Laboratory of Neurosciences and Functional Medicine, International Center for Biomedicine (ICC), Avda. Vitacura 3568, D 511-512, Vitacura, Santiago, Chile.
Faculty of Sciences, University of Chile, Las Encinas 3370, Ñuñoa, Santiago, Chile.
Alzheimers Res Ther. 2022 Apr 20;14(1):56. doi: 10.1186/s13195-022-00996-8.
Alzheimer's disease is the most prevalent cause of dementia in the elderly. Neuronal death and synaptic dysfunctions are considered the main hallmarks of this disease. The latter could be directly associated to an impaired metabolism. In particular, glucose metabolism impairment has demonstrated to be a key regulatory element in the onset and progression of AD, which is why nowadays AD is considered the type 3 diabetes.
We provide a thread regarding the influence of glucose metabolism in AD from three different perspectives: (i) as a regulator of the energy source, (ii) through several metabolic alterations, such as insulin resistance, that modify peripheral signaling pathways that influence activation of the immune system (e.g., insulin resistance, diabetes, etc.), and (iii) as modulators of various key post-translational modifications for protein aggregation, for example, influence on tau hyperphosphorylation and other important modifications, which determine its self-aggregating behavior and hence Alzheimer's pathogenesis.
In this revision, we observed a 3 edge-action in which glucose metabolism impairment is acting in the progression of AD: as blockade of energy source (e.g., mitochondrial dysfunction), through metabolic dysregulation and post-translational modifications in key proteins, such as tau. Therefore, the latter would sustain the current hypothesis that AD is, in fact, the novel diabetes type 3.
阿尔茨海默病是老年人中最常见的痴呆症病因。神经元死亡和突触功能障碍被认为是这种疾病的主要标志。后者可能与代谢受损直接相关。特别是，葡萄糖代谢受损已被证明是 AD 发病和进展的关键调节因素，这就是为什么现在 AD 被认为是 3 型糖尿病。
我们从三个不同角度提供了关于葡萄糖代谢对 AD 影响的线索：（i）作为能量来源的调节剂，（ii）通过几种代谢改变，如胰岛素抵抗，改变影响免疫系统激活的外周信号通路（例如，胰岛素抵抗、糖尿病等），和（iii）作为各种关键翻译后修饰的调节剂，例如对 tau 过度磷酸化和其他重要修饰的影响，这些修饰决定了其自身聚集行为，从而决定了阿尔茨海默病的发病机制。
在本次综述中，我们观察到葡萄糖代谢受损在 AD 进展中存在 3 种作用机制：作为能量来源的阻断（例如线粒体功能障碍），通过关键蛋白的代谢失调和翻译后修饰，如 tau。因此，后者支持了当前的假设，即 AD 实际上是新型 3 型糖尿病。
