Lack of BACE1 S-palmitoylation reduces amyloid burden and mitigates memory deficits in transgenic mouse models of Alzheimer's disease
Lack of BACE1 S-palmitoylation reduces amyloid burden and mitigates memory deficits in transgenic mouse models of Alzheimer's disease
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缺乏 BACE1 S-棕榈酰化可减少阿尔茨海默病转基因小鼠模型中的淀粉样蛋白负担并减轻记忆缺陷
DOI：
10.1073/pnas.1708568114
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发表时间：
2017-11-07
影响因子：
11.1
通讯作者：
Thinakaran, Gopal
中科院分区：
文献类型：
--
作者：
Andrew, Robert J.;Fernandez, Celia G.;Thinakaran, Gopal
阿尔茨海默病（AD）是一种毁灭性的神经退行性疾病，其特征是病理性脑损伤和认知功能下降。 β-淀粉样肽 (Aβ) 源自淀粉样前体蛋白 (APP) 的蛋白水解加工，在 AD 发病机制中发挥着核心作用。 β 位点 APP 裂解酶 1 (BACE1) 是一种跨膜天冬氨酰蛋白酶，可启动 Aβ 的产生，在神经元中进行轴突运输，并在 AD 患者大脑淀粉样蛋白沉积物附近的营养不良性神经突中积累。 BACE1 通过四个近膜半胱氨酸残基的 S-棕榈酰化进行修饰。 S-棕榈酰化是一种动态翻译后修饰，对于多种突触蛋白的运输和功能非常重要。在这里，我们通过分析棕榈酰化残基上半胱氨酸替换为丙氨酸的敲入小鼠（4CA 小鼠），研究了 BACE1 S-棕榈酰化的体内意义。尽管缺乏 BACE1 S-棕榈酰化且脂筏关联减少，但 4CA 小鼠中的 BACE1 表达以及 APP 和其他神经元底物的加工未发生改变。尽管稳态 Aβ 水平相似，但在 4CA 小鼠中未观察到突触活动诱导的内源性 Aβ 产生。此外，我们报告在 AD 淀粉样变性小鼠模型中，在缺乏 BACE1 S-棕榈酰化的情况下，大脑淀粉样蛋白负荷和营养不良性神经突中 BACE1 的积累显着减少。对培养神经元的研究表明，S-棕榈酰化对于 BACE1 的树突棘定位和轴突靶向是必需的。最后，BACE1 S-棕榈酰化的缺乏减轻了 5XFAD 小鼠的认知缺陷。使用转基因小鼠模型，这些结果表明 BACE1 内在的翻译后 S-棕榈酰化对淀粉样蛋白发病机制和随后的认知能力下降具有显着影响。
Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by pathological brain lesions and a decline in cognitive function. beta-Amyloid peptides (A beta), derived from proteolytic processing of amyloid precursor protein (APP), play a central role in AD pathogenesis. beta-Site APP cleaving enzyme 1 (BACE1), the transmembrane aspartyl protease which initiates A beta production, is axonally transported in neurons and accumulates in dystrophic neurites near cerebral amyloid deposits in AD. BACE1 is modified by S-palmitoylation at four juxtamembrane cysteine residues. S-palmitoylation is a dynamic posttranslational modification that is important for trafficking and function of several synaptic proteins. Here, we investigated the in vivo significance of BACE1 S-palmitoylation through the analysis of knock-in mice with cysteine-to-alanine substitution at the palmitoylated residues (4CA mice). BACE1 expression, as well as processing of APP and other neuronal substrates, was unaltered in 4CA mice despite the lack of BACE1 S-palmitoylation and reduced lipid raft association. Whereas steady-state A beta levels were similar, synaptic activity-induced endogenous A beta production was not observed in 4CA mice. Furthermore, we report a significant reduction of cerebral amyloid burden and BACE1 accumulation in dystrophic neurites in the absence of BACE1 S-palmitoylation in mouse models of AD amyloidosis. Studies in cultured neurons suggest that S-palmitoylation is required for dendritic spine localization and axonal targeting of BACE1. Finally, the lack of BACE1 S-palmitoylation mitigates cognitive deficits in 5XFAD mice. Using transgenic mouse models, these results demonstrate that intrinsic posttranslational S-palmitoylation of BACE1 has a significant impact on amyloid pathogenesis and the consequent cognitive decline.