The pathogenic mechanisms underlying the development of Alzheimer’s disease (AD) remain elusive and to date there are no effective prevention or treatment for AD. Farnesyltransferase (FT) catalyzes a key posttranslational modification process called farnesylation, in which the isoprenoid farnesyl pyrophosphate is attached to target proteins, facilitating their membrane localization and their interactions with downstream effectors. Farnesylated proteins, including the Ras superfamily of small GTPases, are involved in regulating diverse physiological and pathological processes. Emerging evidence suggests that isoprenoids and farnesylated proteins may play an important role in the pathogenesis of AD. However, the dynamics of FT and protein farnesylation in human brains and the specific role of neuronal FT in the pathogenic progression of AD are not known. Here, using postmortem brain tissue from individuals with no cognitive impairment (NCI), mild cognitive impairment (MCI), or Alzheimer’s dementia, we found that the levels of FT and membrane-associated H-Ras, an exclusively farnesylated protein, and its downstream effector ERK were markedly increased in AD and MCI compared with NCI. To elucidate the specific role of neuronal FT in AD pathogenesis, we generated the transgenic AD model APP/PS1 mice with forebrain neuron-specific FT knockout, followed by a battery of behavioral assessments, biochemical assays, and unbiased transcriptomic analysis. Our results showed that the neuronal FT deletion mitigates memory impairment and amyloid neuropathology in APP/PS1 mice through suppressing amyloid generation and reversing the pathogenic hyperactivation of mTORC1 signaling. These findings suggest that aberrant upregulation of protein farnesylation is an early driving force in the pathogenic cascade of AD and that targeting FT or its downstream signaling pathways presents a viable therapeutic strategy against AD.

中文翻译：

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阿尔茨海默病人脑中蛋白质法尼基化上调，神经元特异性抑制法尼基转移酶可减轻阿尔茨海默病模型小鼠的致病过程

阿尔茨海默病 (AD) 发展的致病机制仍然难以捉摸，迄今为止还没有针对 AD 的有效预防或治疗方法。法呢基转移酶 (FT) 催化称为法呢基化的关键翻译后修饰过程，其中类异戊二烯焦磷酸法呢基连接到靶蛋白上，促进它们的膜定位及其与下游效应物的相互作用。Farnesylated 蛋白质，包括小 GTP 酶的 Ras 超家族，参与调节多种生理和病理过程。新出现的证据表明，类异戊二烯和法尼基化蛋白可能在 AD 的发病机制中起重要作用。然而，人脑中 FT 和蛋白质法呢基化的动力学以及神经元 FT 在 AD 致病进展中的具体作用尚不清楚。在这里，我们使用没有认知障碍 (NCI)、轻度认知障碍 (MCI) 或阿尔茨海默氏痴呆的个体的死后脑组织，发现 FT 和膜相关 H-Ras（一种完全法尼基化的蛋白质）及其下游的水平与 NCI 相比，AD 和 MCI 中的效应 ERK 显着增加。为了阐明神经元 FT 在 AD 发病机制中的特定作用，我们生成了具有前脑神经元特异性 FT 敲除的转基因 AD 模型 APP/PS1 小鼠，然后进行了一系列行为评估、生化分析和无偏转录组学分析。我们的研究结果表明，神经元 FT 缺失通过抑制淀粉样蛋白的产生和逆转 mTORC1 信号的致病性过度激活来减轻 APP/PS1 小鼠的记忆障碍和淀粉样蛋白神经病理学。这些发现表明，蛋白质法尼基化的异常上调是 AD 致病级联的早期驱动力，靶向 FT 或其下游信号通路是一种可行的 AD 治疗策略。