Loss of caveolin-1 accelerates neurodegeneration and aging.
Loss of caveolin-1 accelerates neurodegeneration and aging.
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DOI：
10.1371/journal.pone.0015697
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发表时间：
2010-12-23
期刊：
影响因子：
3.7
通讯作者：
Patel HH
中科院分区：
文献类型：
--
作者：
Head BP;Peart JN;Panneerselvam M;Yokoyama T;Pearn ML;Niesman IR;Bonds JA;Schilling JM;Miyanohara A;Headrick J;Ali SS;Roth DM;Patel PM;Patel HH
衰老的大脑表现出灰质的丧失以及棘和突触密度的减少，这可能是阿尔茨海默氏症等神经退行性疾病的后遗症。膜/脂筏 (MLR) 是富含胆固醇、鞘糖脂和鞘磷脂的质膜离散区域，对于突触的发育和稳定至关重要。 Caveolin-1 (Cav-1) 是一种胆固醇结合蛋白，在 MLR 内组织突触信号传导成分。目前尚不清楚突触的丧失是否取决于与年龄相关的 Cav-1 表达的丧失，以及这是否对阿尔茨海默病等神经退行性疾病有影响。我们分析了年轻小鼠（Yg，3-6 个月）、中年小鼠（Md，12 个月）、老年小鼠（Ag，>18 个月）和年轻 Cav-1 KO 小鼠的大脑，结果表明，老年海马中 PSD-95、NR2A、NR2B、TrkBR、AMPAR 和 Cav-1 对 MLR 的定位减少。年轻的 Cav-1 KO 小鼠表现出神经元过早衰老和变性的迹象。 Cav-1 KO 小鼠的海马突触体显示 PSD-95、NR2A、NR2B 和 Cav-1 减少，与年轻 WT 小鼠相比，无法防止脑缺血再灌注损伤；与年轻 WT 小鼠相比，Aβ、P-Tau 和星形胶质细胞增多，脑血管体积减少。与衰老的海马一样，Cav-1 KO 大脑的突触显着减少。体外 Cav-1 KO 神经元中 Cav-1 的神经元靶向重新表达降低了 Aβ 表达。因此，Cav-1 代表了健康神经元衰老的新控制点，而 Cav-1 的缺失代表了阿尔茨海默病的非突变模型。
The aged brain exhibits a loss in gray matter and a decrease in spines and synaptic densities that may represent a sequela for neurodegenerative diseases such as Alzheimer's. Membrane/lipid rafts (MLR), discrete regions of the plasmalemma enriched in cholesterol, glycosphingolipids, and sphingomyelin, are essential for the development and stabilization of synapses. Caveolin-1 (Cav-1), a cholesterol binding protein organizes synaptic signaling components within MLR. It is unknown whether loss of synapses is dependent on an age-related loss of Cav-1 expression and whether this has implications for neurodegenerative diseases such as Alzheimer's disease. We analyzed brains from young (Yg, 3-6 months), middle age (Md, 12 months), aged (Ag, >18 months), and young Cav-1 KO mice and show that localization of PSD-95, NR2A, NR2B, TrkBR, AMPAR, and Cav-1 to MLR is decreased in aged hippocampi. Young Cav-1 KO mice showed signs of premature neuronal aging and degeneration. Hippocampi synaptosomes from Cav-1 KO mice showed reduced PSD-95, NR2A, NR2B, and Cav-1, an inability to be protected against cerebral ischemia-reperfusion injury compared to young WT mice, increased Aβ, P-Tau, and astrogliosis, decreased cerebrovascular volume compared to young WT mice. As with aged hippocampi, Cav-1 KO brains showed significantly reduced synapses. Neuron-targeted re-expression of Cav-1 in Cav-1 KO neurons in vitro decreased Aβ expression. Therefore, Cav-1 represents a novel control point for healthy neuronal aging and loss of Cav-1 represents a non-mutational model for Alzheimer's disease.
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影响因子：
3.1
作者：
Elder, Gregory A.;Sosa, Miguel A. Gama;De Gasperi, Rita;Dickstein, Dara L.;Hof, Patrick R.
通讯作者：
Hof, Patrick R.
影响因子：
--
作者：
Dickstein, Dara L.;Walsh, Jessica;Brautigam, Hannah;Stockton, Steven D., Jr.;Gandy, Samuel;Hof, Patrick R.
通讯作者：
Hof, Patrick R.
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
5.3
作者：
Cecchi C;Rosati F;Pensalfini A;Formigli L;Nosi D;Liguri G;Dichiara F;Morello M;Danza G;Pieraccini G;Peri A;Serio M;Stefani M
通讯作者：
Stefani M
影响因子：
16.2
作者：
Elia, Lisa P.;Yamamoto, Miya;Reichardt, Louis F.
通讯作者：
Reichardt, Louis F.