University of Edinburgh Centre for Discovery Brain Sciences and UK Dementia Research Institute, Edinburgh, UK.
Centre for Clinical Brain Sciences and Sudden Death Brain Bank, University of Edinburgh, Edinburgh, UK.
Eur J Neurol. 2022 May;29(5):1311-1323. doi: 10.1111/ene.15043. Epub 2021 Aug 12.
Synapse degeneration in Alzheimer's disease (AD) correlates strongly with cognitive decline. There is well-established excitatory synapse loss in AD with known contributions of pathological amyloid beta (Aβ) to excitatory synapse dysfunction and loss. Despite clear changes in circuit excitability in AD and model systems, relatively little is known about pathology in inhibitory synapses.
Here human postmortem brain samples (n = 5 control, 10 AD cases) from temporal and occipital cortices were examined to investigate whether inhibitory synapses and neurons are lost in AD and whether Aβ may contribute to inhibitory synapse degeneration. Inhibitory neurons were counted in all six cortical layers using stereology software, and array tomography was used to examine synapse density and the accumulation of Aβ in synaptic terminals.
Differing inhibitory neuron densities were observed in the different cortical layers. The highest inhibitory neuron density was observed in layer 4 in both brain regions and the visual cortex had a higher inhibitory neuron density than the temporal cortex. There was significantly lower inhibitory neuron density in AD than in control cases in all six cortical layers. High-resolution array tomography imaging revealed plaque-associated loss of inhibitory synapses and accumulation of Aβ in a small subset of inhibitory presynaptic terminals with the most accumulation near amyloid plaques.
Inhibitory neuron and synapse loss in AD may contribute to disrupted excitatory/inhibitory balance and cognitive decline. Future work is warranted to determine whether targeting inhibitory synapse loss could be a useful therapeutic strategy.
阿尔茨海默病（AD）中的突触退化与认知能力下降密切相关。AD 中存在明确的兴奋性突触丧失，已知病理性淀粉样β（Aβ）对兴奋性突触功能障碍和丧失有贡献。尽管 AD 和模型系统中的电路兴奋性发生了明显变化，但关于抑制性突触的病理变化知之甚少。
本研究使用来自颞叶和枕叶皮质的人类死后脑组织样本（n=5 例对照，10 例 AD 病例），以研究 AD 中是否存在抑制性突触和神经元丧失，以及 Aβ 是否可能导致抑制性突触退化。使用立体学软件在所有 6 个皮质层中计数抑制性神经元，并使用阵列断层扫描检查突触密度和突触末端 Aβ的积累。
在不同的皮质层中观察到不同的抑制性神经元密度。在两个脑区和视觉皮质中，最高的抑制性神经元密度出现在第 4 层，而颞叶皮质的抑制性神经元密度高于颞叶皮质。在所有 6 个皮质层中，AD 患者的抑制性神经元密度明显低于对照组。高分辨率阵列断层扫描成像显示，斑块相关的抑制性突触丧失和 Aβ在一小部分抑制性突触前末端的积累，在淀粉样斑块附近积累最多。
AD 中的抑制性神经元和突触丧失可能导致兴奋性/抑制性平衡破坏和认知能力下降。未来需要进一步研究，以确定靶向抑制性突触丧失是否是一种有用的治疗策略。
