Parahippocampal gyrus expression of endothelial and insulin receptor signaling pathway genes is modulated by Alzheimer's disease and normalized by treatment with anti-diabetic agents.
Parahippocampal gyrus expression of endothelial and insulin receptor signaling pathway genes is modulated by Alzheimer's disease and normalized by treatment with anti-diabetic agents.
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DOI：
10.1371/journal.pone.0206547
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Haroutunian V
中科院分区：
文献类型：
--
作者：
Katsel P;Roussos P;Beeri MS;Gama-Sosa MA;Gandy S;Khan S;Haroutunian V
大量文献将认知能力下降、轻度认知障碍（MCI）和痴呆的风险与2型糖尿病（T2D）或糖尿病前期联系起来。越来越多的证据表明，脑胰岛素受体信号通路（IRSP）与β淀粉样蛋白、过度磷酸化和构象异常的tau蛋白的积累密切相关。我们之前的研究表明，在接受胰岛素和口服降糖药治疗的糖尿病患者中，阿尔茨海默病（AD）的神经病理特征有所降低。为了更好地了解AD中T2D和T2D药物的神经生物学底物，我们检测了对照组（N = 30）、AD患者（N = 19）和AD合并T2D患者海马旁回的IRSP和内皮细胞标志物，这些患者依次接受了抗糖尿病药物（胰岛素和/或口服药物；N = 34）的治疗。我们研究了来自海马旁回的大量死后组织和来自同一脑区域的内皮细胞富集分离物中IRSP选定成员和选择性内皮细胞标记物的基因表达。结果表明，AD患者海马旁回的基因表达（大块组织匀浆和内皮细胞分离物）明显异常和减少，这些基因直接与微血管和IRSP相关。我们的研究结果还显示，在糖尿病性AD供者中，接受抗糖尿病药物治疗的微血管和IRSP相关基因的异常表达数量显著减少。这些发现表明，抗糖尿病治疗可以降低或使AD患者微血管和IRSP功能受损或正常化。
A large body of literature links risk of cognitive decline, mild cognitive impairment (MCI) and dementia with Type 2 Diabetes (T2D) or pre-diabetes. Accumulating evidence implicates a close relationship between the brain insulin receptor signaling pathway (IRSP) and the accumulation of amyloid beta and hyperphosphorylated and conformationally abnormal tau. We showed previously that the neuropathological features of Alzheimer’s disease (AD were reduced in patients with diabetes who were treated with insulin and oral antidiabetic medications. To understand better the neurobiological substrates of T2D and T2D medications in AD, we examined IRSP and endothelial cell markers in the parahippocampal gyrus of controls (N = 30), of persons with AD (N = 19), and of persons with AD and T2D, who, in turn, had been treated with anti-diabetic drugs (insulin and or oral agents; N = 34). We studied the gene expression of selected members of the IRSP and selective endothelial cell markers in bulk postmortem tissue from the parahippocampal gyrus and in endothelial cell enriched isolates from the same brain region. The results indicated that there are considerable abnormalities and reductions in gene expression (bulk tissue homogenates and endothelial cell isolates) in the parahippocampal gyri of persons with AD that map directly to genes associated with the microvasculature and the IRSP. Our results also showed that the numbers of abnormally expressed microvasculature and IRSP associated genes in diabetic AD donors who had been treated with anti-diabetic agents were reduced significantly. These findings suggest that anti-diabetic treatments may reduce or normalize compromised microvascular and IRSP functions in AD.
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DOI：
10.1038/nrneurol.2017.185
发表时间：
2018-03
期刊：
Nature reviews. Neurology
影响因子：
--
作者：
Arnold SE;Arvanitakis Z;Macauley-Rambach SL;Koenig AM;Wang HY;Ahima RS;Craft S;Gandy S;Buettner C;Stoeckel LE;Holtzman DM;Nathan DM
通讯作者：
Nathan DM
影响因子：
--
作者：
Craft, Suzanne;Baker, Laura D.;Montine, Thomas J.;Minoshima, Satoshi;Watson, G. Stennis;Claxton, Amy;Arbuckle, Matthew;Callaghan, Maureen;Tsai, Elaine;Plymate, Stephen R.;Green, Pattie S.;Leverenz, James;Cross, Donna;Gerton, Brooke
通讯作者：
Gerton, Brooke
DOI：
10.1093/gerona/60.4.471
发表时间：
2005-04-01
影响因子：
5.1
作者：
Beeri, MS;Silverman, JM;Haroutunian, V
通讯作者：
Haroutunian, V
影响因子：
9.9
作者：
Beeri, M. S.;Schmeidler, J.;Haroutunian, V.
通讯作者：
Haroutunian, V.
影响因子：
6.1
作者：
Arnold SE;Lucki I;Brookshire BR;Carlson GC;Browne CA;Kazi H;Bang S;Choi BR;Chen Y;McMullen MF;Kim SF
通讯作者：
Kim SF