during AD in the hippocampus and entorhinal cortex. In contrast to mature NGF, pro-NGF exerts adverse functions in survival, proliferation, and differentiation. Hence, we hypothesized that pro-NGF and its p75 neurotrophin receptor (p75NTR) contribute to disrupting adult hippocampal neurogenesis during AD. To test this hypothesis, in this study, we took advantage of the availability of mouse models of AD (APP/PS1), which display memory impairment, and AD human samples to address the role of pro-NGF/p75NTR signaling in different aspects of adult neurogenesis. First, we observed that DG doublecortin (DCX) + progenitors express p75NTR both, in healthy humans and control animals, although the percentage of DCX+ cells are significantly reduced in AD. Interestingly, the expression of p75NTR in these progenitors is significantly decreased in AD conditions compared to controls. In order to assess the contribution of the pro-NGF/p75NTR pathway to the memory deficits of APP/PS1 mice, we injected pro-NGF neutralizing antibodies (anti-proNGF) into the DG of control and APP/PS1 mice and animals are subjected to a Morris water maze test. Intriguingly, we observed that anti-pro-NGF significantly restored memory performance of APP/PS1 animals and significantly increase the percentage of DCX+ progenitors in the DG region of these animals. In summary, our results suggest that pro-NGF is involved in disrupting spatial memory in AD, at least in part by blocking adult neurogenesis. Moreover, we propose that adult neurogenesis alteration should be taken into consideration for better understanding of AD pathology. Additionally, we provide a new molecular entry point (pro-NGF/p75NTR signaling) as a promising therapeutic target in AD.
在最近几十年中，许多动物物种（包括人类）的成年大脑中已经证明了神经发生。有趣的是，啮齿动物的研究表明，海马齿状回（DG）中的成年神经发生对于某些认知方面至关重要，因为增加神经发生可以改善记忆，而破坏其神经发生则会产生相反的效果。成年神经发生随着年龄的增长而下降，并且被认为在阿尔茨海默病（AD）中观察到的进行性学习和记忆丧失中起作用。因此，旨在促进成年海马神经发生的治疗策略可能对 AD 的治疗有益。神经生长因子的前体形式，例如前神经生长因子（pro-NGF），在 AD 中海马和内嗅皮层中显示出显著增加。与成熟的 NGF 相反，pro-NGF 在存活，增殖和分化中发挥不利作用。因此，我们假设 pro-NGF 和其 p75 神经营养因子受体（p75NTR）有助于在 AD 期间破坏成年海马神经发生。为了验证这一假设，在这项研究中，我们利用了 AD （APP / PS1）小鼠模型的可用性，该模型显示出记忆障碍和 AD 人类样本，以解决 pro-NGF / p75NTR 信号在成年神经发生的不同方面的作用。首先，我们观察到 DG 双皮质素（DCX）+祖细胞在健康的人类和对照动物中均表达 p75NTR，尽管 AD 中的 DCX +细胞的百分比明显降低。有趣的是，与对照相比，这些祖细胞中 p75NTR 的表达在 AD 条件下显着降低。为了评估 pro-NGF / p75NTR 途径对 APP / PS1 小鼠记忆缺陷的贡献，我们将 pro-NGF 中和抗体（抗 proNGF）注入对照组和 APP / PS1 小鼠的 DG 中，然后将动物进行 Morris 水迷宫测试。有趣的是，我们观察到抗 pro-NGF 可显着恢复 APP / PS1 动物的记忆表现，并显着增加这些动物 DG 区域的 DCX +祖细胞的百分比。总之，我们的研究结果表明，pro-NGF 参与了 AD 中空间记忆的破坏，至少部分是通过阻断成年神经发生来实现的。此外，我们认为，对于更好地理解 AD 病理学，应考虑成年神经发生的改变。此外，我们提供了一个新的分子切入点（pro-NGF / p75NTR 信号传导），作为 AD 的有希望的治疗靶标。
