Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Geriatric Research Education and Clinical Center, VA Pittsburgh Healthcare System, Pittsburgh, PA, USA.
J Alzheimers Dis. 2023;94(1):227-246. doi: 10.3233/JAD-221063.
Altered glutamatergic neurotransmission may contribute to impaired default mode network (DMN) function in Alzheimer's disease (AD). Among the DMN hub regions, frontal cortex (FC) was suggested to undergo a glutamatergic plasticity response in prodromal AD, while the status of glutamatergic synapses in the precuneus (PreC) during clinical-neuropathological AD progression is not known.
To quantify vesicular glutamate transporter VGluT1- and VGluT2-containing synaptic terminals in PreC and FC across clinical stages of AD.
Unbiased sampling and quantitative confocal immunofluorescence of cortical VGluT1- and VGluT2-immunoreactive profiles and spinophilin-labeled dendritic spines were performed in cases with no cognitive impairment (NCI), mild cognitive impairment (MCI), mild-moderate AD (mAD), or moderate-severe AD (sAD).
In both regions, loss of VGluT1-positive profile density was seen in sAD compared to NCI, MCI, and mAD. VGluT1-positive profile intensity in PreC did not differ across groups, while in FC it was greater in MCI, mAD, and sAD compared to NCI. VGluT2 measures were stable in PreC while FC had greater VGluT2-positive profile density in MCI compared to sAD, but not NCI or mAD. Spinophilin measures in PreC were lower in mAD and sAD compared to NCI, while in FC they were stable across groups. Lower VGluT1 and spinophilin measures in PreC, but not FC, correlated with greater neuropathology.
Frank loss of VGluT1 in advanced AD relative to NCI occurs in both DMN regions. In FC, an upregulation of VGluT1 protein content in remaining glutamatergic terminals may contribute to this region's plasticity response in AD.
谷氨酸能神经传递的改变可能导致阿尔茨海默病（AD）中默认模式网络（DMN）功能受损。在 DMN 枢纽区域中，额叶皮层（FC）在 AD 前驱期被认为经历了谷氨酸能可塑性反应，而在临床-神经病理学 AD 进展过程中，楔前叶（PreC）的谷氨酸能突触状态尚不清楚。
定量 AD 各临床阶段 PreC 和 FC 中囊泡谷氨酸转运体 VGluT1 和 VGluT2 包含的突触末端。
在无认知障碍（NCI）、轻度认知障碍（MCI）、轻度中度 AD（mAD）或中度重度 AD（sAD）病例中，进行皮质 VGluT1 和 VGluT2 免疫反应性轮廓和 spinophilin 标记的树突棘的无偏采样和定量共聚焦免疫荧光。
在两个区域，sAD 中 VGluT1 阳性轮廓密度的丧失均高于 NCI、MCI 和 mAD。PreC 中 VGluT1 阳性轮廓强度在各组之间没有差异，而在 FC 中，MCI、mAD 和 sAD 均高于 NCI。在 PreC 中 VGluT2 测量值稳定，而在 FC 中，MCI 中 VGluT2 阳性轮廓密度高于 sAD，但低于 NCI 或 mAD。PreC 中的 spinophilin 测量值在 mAD 和 sAD 中低于 NCI，而在 FC 中各组之间稳定。PreC 中较低的 VGluT1 和 spinophilin 测量值与较大的神经病理学相关，而在 FC 中则与各组无相关性。
与 NCI 相比，AD 晚期 FC 和 DMN 两个区域中均出现 VGluT1 的明显丧失。在 FC 中，剩余谷氨酸能末梢中 VGluT1 蛋白含量的上调可能导致该区域在 AD 中的可塑性反应。
