Alzheimer's disease neurofibrillary degeneration: pivotal and multifactorial.
Alzheimer's disease neurofibrillary degeneration: pivotal and multifactorial.
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DOI：
10.1042/bst0380962
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发表时间：
2010-08
影响因子：
3.9
通讯作者：
Grundke-Iqbal I
中科院分区：
文献类型：
--
作者：
Iqbal K;Wang X;Blanchard J;Liu F;Gong CX;Grundke-Iqbal I
与病因无关，AD（阿尔茨海默病）异常高磷酸化tau的神经原纤维变性是AD和相关tau病的标志，显然是该疾病临床表达所必需的，因此是药物开发的主要治疗靶点。然而，阿尔茨海默病是多因素和异质性的，可能涉及几种不同的病因机制。根据脑脊液（脑脊液）Aβ1-42（其中Aβ是淀粉样β肽）、tau和泛素的水平，已经确定了五个不同的亚群，每个亚群都有自己的临床特征。要想成功开发出合理的阿尔茨海默病治疗药物，就需要了解不同的病因机制，并在临床试验中根据不同的疾病亚组对阿尔茨海默病患者进行分层。我们已经确定了一种新的AD的病因机制，它是由Asn175上的PP2A（蛋白磷酸酶2A）的抑制剂-2 （I2PP2A）裂解成n端（I2NTF）和c端（I2CTF）半段并将它们从神经元核转移到细胞质中引发的。AAV1（腺相关病毒1）诱导大鼠脑中I2CTF的表达可导致PP2A活性抑制、tau异常过度磷酸化、大鼠神经变性和认知障碍。通过抑制PP2A的裂解和I2PP2A/SET活性来恢复PP2A的活性，为具有这种病原机制的AD提供了一个有希望的治疗机会。
Independent of the aetiology, AD (Alzheimer's disease) neurofibrillary degeneration of abnormally hyperphosphorylated tau, a hallmark of AD and related tauopathies, is apparently required for the clinical expression of the disease and hence is a major therapeutic target for drug development. However, AD is multifactorial and heterogeneous and probably involves several different aetiopathogenic mechanisms. On the basis of CSF (cerebrospinal fluid) levels of Aβ1-42 (where Aβ is amyloid β-peptide), tau and ubiquitin, five different subgroups, each with its own clinical profile, have been identified. A successful development of rational therapeutic disease-modifying drugs for AD will require understanding of the different aetiopathogenic mechanisms involved and stratification of AD patients by different disease subgroups in clinical trials. We have identified a novel aetiopathogenic mechanism of AD which is initiated by the cleavage of SET, also known as inhibitor-2 (I2PP2A) of PP2A (protein phosphatase 2A) at Asn175 into N-terminal (I2NTF) and C-terminal (I2CTF) halves and their translocation from neuronal nucleus to the cytoplasm. AAV1 (adeno-associated virus 1)-induced expression of I2CTF in rat brain induces inhibition of PP2A activity, abnormal hyperphosphorylation of tau, neurodegeneration and cognitive impairment in rats. Restoration of PP2A activity by inhibition of the cleavage and of I2PP2A/SET activity offers a promising therapeutic opportunity in AD with this aetiopathogenic mechanism.