Therapeutics for Alzheimer's disease based on the metal hypothesis.
Therapeutics for Alzheimer's disease based on the metal hypothesis.
复制标题
DOI：
10.1016/j.nurt.2008.05.001
复制
发表时间：
2008-07
期刊：
影响因子：
--
通讯作者：
Tanzi RE
中科院分区：
文献类型：
--
作者：
Bush AI;Tanzi RE
阿尔茨海默病（AD）是老年人中最常见的痴呆形式，其特征在于脑铁水平升高以及铜和锌在脑β-淀粉样蛋白沉积物中的积累;例如，老年斑锌离子和铜离子都能够加速Aβ的聚集，A β是β-淀粉样蛋白沉积物的主要成分。铜（和铁）还可促进Aβ的神经毒性氧化还原活性，并诱导肽氧化交联成稳定的寡聚体。最近的报道已经证明了兴奋后在皮层神经元能突触中Aβ与离子锌和铜一起释放。这反过来又导致Aβ寡聚体的形成，A β寡聚体反过来又调节长时程增强（通过控制NMDA受体的突触水平）。Aβ寡聚体在突触间隙中的过度积累将对突触神经传递产生不利影响。基于这些发现，我们提出了“阿尔茨海默病的金属假说”，该假说认为Aβ在AD中的神经病理作用是由Aβ-金属相互作用促进的，甚至可能依赖于Aβ-金属相互作用。目前正在实施越来越复杂的药物方法来减弱异常的Aβ-金属相互作用，而不会引起必需金属的全身性干扰。靶向Aβ-金属相互作用的小分子，例如PBT 2，目前正在通过临床试验取得进展，并且基于“金属假说”显示出作为AD的疾病修饰剂的前景越来越大。
Alzheimer’s disease (AD), the most common form of dementia in the elderly, is characterized by elevated brain iron levels and accumulation of copper and zinc in cerebral β-amyloid deposits; e.g., senile plaques. Both ionic zinc and copper are able to accelerate the aggregation of Aβ, the principle component of β-amyloid deposits. Copper (and iron) can also promote the neurotoxic redox activity of Aβ and induce oxidative cross-linking of the peptide into stable oligomers. Recent reports have documented the release of Aβ together with ionic zinc and copper in cortical glutamatergic synapses following excitation. This, in turn, leads to the formation of Aβ oligomers, which, in turn, modulate long-term potentiation (by controlling synaptic levels of the NMDA receptor). The excessive accumulation of Aβ oligomers in the synaptic cleft would then be predicted to adversely affect synaptic neurotransmisson. Based on these findings, we have proposed the “Metal Hypothesis of Alzheimer’s Disease” which stipulates that the neuropathogenic effects of Aβ in AD are promoted by, and possibly even dependent upon Aβ-metal interactions. Increasingly sophisticated pharmaceutical approaches are now being implemented to attenuate abnormal Aβ-metal interactions without causing systemic disturbance of essential metals. Small molecules targeting Aβ–metal interactions, e.g. PBT2, are currently advancing through clinical trials and show increasing promise as disease-modifying agents for AD based on the “metal hypothesis”.
登录
查看更多内容
影响因子：
82.9
作者：
Citron, M;Westaway, D;Selkoe, DJ
通讯作者：
Selkoe, DJ
影响因子：
16.6
作者：
da Silva, GFZ;Ming, LJ
通讯作者：
Ming, LJ
影响因子：
4.6
作者：
Armendariz, AD;Gonzalez, M;Vulpe, CD
通讯作者：
Vulpe, CD
影响因子：
56.9
作者：
BUSH, AI;PETTINGELL, WH;TANZI, RE
通讯作者：
TANZI, RE
影响因子：
4.8
作者：
Curtain, CC;Ali, F;Barnham, KJ
通讯作者：
Barnham, KJ