Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York, USA.
The University of Kansas Alzheimer's Disease Research Center, Fairway, Kansas, USA.
Alzheimers Dement. 2023 Jan;19(1):333-342. doi: 10.1002/alz.12683. Epub 2022 May 6.
To promote new thinking of the pathogenesis of Alzheimer's disease (AD), we examine the central role of mitochondrial dysfunction in AD. Pathologically, AD is characterized by progressive neuronal loss and biochemical abnormalities including mitochondrial dysfunction. Conventional thinking has dictated that AD is driven by amyloid beta pathology, per the Amyloid Cascade Hypothesis. However, the underlying mechanism of how amyloid beta leads to cognitive decline remains unclear. A model correctly identifying the pathogenesis of AD is critical and needed for the development of effective therapeutics. Mitochondrial dysfunction is closely linked to the core pathological feature of AD: neuronal dysfunction. Targeting mitochondria and associated proteins may hold promise for new strategies for the development of disease-modifying therapies. According to the Mitochondrial Cascade Hypothesis, mitochondrial dysfunction drives the pathogenesis of AD, as baseline mitochondrial function and mitochondrial change rates influence the progression of cognitive decline. HIGHLIGHTS: The Amyloid Cascade Model does not readily account for various parameters associated with Alzheimer's disease (AD). A unified model correctly identifying the pathogenesis of AD is greatly needed to inform the development of successful therapeutics. Mitochondria play a key and central role in the maintenance of optimal neuronal and synaptic function, the core pathological feature of AD. Mitochondrial dysfunction may be the primary cause of AD, and is a promising target for new therapeutic strategies.
为了推动阿尔茨海默病（AD）发病机制的新思维，我们研究了线粒体功能障碍在 AD 中的核心作用。从病理学角度来看，AD 的特征是进行性神经元丧失和生化异常，包括线粒体功能障碍。传统观点认为，AD 是由淀粉样β病理学驱动的，这符合淀粉样蛋白级联假说。然而，淀粉样β如何导致认知能力下降的潜在机制仍不清楚。正确识别 AD 发病机制的模型对于开发有效的治疗方法至关重要。线粒体功能障碍与 AD 的核心病理特征密切相关：神经元功能障碍。针对线粒体和相关蛋白的治疗可能为开发疾病修饰治疗的新策略提供希望。根据线粒体级联假说，线粒体功能障碍驱动 AD 的发病机制，因为基线线粒体功能和线粒体变化率会影响认知能力下降的进展。要点：淀粉样蛋白级联模型不易解释与阿尔茨海默病（AD）相关的各种参数。为了为成功的治疗方法提供信息，非常需要一个能够正确识别 AD 发病机制的统一模型。线粒体在维持最佳神经元和突触功能中起着关键和核心作用，这是 AD 的核心病理特征。线粒体功能障碍可能是 AD 的主要原因，是新治疗策略的有希望的靶点。
