背景:阿尔茨海默病(AD)是痴呆的最常见形式,其特征是神经可塑性大大降低。我们以前的工作表明,参与记忆功能的神经元可能会失去可塑性,因为在人类AD大脑的内嗅皮层(EC)中多唾液酸化神经细胞粘附分子(PSA-NCAM)的蛋白质水平降低,但这种下降的原因尚不清楚。
目的:研究参与PSA-NCAM调控的基因,这些基因可能是其在ADEC中降低的基础。
方法:我们对神经正常和AD人类EC切片进行多重荧光原位杂交和免疫组织化学,以研究参与PSA-NCAM调节的基因。试图在人组织和AD小鼠模型中验证基因表达变化。
结果:在ADEC中,表达高水平CALB2mRNA的细胞群体和表达高水平PSTmRNA的细胞群体均减少。CALB2mRNA和蛋白在全球范围内没有下降,表明CALB2的减少是细胞亚群特有的。在AD患者的颞中回组织微阵列核心中,通过单重原位杂交观察到PSTmRNA表达显着降低,与tau病理学呈负相关,暗示整个AD大脑中PST表达的整体损失。在9月龄的MAPTP301S小鼠脑中没有观察到PSA-NCAM或PST蛋白表达的显著差异。
结论:我们得出结论,PSA-NCAM失调可能会导致AD随后的结构可塑性丧失,这可能是由于PSTmRNA表达的丧失。由于PST参与结构可塑性,通过靶向这个被破坏的可塑性途径,可能对AD进行干预.
Alzheimer\'s disease (AD) is the most common form of dementia and is characterized by a substantial reduction of neuroplasticity. Our previous work demonstrated that neurons involved in memory function may lose plasticity because of decreased protein levels of polysialylated neural cell adhesion molecule (PSA-NCAM) in the entorhinal cortex (EC) of the human AD brain, but the cause of this decrease is unclear.
To investigate genes involved in PSA-NCAM regulation which may underlie its decrease in the AD EC.
We subjected neurologically normal and AD human EC sections to multiplexed fluorescent in situ hybridization and immunohistochemistry to investigate genes involved in PSA-NCAM regulation. Gene expression changes were sought to be validated in both human tissue and a mouse model of AD.
In the AD EC, a cell population expressing a high level of CALB2 mRNA and a cell population expressing a high level of PST mRNA were both decreased. CALB2 mRNA and protein were not decreased globally, indicating that the decrease in CALB2 was specific to a sub-population of cells. A significant decrease in PST mRNA expression was observed with single-plex in situ hybridization in middle temporal gyrus tissue microarray cores from AD patients, which negatively correlated with tau pathology, hinting at global loss in PST expression across the AD brain. No significant differences in PSA-NCAM or PST protein expression were observed in the MAPT P301S mouse brain at 9 months of age.
We conclude that PSA-NCAM dysregulation may cause subsequent loss of structural plasticity in AD, and this may result from a loss of PST mRNA expression. Due PSTs involvement in structural plasticity, intervention for AD may be possible by targeting this disrupted plasticity pathway.