Homocysteic acid induces intraneuronal accumulation of neurotoxic Aβ42:: Implications for the pathogenesis of Alzheimer's disease
Homocysteic acid induces intraneuronal accumulation of neurotoxic Aβ42:: Implications for the pathogenesis of Alzheimer's disease
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DOI：
10.1002/jnr.20514
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发表时间：
2005-06-15
影响因子：
4.2
通讯作者：
Yamada, T
中科院分区：
文献类型：
--
作者：
Hasegawa, T;Ukai, W;Yamada, T
阿尔茨海默病 (AD) 中神经元功能障碍和退化的原因尚不完全清楚，但神经毒性形式的淀粉样蛋白 β-肽 42 (A β 42) 的产生增加似乎具有重要意义。聚集的 A beta 42（斑块）的大量细胞外沉积物是 AD 的一个诊断特征，但 A beta 42 在神经元内部积聚时可能具有特别的细胞毒性。可能促进 AD 细胞内 Aβ42 积累的因素尚不清楚，但最近的研究结果表明，同型半胱氨酸水平升高的个体患 AD 的风险增加。我们发现同型半胱氨酸 (HA) 是同型半胱氨酸的氧化代谢物，可诱导与细胞毒性相关的 A beta 42 的神经元内积累。 HA 的神经毒性可以通过γ-分泌酶（产生 Aβ42 的酶活性）抑制剂来减弱，这表明细胞内 Aβ42 积累在 HA 的神经毒性作用中发挥着关键作用。 AD 受试者和对照受试者的脑脊液 (CSF) 中 HA 浓度相似。然而，AD 患者脑脊液同型半胱氨酸水平显着升高，并且同型半胱氨酸加剧了 HA 诱导的神经毒性，表明 HA 在 AD 中同型半胱氨酸水平升高的致病作用中发挥作用。这些发现表明，Aβ42 的细胞内积累在 HA 的神经毒性作用中发挥作用，并表明改变 HA 和同型半胱氨酸的产生和神经毒性作用的药物具有潜在的治疗益处。 (c) 2005 年 Wiley-Liss, Inc.
The causes of neuronal dysfunction and degeneration in Alzheimer's disease (AD) are not fully understood, but increased production of neurotoxic forms of amyloid beta-peptide-42 (A beta 42) seems of major importance. Large extracellular deposits of aggregated A beta 42 (plaques) is a diagnostic feature of AD, but A beta 42 may be particularly cytotoxic when it accumulates inside neurons. The factors that may promote the intracellular accumulation of A beta 42 in AD are unknown, but recent findings suggest that individuals with elevated homocysteine levels are at increased risk for AD. We show that homocysteic acid (HA), an oxidized metabolite of homocysteine, induces intraneuronal accumulation of a A beta 42 that is associated with cytotoxicity. The neurotoxicity of HA can be attenuated by an inhibitor of gamma-secretase, the enzyme activity that generates A beta 42, suggesting a key role for intracellular A beta 42 accumulation in the neurotoxic action of HA. Concentrations of HA in cerebrospinal fluid (CSF) were similar in AD and control subjects. CSF homocysteine levels were elevated significantly in AD patients, however, and homocysteine exacerbated HA-induced neurotoxicity, suggesting a role for HA in the pathogenic action of elevated homocysteine levels in AD. These findings suggest that the intracellular accumulation of A beta 42 plays a role in the neurotoxic action of HA, and suggest a potential therapeutic benefit of agents that modify the production and neurotoxic actions of HA and homocysteine. (c) 2005 Wiley-Liss, Inc.