ABCA1 is Necessary for Bexarotene-Mediated Clearance of Soluble Amyloid Beta from the Hippocampus of APP/PS1 Mice.
ABCA1 is Necessary for Bexarotene-Mediated Clearance of Soluble Amyloid Beta from the Hippocampus of APP/PS1 Mice.
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DOI：
10.1007/s11481-015-9627-8
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发表时间：
2016-03
期刊：
影响因子：
--
通讯作者：
Landreth GE
中科院分区：
文献类型：
--
作者：
Corona AW;Kodoma N;Casali BT;Landreth GE
阿尔茨海默病（AD）的特征在于淀粉样蛋白β（Aβ）肽的清除受损，导致Aβ在脑中的积累以及随后的神经变性和认知障碍。ApoE在可溶性Aβ的蛋白水解降解中起关键作用。这种作用依赖于ABCA 1介导的磷脂和胆固醇转移对ApoE的脂化作用。ApoE和ABCA 1由RXR激动剂贝沙罗汀的作用诱导。我们之前已经证明贝沙罗汀可以降低AD小鼠模型中的Aβ水平，我们假设这种作用需要ABCA 1介导的ApoE脂化。为了验证这一假设，我们将ABCA 1缺陷（ABCA 1 KO）小鼠与AD的APP/PS1模型杂交。用溶剂或贝沙罗汀（100 mg/kg/天）处理老年ABCA 1 WT和ABCA 1 KO APP/PS 1小鼠7天。贝沙罗汀降低了ABCA 1 WT但不降低ABCA 1 KO APP/PS 1小鼠海马中可溶性Aβ 1-40和1-42的水平。相比之下，在本研究中，不溶性Aβ水平和菌斑负荷不受贝沙罗汀影响。与ABCA 1 WT小鼠相比，ABCA 1 KO小鼠的炎症水平增加。贝沙罗汀也增加了大多数炎症基因标记物的评价。然而，贝沙罗汀对小胶质细胞炎症特征的影响与ABCA 1基因型无关。重要的是，贝沙罗汀改善了ABCA 1 WT而不是ABCA 1 KO APP/PS 1小鼠的新物体识别缺陷。这些数据表明，ABCA 1诱导的ApoE脂化是贝沙罗汀清除海马可溶性Aβ和改善认知缺陷的能力所必需的。
Alzheimer’s disease (AD) is characterized by impaired clearance of amyloid beta (Aβ) peptides, leading to the accumulation of Aβ in the brain and subsequent neurodegeneration and cognitive impairment. ApoE plays a critical role in the proteolytic degradation of soluble forms of Aβ. This effect is dependent upon lipidation of ApoE by ABCA1-mediated transfer of phospholipids and cholesterol. ApoE and ABCA1 are induced by the action of the RXR agonist, bexarotene. We have previously shown that bexarotene reduces Aβ levels in AD mouse models and we have hypothesized that this effect requires ABCA1-mediated lipidation of ApoE. To test this hypothesis, we crossed ABCA1-deficient (ABCA1 KO) mice with the APP/PS1 model of AD. Aged ABCA1 WT and ABCA1 KO APP/PS1 mice were treated for 7 days with vehicle or bexarotene (100 mg/kg/day). Bexarotene reduced levels of soluble Aβ 1–40 and 1–42 in the hippocampus of ABCA1 WT but not ABCA1 KO APP/PS1 mice. In contrast, insoluble levels of Aβ, and plaque loads were unaffected by bexarotene in this study. ABCA1 KO mice had increased levels of inflammation compared with ABCA1 WT mice. Bexarotene also increased most inflammatory gene markers evaluated. The effect of bexarotene on microglial inflammatory profiles, however, was independent of ABCA1 genotype. Importantly, bexarotene ameliorated deficits in novel object recognition in ABCA1 WT but not ABCA1 KO APP/PS1 mice. These data indicate that ABCA1-induced lipidation of ApoE is necessary for the ability of bexarotene to clear hippocampal soluble Aβ and ameliorate cognitive deficits.
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DOI：
10.1523/jneurosci.5268-11.2012
发表时间：
2012-07-25
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Mandrekar-Colucci S;Karlo JC;Landreth GE
通讯作者：
Landreth GE
DOI：
10.1523/jneurosci.1729-12.2012
发表时间：
2012-10-24
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Cameron B;Tse W;Lamb R;Li X;Lamb BT;Landreth GE
通讯作者：
Landreth GE
影响因子：
25
作者：
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通讯作者：
Mucke, Lennart
影响因子：
82.9
作者：
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通讯作者：
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影响因子：
82.9
作者：
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通讯作者：
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