Alzheimer's disease.
Alzheimer's disease.
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DOI：
10.1007/978-94-007-5416-4_14
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发表时间：
2012-01-01
影响因子：
--
通讯作者：
Forlenza, Orestes V
中科院分区：
文献类型：
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作者：
De-Paula, Vanessa J;Radanovic, Marcia;Forlenza, Orestes V
阿尔茨海默病(AD)是一种慢性神经退行性疾病，具有明确的病理生理机制，主要累及内侧颞叶和相关的新皮质结构。神经性斑块和神经原纤维缠结是AD的病理特征，分别与脑组织中淀粉样β蛋白(Abeta)的积聚和神经元中微管相关Tau蛋白过度磷酸化引起的细胞骨架改变有关。根据AD的淀粉样蛋白假说，Abeta的过度产生是调节淀粉样前体蛋白(APP)蛋白分解的动态平衡过程破坏的结果。遗传、年龄相关和环境因素有助于APP的代谢转变，有利于APP的淀粉样蛋白生成过程，损害生理分泌途径。β-分泌酶(BACE-1)和γ-分泌酶是APP被β-分泌酶(BACE-1)和γ-分泌酶连续裂解而产生的多肽，最近被认为是早老素复合体的一部分。在几种依赖于C末端氨基酸数量的微小差异的β-淀粉样蛋白亚型中，Abeta(1-42)在AD的发病机制中起着关键作用。Abeta多肽的神经毒性潜力源于它的生化特性，它有利于聚集成不溶性低聚物和原纤维。这些进一步起源于聚集成老年斑和神经炎性斑块的纤维状Abeta物种。这些过程伴随着Abeta从大脑中清除的减少，导致Abeta在细胞外积累，随后激活神经毒级联反应，最终导致细胞骨架改变、神经元功能障碍和细胞死亡。脑内淀粉样变性在AD患者中呈年龄依赖性发展，但最近的证据表明，一些受试者可能早在生命的第三或第四年就观察到这种疾病，在中年后期增加，在老年时估计最高。根据最近的主张，阿尔茨海默病可以被定义为三个临床阶段：(I)症状前(或临床前)AD，可能持续数年或数十年，直到脑内Abeta的过度产生和积累达到触发淀粉样级联反应的临界水平；(Ii)AD的痴呆前阶段(符合进行性、遗忘性轻度认知障碍的定义)，其中存在早期病理，从轻度神经元营养不良到早期Braak病理，根据个体的韧性和脑储备，可能持续数年；(Iii)临床定义的阿尔茨海默病的痴呆期，认知和功能损害严重到足以超过痴呆症阈值；在这个阶段，受影响的脑区有显著的神经炎斑块和神经原纤维缠结，与整体损害的程度有关。基于结构和功能神经成像以及脑脊液生化分析的新技术可能描述具有轻度痴呆前期症状的人的大脑内淀粉样变性的相关性。这些方法通常被称为AD相关生物标志物，临床和生物信息的结合产生了良好的诊断准确性，以识别AD的高危个体。换句话说，通过生物体液的生化分析或通过分子神经成像来表征致病性Abeta是作为诊断工具提出的，以帮助在疾病过程的最早阶段识别AD病例。阿尔茨海默病早期诊断的相关性依赖于这样一个假设，即如果在痴呆症的连续过程中足够早地开始使用抗疾病化合物的药物干预，更有可能产生临床相关的益处。针对淀粉样蛋白相关级联反应的修饰治疗可能被视为减轻甚至预防痴呆症的有希望的策略。因此，从基础科学模型中获得的关于AD发病机制的累积知识有望在未来几年转化为临床实践。
Alzheimer's disease (AD) is a chronic neurodegenerative disease with well-defined pathophysiological mechanisms, mostly affecting medial temporal lobe and associative neocortical structures. Neuritic plaques and neurofibrillary tangles represent the pathological hallmarks of AD, and are respectively related to the accumulation of the amyloid-beta peptide (Abeta) in brain tissues, and to cytoskeletal changes that arise from the hyperphosphorylation of microtubule-associated Tau protein in neurons. According to the amyloid hypothesis of AD, the overproduction of Abeta is a consequence of the disruption of homeostatic processes that regulate the proteolytic cleavage of the amyloid precursor protein (APP). Genetic, age-related and environmental factors contribute to a metabolic shift favoring the amyloidogenic processing of APP in detriment of the physiological, secretory pathway. Abeta peptides are generated by the successive cleavage of APP by beta-secretase (BACE-1) and gamma-secretase, which has been recently characterized as part of the presenilin complex. Among several beta-amyloid isoforms that bear subtle differences depending on the number of C-terminal amino acids, Abeta (1-42) plays a pivotal role in the pathogenesis of AD. The neurotoxic potential of the Abeta peptide results from its biochemical properties that favor aggregation into insoluble oligomers and protofibrils. These further originate fibrillary Abeta species that accumulate into senile and neuritic plaques. These processes, along with a reduction of Abeta clearance from the brain, leads to the extracellular accumulation of Abeta, and the subsequent activation of neurotoxic cascades that ultimately lead to cytoskeletal changes, neuronal dysfunction and cellular death. Intracerebral amyloidosis develops in AD patients in an age-dependent manner, but recent evidence indicate that it may be observed in some subjects as early as in the third or fourth decades of life, with increasing magnitude in late middle age, and highest estimates in old age. According to recent propositions, three clinical phases of Alzheimer's disease may be defined: (i) pre-symptomatic (or pre-clinical) AD, which may last for several years or decades until the overproduction and accumulation of Abeta in the brain reaches a critical level that triggers the amyloid cascade; (ii) pre-dementia phase of AD (compatible with the definition of progressive, amnestic mild cognitive impairment), in which early-stage pathology is present, ranging from mild neuronal dystrophy to early-stage Braak pathology, and may last for several years according to individual resilience and brain reserve; (iii) clinically defined dementia phase of AD, in which cognitive and functional impairment is severe enough to surmount the dementia threshold; at this stage there is significant accumulation of neuritic plaques and neurofibrillary tangles in affected brain areas, bearing relationship with the magnitude of global impairment. New technologies based on structural and functional neuroimaging, and on the biochemical analysis of cerebrospinal fluid may depict correlates of intracerebral amyloidosis in individuals with mild, pre-dementia symptoms. These methods are commonly referred to as AD-related biomarkers, and the combination of clinical and biological information yields good diagnostic accuracy to identify individuals at high risk of AD. In other words, the characterization of pathogenic Abeta by means of biochemical analysis of biological fluids or by molecular neuroimaging are presented as diagnostic tools to help identify AD cases at the earliest stages of the disease process. The relevance of this early diagnosis of AD relies on the hypothesis that pharmacological interventions with disease-modifying compounds are more likely to produce clinically relevant benefits if started early enough in the continuum towards dementia. Therapies targeting the modification of amyloid-related cascades may be viewed as promising strategies to attenuate or even to prevent dementia. Therefore, the cumulative knowledge on the pathogenesis of AD derived from basic science models will hopefully be translated into clinical practice in the forthcoming years.