Rivera Enrique J, Goldin Alison, Fulmer Noah, Tavares Rose, Wands Jack R, de la Monte Suzanne M
Department of Pathology, Rhode Island Hospital and Brown Medical School, Providence, RI 02903, USA.
J Alzheimers Dis. 2005 Dec;8(3):247-68. doi: 10.3233/jad-2005-8304.
Reduced glucose utilization and energy metabolism occur early in the course of Alzheimer's disease (AD) and correlate with impaired cognition. Glucose utilization and energy metabolism are regulated by insulin and insulin-like growth factor I (IGF-I), and correspondingly, studies have shown that cognitive impairment may be improved by glucose or insulin administration. Recently, we demonstrated significantly reduced levels of insulin and IGF-I polypeptide genes and their corresponding receptors in advanced AD relative to aged control brains. The abnormalities in gene expression were accompanied by impaired survival signaling downstream through PI3 kinase-Akt. The present work characterizes the abnormalities in insulin and IGF gene expression and receptor binding in brains with different Braak stage severities of AD. Realtime quantitative RT-PCR analysis of frontal lobe tissue demonstrated that increasing AD Braak Stage was associated with progressively reduced levels of mRNA corresponding to insulin, IGF-I, and IGF-II polypeptides and their receptors, tau, which is regulated by insulin and IGF-I, and the Hu D neuronal RNA binding protein. In contrast, progressively increased levels of amyloid beta protein precursor (AbetaPP), glial fibrillary acidic protein, and the IBA1/AIF1 microglial mRNA transcripts were detected with increasing AD Braak Stage. Impairments in growth factor and growth factor receptor expression and function were associated with increasing AD Braak stage dependent reductions in insulin, IGF-I, and IGF-II receptor binding, ATP levels, and choline acetyltransferase (ChAT) expression. Further studies demonstrated that: 1) ChAT expression increases with insulin or IGF-I stimulation; 2) ChAT is expressed in insulin and IGF-I receptor-positive cortical neurons; and 3) ChAT co-localization in insulin or IGF-I receptor-positive neurons is reduced in AD. Together, these data provide further evidence that AD represents a neuro-endocrine disorder that resembles a unique form of diabetes mellitus (? Type 3) and progresses with severity of neurodegeneration.
葡萄糖利用和能量代谢的降低在阿尔茨海默病（AD）病程早期就会出现，且与认知功能受损相关。葡萄糖利用和能量代谢受胰岛素和胰岛素样生长因子I（IGF-I）调节，相应地，研究表明给予葡萄糖或胰岛素可改善认知障碍。最近，我们发现相对于老年对照脑，晚期AD患者胰岛素和IGF-I多肽基因及其相应受体水平显著降低。基因表达异常伴随着PI3激酶-Akt下游存活信号受损。本研究描述了不同Braak分期严重程度的AD脑内胰岛素和IGF基因表达及受体结合的异常情况。额叶组织的实时定量RT-PCR分析表明，随着AD Braak分期增加，与胰岛素、IGF-I、IGF-II多肽及其受体、受胰岛素和IGF-I调节的tau以及Hu D神经元RNA结合蛋白相对应的mRNA水平逐渐降低。相反，随着AD Braak分期增加，淀粉样β蛋白前体（AbetaPP）、胶质纤维酸性蛋白和IBA1/AIF1小胶质细胞mRNA转录本水平逐渐升高。生长因子和生长因子受体表达及功能的受损与AD Braak分期依赖性增加的胰岛素、IGF-I和IGF-II受体结合减少、ATP水平降低以及胆碱乙酰转移酶（ChAT）表达减少相关。进一步研究表明：1）胰岛素或IGF-I刺激可使ChAT表达增加；2）ChAT在胰岛素和IGF-I受体阳性的皮质神经元中表达；3）AD患者中ChAT在胰岛素或IGF-I受体阳性神经元中的共定位减少。总之，这些数据进一步证明AD代表一种神经内分泌疾病，类似于一种独特形式的糖尿病（？3型），并随着神经退行性变的严重程度而进展。
