Inhibitory synapse loss and accumulation of amyloid beta in inhibitory presynaptic terminals in Alzheimer's disease
Inhibitory synapse loss and accumulation of amyloid beta in inhibitory presynaptic terminals in Alzheimer's disease
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DOI：
10.1111/ene.15043
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发表时间：
2021-08-12
影响因子：
5.1
通讯作者：
Spires-Jones, Tara L.
中科院分区：
文献类型：
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作者：
Kurucu, Hatice;Colom-Cadena, Marti;Spires-Jones, Tara L.
背景和目的阿尔茨海默病 (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，已知病理性淀粉样蛋白 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的变化，但人们对抑制性突触的病理学知之甚少。方法 这里对来自颞叶和枕叶皮质的人类死后大脑样本（n = 5 名对照，10 名 AD 病例）进行了检查，以研究 AD 中抑制性突触和神经元是否丢失以及 Aβ 是否可能导致抑制性突触变性。使用立体学软件对所有六个皮质层中的抑制性神经元进行计数，并使用阵列断层扫描检查突触密度和突触末端 Aβ 的积累。结果在不同的皮质层中观察到不同的抑制神经元密度。在两个大脑区域的第 4 层观察到最高的抑制性神经元密度，并且视觉皮层的抑制性神经元密度高于颞叶皮层。 AD 患者所有六个皮质层的抑制性神经元密度均显着低于对照病例。高分辨率阵列断层扫描成像显示，与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梢中积聚，其中在淀粉样蛋白斑块附近积聚最多。结论 AD 中的抑制性神经元和突触丢失可能导致兴奋/抑制平衡破坏和认知能力下降。未来的工作有必要确定针对抑制性突触损失是否可能是一种有用的治疗策略。
Background and purpose 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 (A beta) 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. Methods 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 A beta 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 A beta in synaptic terminals. Results 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 A beta in a small subset of inhibitory presynaptic terminals with the most accumulation near amyloid plaques. Conclusions 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.