Transcriptome Analysis of Synaptoneurosomes Identifies Neuroplasticity Genes Overexpressed in Incipient Alzheimer's Disease

In Alzheimer's disease (AD), early deficits in learning and memory are a consequence of synaptic modification induced by toxic beta-amyloid oligomers (oAβ). To identify immediate molecular targets downstream of oAβ binding, we prepared synaptoneurosomes from prefrontal cortex of control and incipient AD (IAD) patients, and isolated mRNAs for comparison of gene expression. This novel approach concentrates synaptic mRNA, thereby increasing the ratio of synaptic to somal mRNA and allowing discrimination of expression changes in synaptically localized genes. In IAD patients, global measures of cognition declined with increasing levels of dimeric Aβ (dAβ). These patients also showed increased expression of neuroplasticity related genes, many encoding 3′UTR consensus sequences that regulate translation in the synapse. An increase in mRNA encoding the GluR2 subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) was paralleled by elevated expression of the corresponding protein in IAD. These results imply a functional impact on synaptic transmission as GluR2, if inserted, maintains the receptors in a low conductance state. Some overexpressed genes may induce early deficits in cognition and others compensatory mechanisms, providing targets for intervention to moderate the response to dAβ.

阿尔茨海默病（Alzheimer's disease, AD）中，早期学习与记忆缺陷是毒性β淀粉样蛋白寡聚体（beta-amyloid oligomers, oAβ）诱导突触修饰的结果。为鉴定oAβ结合下游的直接分子靶点，我们从对照个体及始发期阿尔茨海默病（incipient AD, IAD）患者的前额叶皮层制备了突触神经小体（synaptoneurosomes），并分离mRNA以进行基因表达比较。该创新方法可富集突触mRNA，从而提升突触mRNA与胞体mRNA的比例，便于区分突触定位基因的表达变化。在IAD患者中，整体认知评分随二聚体Aβ（dAβ）水平升高而下降。此类患者还表现出神经可塑性相关基因的表达上调，其中诸多基因编码可调控突触翻译的3'非翻译区（3' untranslated region, 3′UTR）保守序列。编码α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor, AMPAR）GluR2亚基的mRNA水平上调，与IAD患者中对应蛋白的表达升高相平行。上述结果提示其对突触传递具有功能性影响：若GluR2亚基被插入受体，可使受体维持于低电导状态。部分过表达基因可诱发早期认知缺陷，另有部分则介导代偿机制，这些发现可为干预手段提供靶点，以调节机体对dAβ的应答反应。