Ho Lap, Qin Weiping, Pompl Patrick N, Xiang Zhongmin, Wang Jun, Zhao Zhong, Peng Yuanzhen, Cambareri Gina, Rocher Anne, Mobbs Charles V, Hof Patrick R, Pasinetti Giulio Maria
Neuroinflammation Research Laboratories, Department of Psychiatry, Mount Sinai School of Medicine, New York, New York, USA.
FASEB J. 2004 May;18(7):902-4. doi: 10.1096/fj.03-0978fje. Epub 2004 Mar 19.
Recent epidemiological evidence indicates that insulin resistance, a proximal cause of Type II diabetes [a non-insulin dependent form of diabetes mellitus (NIDDM)], is associated with an increased relative risk for Alzheimer's disease (AD). In this study we examined the role of dietary conditions leading to NIDDM-like insulin resistance on amyloidosis in Tg2576 mice, which model AD-like neuropathology. We found that diet-induced insulin resistance promoted amyloidogenic beta-amyloid (Abeta) Abeta1-40 and Abeta1-42 peptide generation in the brain that corresponded with increased gamma-secretase activities and decreased insulin degrading enzyme (IDE) activities. Moreover, increased Abeta production also coincided with increased AD-type amyloid plaque burden in the brain and impaired performance in a spatial water maze task. Further exploration of the apparent interrelationship of insulin resistance to brain amyloidosis revealed a functional decrease in insulin receptor (IR)-mediated signal transduction in the brain, as suggested by decreased IR beta-subunit (IRbeta) Y1162/1163 autophosphorylation and reduced phosphatidylinositol 3 (PI3)-kinase/pS473-AKT/Protein kinase (PK)-B in these same brain regions. This latter finding is of particular interest given the known inhibitory role of AKT/PKB on glycogen synthase kinase (GSK)-3alpha activity, which has previously been shown to promote Abeta peptide generation. Most interestingly, we found that decreased pS21-GSK-3alpha and pS9-GSK-3beta phosphorylation, which is an index of GSK activation, positively correlated with the generation of brain C-terminal fragment (CTF)-gamma cleavage product of amyloid precursor protein, an index of gamma-secretase activity, in the brain of insulin-resistant relative to normoglycemic Tg2576 mice. Our study is consistent with the hypothesis that insulin resistance may be an underlying mechanism responsible for the observed increased relative risk for AD neuropathology, and presents the first evidence to suggest that IR signaling can influence Abeta production in the brain.
近期的流行病学证据表明，胰岛素抵抗作为II型糖尿病（一种非胰岛素依赖型糖尿病，即NIDDM）的近端病因，与阿尔茨海默病（AD）的相对风险增加有关。在本研究中，我们研究了导致类似NIDDM的胰岛素抵抗的饮食条件对Tg2576小鼠淀粉样变性的作用，该小鼠模型具有类似AD的神经病理学特征。我们发现，饮食诱导的胰岛素抵抗促进了大脑中淀粉样β淀粉样蛋白（Aβ）Aβ1-40和Aβ1-42肽的生成，这与γ-分泌酶活性增加和胰岛素降解酶（IDE）活性降低相对应。此外，Aβ生成增加还与大脑中AD型淀粉样斑块负担增加以及空间水迷宫任务中的行为表现受损同时出现。对胰岛素抵抗与大脑淀粉样变性之间明显相互关系的进一步探索揭示，大脑中胰岛素受体（IR）介导的信号转导功能下降，这表现为这些相同脑区中IRβ亚基（IRβ）Y1162/1163自身磷酸化减少以及磷脂酰肌醇3（PI3）-激酶/pS473-AKT/蛋白激酶（PK）-B减少。鉴于已知AKT/PKB对糖原合酶激酶（GSK）-3α活性具有抑制作用，而此前已证明GSK-3α活性可促进Aβ肽生成，后一发现尤其令人感兴趣。最有趣的是，我们发现胰岛素抵抗的Tg2576小鼠大脑中，作为GSK激活指标的pS21-GSK-3α和pS9-GSK-3β磷酸化水平降低，与淀粉样前体蛋白的大脑C末端片段（CTF）-γ裂解产物的生成呈正相关，而CTF-γ裂解产物是γ-分泌酶活性的指标。我们的研究与以下假设一致，即胰岛素抵抗可能是导致观察到的AD神经病理学相对风险增加的潜在机制，并首次提供证据表明IR信号传导可影响大脑中Aβ的生成。
