Humanin; a defender against Alzheimer's disease?
Humanin; a defender against Alzheimer's disease?
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DOI：
10.2174/157488909787002609
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发表时间：
2009
期刊：
影响因子：
--
通讯作者：
M. Matsuoka
中科院分区：
文献类型：
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作者：
M. Matsuoka
阿尔茨海默病（AD）是最常见的伴有痴呆的神经系统疾病。 AD 相关痴呆是由参与认知功能的神经元死亡和功能障碍引起的。人们普遍认为，有毒的β-淀粉样蛋白（Abeta）水平升高与神经元死亡和功能障碍的发生有关（Abeta 级联理论）。因此，降低大脑中有毒 Abeta 的水平被认为是 AD 治疗的核心。基于这种治疗策略的多种候选药物已经开发出来并正在大力开发中。一些临床研究表明这种策略是有效的。除了这一理论之外，Abeta 独立的病理机制已被证明有助于 AD 相关痴呆的进展，这证明了有效对抗 Abeta 独立的病理机制的 AD 治疗替代策略的合理性。他们的一种可能的治疗策略是直接抑制AD相关的神经元死亡和功能障碍。一系列研究表明，一种名为护脑素 (Humanin) 的 24 个氨基酸生物活性肽可抑制因家族性 AD 相关基因强制表达而诱导的神经元细胞死亡。护脑素还可以在体外保护神经元免受有毒 Abeta 的杀死。此外，由毒蕈碱受体拮抗剂和颅内注射有毒 Abeta 引起的小鼠神经元功能障碍相关痴呆症通过护脑素治疗得到改善。多项研究表明细胞膜上存在假定的特定护脑素受体。这些结果共同表明，内源性 AD 相关体液因子可能通过抑制体内神经元细胞死亡和功能障碍来抑制 AD 相关痴呆的进展。这种自卫机制的故障也被认为是 AD 的另一种病因或加重因素。此外，从 AD 治疗的角度来看，通过有效的护脑素衍生物刺激 AD 防御机制是 AD 治疗的一种有前途的替代策略。目前的专利涵盖护脑素及其临床使用方法。
Alzheimer's disease (AD) is the most prevalent neurological disease with dementia. AD-related dementia is caused by death and dysfunction of neurons involved in cognitive function. It has been generally believed that increased levels of toxic amyloid-betas (Abetas) are linked to the occurrence of neuronal death as well as dysfunction (Abeta cascade theory). Consequently, lowering levels of toxic Abetas in the brain is considered to be central for therapy of AD. Multiple drug candidates based on this therapeutic strategy have been developed and are being vigorously developed. Some clinical studies have indicated that this strategy is effective. In addition to this theory, Abeta-independent pathomechanisms have been shown to contribute to the progression of AD-related dementia, justifying alternative strategies for AD treatment that are effective against Abeta-independent pathomechanisms. A possible therapeutic strategy belonging to them is to directly suppress AD-related neuronal death and dysfunction. A series of studies indicated that a 24-amino-acid bioactive peptide named Humanin was shown to inhibit neuronal cell death induced by enforced expression of familial AD-related genes. Humanin also protected neurons from being killed by toxic Abetas in vitro. In addition, neuronal dysfunction-associated dementia of mice caused by muscarinic receptor antagonists and intracranially injected toxic Abetas was ameliorated by Humanin therapy. Multiple studies have indicated the existence of a putative specific Humanin receptor on the cell membrane. These results together suggest that an endogenous AD-related humoral factor(s) may inhibit the progression of AD-related dementia by inhibiting both neuronal cell death and dysfunction in vivo. Malfunction of this self-defense mechanism is also hypothesized to be another etiology or an aggravator of AD. Moreover, from a standpoint of AD therapy, stimulation of the AD defense mechanism by a potent Humanin derivative is a promising alternative strategy for AD treatment. The present patents cover Humanin and the methods of its clinical usage.