Laboratory of Neurophysiology, Department of Physiology, Universidad de Concepción, Barrio Universitario S/N, P. O. Box 160-C, Concepción, Chile.
Sci Rep. 2020 Nov 11;10(1):19606. doi: 10.1038/s41598-020-76456-w.
Several previous studies showed that hippocampus and cortex are affected in Alzheimer's disease (AD). However, other brain regions have also been found to be affected and could contribute with new critical information to the pathophysiological basis of AD. For example, volumetric studies in humans have shown a significant atrophy of the striatum, particularly in the nucleus Accumbens (nAc). The nAc is a key component of the limbic reward system and it is involved in cognition and emotional behaviors such as pleasure, fear, aggression and motivations, all of which are affected in neurodegenerative diseases such as AD. However, its role in AD has not been extensively studied. Therefore, using an AD mouse model, we investigated if the nAc was affected in 6 months old transgenic 2xTg (APP/PS1) mice. Immunohistochemistry (IHC) analysis in 2xTg mice showed increased intraneuronal Aβ accumulation, as well as occasional extracellular amyloid deposits detected through Thioflavin-S staining. Interestingly, the intracellular Aβ pathology was associated to an increase in membrane excitability in dissociated medium spiny neurons (MSNs) of the nAc. IHC and western blot analyses showed a decrease in glycine receptors (GlyR) together with a reduction in the pre- and post-synaptic markers SV2 and gephyrin, respectively, which correlated with a decrease in glycinergic miniature synaptic currents in nAc brain slices. Additionally, voltage-clamp recordings in dissociated MSNs showed a decrease in AMPA- and Gly-evoked currents. Overall, these results showed intracellular Aβ accumulation together with an increase in excitability and synaptic alterations in this mouse model. These findings provide new information that might help to explain changes in motivation, anhedonia, and learning in the onset of AD pathogenesis.
先前的几项研究表明，海马体和大脑皮层在阿尔茨海默病（AD）中受到影响。然而，其他大脑区域也被发现受到影响，并且可以为 AD 的病理生理基础提供新的关键信息。例如，人类的容积研究表明纹状体，特别是伏隔核（nAc）显著萎缩。nAc 是边缘奖赏系统的关键组成部分，涉及认知和情绪行为，如愉悦、恐惧、攻击和动机，所有这些在神经退行性疾病如 AD 中都受到影响。然而，它在 AD 中的作用尚未得到广泛研究。因此，我们使用 AD 小鼠模型研究了 6 个月大的转基因 2xTg（APP/PS1）小鼠的 nAc 是否受到影响。2xTg 小鼠的免疫组织化学（IHC）分析显示，细胞内 Aβ 积累增加，通过 Thioflavin-S 染色偶尔检测到细胞外淀粉样蛋白沉积。有趣的是，细胞内 Aβ 病理学与分离的中脑伏隔核（nAc）中的中间神经元（MSNs）膜兴奋性增加有关。IHC 和 Western blot 分析显示甘氨酸受体（GlyR）减少，同时突触前和突触后标志物 SV2 和 gephyrin 分别减少，这与 nAc 脑片中甘氨酸能微小突触电流减少相关。此外，分离的 MSNs 的电压钳记录显示 AMPA 和 Gly 诱发电流减少。总体而言，这些结果显示细胞内 Aβ 积累与兴奋性增加和突触改变在该小鼠模型中相关。这些发现提供了新的信息，可能有助于解释 AD 发病机制开始时动机、快感缺失和学习的变化。
