Cerasuolo Michele, Papa Michele, Colangelo Anna Maria, Rizzo Maria Rosaria
Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy.
Laboratory of Neuronal Networks Morphology and System Biology, Department of Mental and Physical Health and Preventive Medicine, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy.
Biomedicines. 2023 Mar 11;11(3):861. doi: 10.3390/biomedicines11030861.
Alzheimer's disease (AD) is a progressive and degenerative disease producing the most common type of dementia worldwide. The main pathogenetic hypothesis in recent decades has been the well-known amyloidogenic hypothesis based on the involvement of two proteins in AD pathogenesis: amyloid β (Aβ) and tau. Amyloid deposition reported in all AD patients is nowadays considered an independent risk factor for cognitive decline. Vascular damage and blood-brain barrier (BBB) failure in AD is considered a pivotal mechanism for brain injury, with increased deposition of both immunoglobulins and fibrin. Furthermore, BBB dysfunction could be an early sign of cognitive decline and the early stages of clinical AD. Vascular damage generates hypoperfusion and relative hypoxia in areas with high energy demand. Long-term hypoxia and the accumulation within the brain parenchyma of neurotoxic molecules could be seeds of a self-sustaining pathological progression. Cellular dysfunction comprises all the elements of the neurovascular unit (NVU) and neuronal loss, which could be the result of energy failure and mitochondrial impairment. Brain glucose metabolism is compromised, showing a specific region distribution. This energy deficit worsens throughout aging. Mild cognitive impairment has been reported to be associated with a glucose deficit in the entorhinal cortex and in the parietal lobes. The current aim is to understand the complex interactions between amyloid β (Aβ) and tau and elements of the BBB and NVU in the brain. This new approach aimed at the study of metabolic mechanisms and energy insufficiency due to mitochondrial impairment would allow us to define therapies aimed at predicting and slowing down the progression of AD.
阿尔茨海默病（AD）是一种进行性退行性疾病，是全球最常见的痴呆类型。近几十年来，主要的发病机制假说是基于两种蛋白质参与AD发病过程的著名淀粉样蛋白生成假说：淀粉样β蛋白（Aβ）和tau蛋白。如今，所有AD患者中报告的淀粉样蛋白沉积被认为是认知衰退的独立危险因素。AD中的血管损伤和血脑屏障（BBB）功能障碍被认为是脑损伤的关键机制，免疫球蛋白和纤维蛋白的沉积均增加。此外，BBB功能障碍可能是认知衰退和临床AD早期阶段的早期迹象。血管损伤在高能量需求区域产生灌注不足和相对缺氧。长期缺氧以及神经毒性分子在脑实质内的积累可能是自我维持的病理进展的根源。细胞功能障碍包括神经血管单元（NVU）的所有要素和神经元丢失，这可能是能量衰竭和线粒体损伤的结果。脑葡萄糖代谢受损，呈现特定的区域分布。这种能量不足在整个衰老过程中会恶化。据报道，轻度认知障碍与内嗅皮质和顶叶的葡萄糖缺乏有关。当前的目标是了解淀粉样β蛋白（Aβ）和tau蛋白与大脑中BBB和NVU要素之间的复杂相互作用。这种旨在研究线粒体损伤导致的代谢机制和能量不足的新方法将使我们能够确定旨在预测和减缓AD进展的疗法。
