Saxena Uday
R and D Strategy, Kareus Therapeutics SA, Switzerland.
Int J Physiol Pathophysiol Pharmacol. 2011;3(2):133-9. Epub 2010 Jun 12.
Alzheimer's disease is rapidly growing worldwide and yet there is no cure for it. Currently available drugs only provide symptomatic relief and do not intervene in disease process sufficiently enough to prevent or cure it. Characteristic features of this disease are decline in neuronal mass and cognitive functions. The most dominant hypothesis proposed for pathogenesis of this disease is called "amyloid hypothesis". It states that excessive production of amyloid peptides called abeta peptides (Aβ) is the underlying cause of neuronal death and dysfunction. However, recent drugs designed based on amyloid hypothesis have failed in clinical trails, demanding fresh assessment. Early and persistent molecular events in this disease progression are energy deficiency and high oxidative stress in the neurons. Our review will put together a disease model based on known human and animal data with regards to breakdown in neuronal energy generation. The model will integrate energy deficits as the cause of neuronal dysfunction and abeta peptide production culminating in catastrophic loss of cognitive functions. Finally, based on this model, we will also suggest enzyme targets in neuronal bioenergetics pathway for design and development of new disease modifying therapies.
阿尔茨海默病在全球范围内正迅速蔓延，然而目前尚无治愈方法。现有的药物仅能缓解症状，无法充分干预疾病进程以预防或治愈该病。这种疾病的特征是神经元数量和认知功能下降。关于该疾病发病机制最主要的假说是“淀粉样蛋白假说”。该假说认为，称为β淀粉样肽（Aβ）的淀粉样肽过度产生是神经元死亡和功能障碍的根本原因。然而，最近基于淀粉样蛋白假说设计的药物在临床试验中失败了，需要重新评估。在这种疾病进展过程中早期且持续存在的分子事件是神经元中的能量缺乏和高氧化应激。我们的综述将基于已知的人类和动物数据，构建一个关于神经元能量生成障碍的疾病模型。该模型将把能量不足整合为神经元功能障碍和Aβ肽产生的原因，最终导致认知功能的灾难性丧失。最后，基于这个模型，我们还将提出神经元生物能量学途径中的酶靶点，用于设计和开发新的疾病修饰疗法。
