阿尔茨海默病(Alzheimer's disease,AD)是一种以进行性认知功能障碍为主要特征的神经退行性疾病,其发病机制与线粒体功能障碍密切相关。PINK1/Parkin信号通路作为调控线粒体自噬的核心途径,在清除受损线粒体及维持神经元稳态中发挥关键作用, 其功能障碍在帕金森病中主要由基因突变导致, 但在AD中则并非原发性致病因素,而是主要受Aβ异常沉积和tau蛋白过度磷酸化等核心病理因素的二次影响。这些病理改变会导致PINK1/Parkin通路功能受损, 进而引发线粒体自噬障碍,形成神经退行性病变的恶性循环。PINK1可通过磷酸化Parkin蛋白和泛素分子激活线粒体自噬程序, 而这一过程在AD 中受到显著抑制。尤为重要的是,AD 中的Aβ异常沉积和tau病理改变,不仅会抑制PINK1/Parkin通路,其自身的生成和毒性作用还受该通路调控, 二者构成了AD特有的复杂双向交互网络,这与帕金森病的病理机制存在显著差异。值得注意的是,在动物模型中,通过药物干预靶向激活PINK1/Parkin通路,已显示出改善AD 病理损伤和认知功能的潜力。本文系统阐述了PINK1/Parkin介导的线粒体自噬在AD中的分子机制与治疗价值,为新型神经保护策略的研发提供了重要理论依据。

Alzheimer's disease(AD)is a neurodegenerative disease characterized by progressive cognitive dysfunction, with its pathogenesis closely associated with mitochondrial dysfunction. The PINK1/Parkin signaling pathway, as a core regulator of mitophagy, plays a key role in clearing damaged mitochondria and maintaining neuronal homeostasis. While dysfunction of this pathway in Parkinson's disease is mainly attributable to genetic mutations,in AD,it is not a primary cause but rather a secondary consequence of core pathological processes such as abnormal amyloid β-protein (Aβ)deposition and tau protein hyperphosphorylation. These pathological changes can lead to impaired function of the PINK1/Parkin pathway, which in turn triggers mitophagy deficits, creating a vicious cycle of neurodegeneration. PINK1 can activate the mitophagy program by phosphorylating Parkin proteins and ubiquitin molecules, a process that is significantly inhibited in AD. Crucially, the abnormal deposition of Aβ and pathological changes of tau in AD not only inhibit the PINK1/Parkin pathway, but also their own production and toxic effects are regulated by this pathway, forming a complex AD-specific bidirectional interactive network, which is significantly different from the pathophysiological mechanism of Parkinson's disease. Notably, pharmacological interventions aimed at activating the PINK1/Parkin pathway have shown potential in improving AD pathology and cognitive function in animal models. In this review, we systematically elucidate the molecular mechanisms and therapeutic implications of PINK1/Parkin-mediated mitophagy in AD, providing a crucial theoretical basis for the development of novel neuroprotective strategies.