Depletion of Caveolin-1 in Type 2 Diabetes Model Induces Alzheimer's Disease Pathology Precursors
Depletion of Caveolin-1 in Type 2 Diabetes Model Induces Alzheimer's Disease Pathology Precursors
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DOI：
10.1523/jneurosci.0730-19.2019
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发表时间：
2019-10-23
影响因子：
5.3
通讯作者：
Lazarov, Orly
中科院分区：
文献类型：
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作者：
Bonds, Jacqueline A.;Shetti, Aashutosh;Lazarov, Orly
2型糖尿病（T2DM）是迟发性阿尔茨海默病（AD）发展的危险因素。然而，迟发性痴呆的发病机制在很大程度上是未知的。本研究表明，与健康衰老相比，T2DM患者大脑中内皮富集蛋白小窝蛋白-1 （Cav-1）水平降低，且与β -淀粉样蛋白（A β）水平呈负相关。Cav-1的消耗在db/db （Lepr(db)）糖尿病小鼠的大脑中重现，并与识别记忆缺陷、淀粉样蛋白前体蛋白（APP）、BACE-1的上调、β -淀粉样蛋白a β(42/40)比例的增加和过度磷酸化的tau （p-tau）物种相对应。重要的是，我们发现使用过表达Cav-1的腺病毒（AAV-Cav-1）恢复雄性db/db小鼠大脑中的Cav-1水平可以挽救学习和记忆缺陷，并减少病理（即APP， BACE-1和p-tau水平）。在表达家族AD-linked APPswe突变变体的HEK细胞中，使用shRNA敲低Cav-1可上调APP、APP羧基末端片段和A β水平。反过来，Cav-1水平的恢复恢复APP代谢。总之，这些结果表明，Cav-1调节APP代谢，并且在T2DM中Cav-1的缺失促进APP的淀粉样变性加工和tau的过度磷酸化。这可能表明，在T2DM中Cav-1的缺失至少在一定程度上是AD发展的基础，并暗示Cav-1的恢复可能是糖尿病相关散发性AD的治疗靶点。
Type 2 diabetes mellitus (T2DM) is a risk factor for the development of late-onset Alzheimer's disease (AD). However, the mechanism underlying the development of late-onsetADis largely unknown. Here we show that levels of the endothelial-enriched protein caveolin-1 (Cav-1) are reduced in the brains of T2DM patients compared with healthy aging, and inversely correlated with levels of beta-amyloid (A beta). Depletion of Cav-1 is recapitulated in the brains of db/db (Lepr(db)) diabetic mice and corresponds with recognition memory deficits as well as the upregulation of amyloid precursor protein (APP), BACE-1, a trending increase in beta-amyloid A beta(42/40) ratio and hyperphosphorylated tau (p-tau) species. Importantly, we show that restoration of Cav-1 levels in the brains of male db/db mice using adenovirus overexpressing Cav-1 (AAV-Cav-1) rescues learning and memory deficits and reduces pathology (i.e., APP, BACE-1 and p-tau levels). Knocking down Cav-1 using shRNA in HEK cells expressing the familial AD-linked APPswe mutant variant upregulates APP, APP carboxyl terminal fragments, and A beta levels. In turn, rescue of Cav-1 levels restores APP metabolism. Together, these results suggest that Cav-1 regulates APP metabolism, and that depletion of Cav-1 in T2DM promotes the amyloidogenic processing of APP and hyperphosphorylation of tau. This may suggest that depletion of Cav-1 in T2DM underlies, at least in part, the development of AD and imply that restoration of Cav-1 may be a therapeutic target for diabetic-associated sporadic AD.