Inhibition of γ-secretase worsens memory deficits in a genetically congruous mouse model of Danish dementia.
Inhibition of γ-secretase worsens memory deficits in a genetically congruous mouse model of Danish dementia.
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DOI：
10.1186/1750-1326-7-19
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发表时间：
2012-04-26
影响因子：
15.1
通讯作者：
D'Adamio L
中科院分区：
文献类型：
--
作者：
Tamayev R;D'Adamio L
BRI 2/ITM 2b基因突变导致家族性丹麦痴呆（FDD）。BRI 2是淀粉样蛋白-β前体蛋白（APP）加工的抑制剂，其在遗传上与阿尔茨海默病（AD）发病机制相关。FDD突变导致BRI 2蛋白的丢失和APP加工的增加。APP单倍缺陷和β-分泌酶对APP裂解的抑制挽救了遗传一致的FDD小鼠模型（FDDKI）的突触/记忆缺陷。APP的β-裂解产生β-羧基末端（β-CTF）和氨基末端可溶性APPβ（sAPPβ）片段。β-CTF的γ-分泌酶加工产生Aβ，这被认为是AD的主要原因。然而，抑制Aβ的产生并不能挽救FDDKI小鼠的缺陷，这表明sAPPβ/β-CTF而不是Aβ是导致记忆丧失的毒性物质。在此，我们进一步分析了γ-分泌酶抑制剂的作用。我们表明，γ-分泌酶抑制剂（GSI）治疗导致FDDKI小鼠记忆缺陷恶化。这种对记忆的有害作用与从FDDKI小鼠的海马分离的突触部分中β/α-CTF APP片段的水平增加相关，这与γ-分泌酶活性的抑制一致。GSI的这种有害作用与Aβ的致病作用形成鲜明对比，并表明记忆缺陷的恶化可能是由于GSI治疗引起的突触毒性β/α-CTF的积累。然而，γ-分泌酶切割超过40种蛋白质;因此，GSI对记忆的有害作用可能取决于对这些其他γ-分泌酶底物中的一种或多种的切割的抑制。这两种可能性不需要相互排斥。我们的结果与GSI Semagacestat的临床试验结果一致，该试验导致认知恶化，并建议在AD治疗中不要靶向γ-分泌酶。总体而言，数据还表明FDDKI是研究AD发病机制和预测AD治疗剂的临床结果的有价值的小鼠模型。
A mutation in the BRI2/ITM2b gene causes familial Danish dementia (FDD). BRI2 is an inhibitor of amyloid-β precursor protein (APP) processing, which is genetically linked to Alzheimer’s disease (AD) pathogenesis. The FDD mutation leads to a loss of BRI2 protein and to increased APP processing. APP haplodeficiency and inhibition of APP cleavage by β-secretase rescue synaptic/memory deficits of a genetically congruous mouse model of FDD (FDDKI). β-cleavage of APP yields the β-carboxyl-terminal (β-CTF) and the amino-terminal-soluble APPβ (sAPPβ) fragments. γ-secretase processing of β-CTF generates Aβ, which is considered the main cause of AD. However, inhibiting Aβ production did not rescue the deficits of FDDKI mice, suggesting that sAPPβ/β-CTF, and not Aβ, are the toxic species causing memory loss. Here, we have further analyzed the effect of γ-secretase inhibition. We show that treatment with a γ-secretase inhibitor (GSI) results in a worsening of the memory deficits of FDDKI mice. This deleterious effect on memory correlates with increased levels of the β/α-CTFs APP fragments in synaptic fractions isolated from hippocampi of FDDKI mice, which is consistent with inhibition of γ-secretase activity. This harmful effect of the GSI is in sharp contrast with a pathogenic role for Aβ, and suggests that the worsening of memory deficits may be due to accumulation of synaptic-toxic β/α-CTFs caused by GSI treatment. However, γ-secretase cleaves more than 40 proteins; thus, the noxious effect of GSI on memory may be dependent on inhibition of cleavage of one or more of these other γ-secretase substrates. These two possibilities do not need to be mutually exclusive. Our results are consistent with the outcome of a clinical trial with the GSI Semagacestat, which caused a worsening of cognition, and advise against targeting γ-secretase in the therapy of AD. Overall, the data also indicate that FDDKI is a valuable mouse model to study AD pathogenesis and predict the clinical outcome of therapeutic agents for AD.
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影响因子：
16.2
作者：
Saura, CA;Choi, SY;Shen, J
通讯作者：
Shen, J
影响因子：
4.8
作者：
Fotinopoulou, A;Tsachaki, M;Efthimiopoulos, S
通讯作者：
Efthimiopoulos, S
影响因子：
5.3
作者：
Matsuda, Shuji;Giliberto, Luca;D'Adamio, Luciano
通讯作者：
D'Adamio, Luciano
影响因子：
82.9
作者：
Jucker, Mathias
通讯作者：
Jucker, Mathias
DOI：
10.1073/pnas.080076097
发表时间：
2000-04-25
影响因子：
11.1
作者：
Vidal, R;Révész, T;Frangione, B
通讯作者：
Frangione, B