Alzheimer’s disease (AD) is the leading form of dementia but lacks curative treatments. Current understanding of AD aetiology attributes the development of the disease to the misfolding of two proteins; amyloid-β (Aβ) and hyperphosphorylated tau, with their pathological accumulation leading to concomitant oxidative stress, neuroinflammation, and neuronal death. These processes are regulated at multiple levels to maintain homeostasis and avert disease. However, many of the relevant regulatory proteins appear to be downregulated in the AD-afflicted brain. Enhancement/restoration of these ‘protective’ proteins, therefore, represents an attractive therapeutic avenue. Gene therapy is a desirable means of achieving this because it is not associated with the side-effects linked to systemic protein administration, and sustained protein expression virtually eliminates compliance issues. The current article represents a focused and succinct review of the better established ‘protective’ protein targets for gene therapy enhancement/restoration rather than being designed as an exhaustive review incorporating less validated protein subjects. In addition, we will discuss how the risks associated with uncontrolled or irreversible gene expression might be mitigated through combining neuronal-specific promoters, inducible expression systems and localised injections. Whilst many of the gene therapy targets reviewed herein are yet to enter clinical trials, preclinical testing has thus far demonstrated encouraging potential for the gene therapy-based treatment of AD.

阿尔茨海默病 (AD) 是痴呆症的主要形式，但缺乏治愈性治疗方法。目前对 AD 病因的理解将这种疾病的发展归因于两种蛋白质的错误折叠；β 淀粉样蛋白 (Aβ) 和过度磷酸化的 tau，其病理性积累导致伴随的氧化应激、神经炎症和神经元死亡。这些过程在多个层面受到调节，以维持体内平衡和避免疾病。然而，许多相关的调节蛋白似乎在受 AD 影响的大脑中被下调。因此，这些“保护性”蛋白质的增强/恢复代表了一种有吸引力的治疗途径。基因疗法是实现这一目标的理想方法，因为它与全身蛋白质给药相关的副作用无关，和持续的蛋白质表达实际上消除了依从性问题。目前的文章代表了对用于基因治疗增强/恢复的更好建立的“保护性”蛋白质靶点的重点和简洁的评论，而不是被设计为包含较少验证的蛋白质主题的详尽评论。此外，我们将讨论如何通过结合神经元特异性启动子、诱导表达系统和局部注射来降低与不受控制或不可逆基因表达相关的风险。虽然本文审查的许多基因治疗目标尚未进入临床试验，但临床前测试迄今已证明基于基因治疗的 AD 治疗具有令人鼓舞的潜力。目前的文章代表了对用于基因治疗增强/恢复的更好建立的“保护性”蛋白质靶点的重点和简洁的评论，而不是被设计为包含较少验证的蛋白质主题的详尽评论。此外，我们将讨论如何通过结合神经元特异性启动子、诱导表达系统和局部注射来降低与不受控制或不可逆基因表达相关的风险。虽然本文审查的许多基因治疗目标尚未进入临床试验，但临床前测试迄今已证明基于基因治疗的 AD 治疗具有令人鼓舞的潜力。目前的文章代表了对用于基因治疗增强/恢复的更好建立的“保护性”蛋白质靶点的重点和简洁的评论，而不是被设计为包含较少验证的蛋白质主题的详尽评论。此外，我们将讨论如何通过结合神经元特异性启动子、诱导表达系统和局部注射来降低与不受控制或不可逆基因表达相关的风险。虽然本文审查的许多基因治疗目标尚未进入临床试验，但临床前测试迄今已证明基于基因治疗的 AD 治疗具有令人鼓舞的潜力。