Mechanisms underlying the rapid peroxisome proliferator-activated receptor-γ-mediated amyloid clearance and reversal of cognitive deficits in a murine model of Alzheimer's disease.
Mechanisms underlying the rapid peroxisome proliferator-activated receptor-γ-mediated amyloid clearance and reversal of cognitive deficits in a murine model of Alzheimer's disease.
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DOI：
10.1523/jneurosci.5268-11.2012
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发表时间：
2012-07-25
期刊：
影响因子：
--
通讯作者：
Landreth GE
中科院分区：
文献类型：
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作者：
Mandrekar-Colucci S;Karlo JC;Landreth GE
阿尔茨海默病与淀粉样蛋白β（Aβ）稳态的破坏有关，导致Aβ肽在脑内蓄积和随后沉积。过氧化物酶体增殖物激活受体-γ（PPARγ）是一种配体激活的核受体，与肝脏X受体（LXR）在偶联代谢循环中起作用，以增加脑载脂蛋白E（apoE）水平。apoE的功能是促进可溶性Aβ的蛋白水解清除，我们发现合成的PPARγ激动剂吡格列酮以LXR和apoE依赖性方式刺激小胶质细胞和星形胶质细胞降解Aβ。值得注意的是，用吡格列酮对APPswe/PS1Δe9小鼠进行短暂9 d经口给药导致可溶性和不溶性Aβ水平的脑水平显著降低，这与皮质内弥漫性和致密核心斑块的丢失相关。预先存在的淀粉样蛋白沉积物的去除与大量Aβ负载的小胶质细胞和星形胶质细胞的出现相关。吡格列酮治疗导致小胶质细胞从促炎M1状态表型极化为抗炎M2状态，这与淀粉样蛋白沉积形式的吞噬作用增强相关。淀粉样蛋白水平的降低与药物治疗小鼠中背景记忆缺陷的逆转有关。这些数据为PPARγ激活如何促进淀粉样蛋白清除提供了机制解释，并支持PPARγ激动剂用于治疗阿尔茨海默病的治疗效用。
Alzheimer's disease is associated with a disruption of amyloid β (Aβ) homeostasis, resulting in the accumulation and subsequent deposition of Aβ peptides within the brain. The peroxisome proliferator-activated receptor-γ (PPARγ) is a ligand-activated nuclear receptor that acts in a coupled metabolic cycle with Liver X Receptors (LXRs) to increase brain apolipoprotein E (apoE) levels. apoE functions to promote the proteolytic clearance of soluble forms of Aβ, and we found that the synthetic PPARγ agonist, pioglitazone, stimulated Aβ degradation by both microglia and astrocytes in an LXR and apoE-dependent manner. Remarkably, a brief 9 d oral treatment of APPswe/PS1Δe9 mice with pioglitazone resulted in dramatic reductions in brain levels of soluble and insoluble Aβ levels which correlated with the loss of both diffuse and dense-core plaques within the cortex. The removal of preexisting amyloid deposits was associated with the appearance of abundant Aβ-laden microglia and astrocytes. Pioglitazone treatment resulted in the phenotypic polarization of microglial cells from a proinflammatory M1 state, into an anti-inflammatory M2 state that was associated with enhanced phagocytosis of deposited forms of amyloid. The reduction in amyloid levels was associated with a reversal of contextual memory deficits in the drug-treated mice. These data provide a mechanistic explanation for how PPARγ activation facilitates amyloid clearance and supports the therapeutic utility of PPARγ agonists for the treatment of Alzheimer's disease.