Delacourte A
Unité Inserm 815, Lille, France.
Rev Neurol (Paris). 2006 Oct;162(10):909-12. doi: 10.1016/s0035-3787(06)75099-8.
The natural and molecular history of familial or sporadic Alzheimer's disease (AD) shows that APP (amyloid protein precursor) dysfunction is a consensual central etiological factor in Alzheimer's disease (AD). This is demonstrated by 1) genetic defects involving APP gene or APP dysfunction (such as PS1 or PS2), leading to the formation of neocortical amyloid plaques in familial AD; 2) transgenic mice with these mutated genes that develop plaques; 3) both sporadic and familial AD develop plaques. But two alternatives to explain the physiopathology can be proposed: a gain of toxic function of AB peptide (reflected by the amyloid cascade hypothesis) or a loss of function of APP, a ubiquitous and well conserved protein with numerous possible neurotrophic activities. On the other hand, AD is also characterized by another inescapable degenerating process: tauopathy, an intraneuronal aggregation of tau proteins into neurofibrillary tangles. Remarkably enough, progression of tauopathy in neocortical areas fully explains the progressive clinical deficits of AD, from memory loss to aphasia, apraxia, agnosia. Also one has to bare in mind that most demented patients and most dementing neurodegenerative disorders have a tauopathy. From that, it is concluded that APP an Tau are solid therapeutic targets. But if we know that APP and Tau dysfunctions interact to boost neurodegeneration in AD, we still do no know what are the intraneuronal signaling pathways to activate or to inhibit to stop the degenerating process. There are many hypotheses and many possible approaches: the inhibition of toxicity of plaque, of AB protofibrils, or of AB oligomers inside or outside the neuron, using vaccination or ligands (Alzhemed). On the other hand, modulation of secretases that cleave APP by inhibiting those involved in the amyloidogenic pathway or by stimulating those of the non-amyloidogenic pathway, is a major route of research. Also modulation of kinases or phosphatases possibly involved in the aggregation of tau is also investigated. Because animal models are not perfectly relevant, at the end of the long and costly pathway of drug discovery, therapeutic trials are the only way to test these different hypotheses.
家族性或散发性阿尔茨海默病（AD）的自然史和分子史表明，APP（淀粉样蛋白前体）功能障碍是阿尔茨海默病（AD）公认的核心病因。这体现在以下几个方面：1）涉及APP基因的遗传缺陷或APP功能障碍（如PS1或PS2），导致家族性AD中形成新皮质淀粉样斑块；2）携带这些突变基因的转基因小鼠会形成斑块；3）散发性和家族性AD都会出现斑块。但可以提出两种解释其病理生理学的替代观点：Aβ肽毒性功能的增强（由淀粉样蛋白级联假说反映）或APP功能的丧失，APP是一种广泛存在且高度保守的蛋白质，具有多种可能的神经营养活性。另一方面，AD的另一个不可避免的特征是另一种退化过程：tau蛋白病，即tau蛋白在神经元内聚集成神经原纤维缠结。值得注意的是，新皮质区域tau蛋白病的进展充分解释了AD从记忆丧失到失语、失用、失认等逐渐出现的临床缺陷。同样，人们必须牢记，大多数痴呆患者和大多数导致痴呆的神经退行性疾病都存在tau蛋白病。由此得出结论，APP和Tau是可靠的治疗靶点。但是，尽管我们知道APP和Tau功能障碍在AD中相互作用以促进神经退行性变，但我们仍然不知道激活或抑制哪些神经元内信号通路才能阻止退化过程。有许多假说和许多可能的方法：使用疫苗或配体（Alzhemed）抑制斑块、Aβ原纤维或神经元内外Aβ寡聚体的毒性。另一方面，通过抑制参与淀粉样蛋白生成途径的分泌酶或刺激非淀粉样蛋白生成途径的分泌酶来调节切割APP的分泌酶，是一个主要的研究方向。此外，还在研究可能参与tau蛋白聚集的激酶或磷酸酶的调节。由于动物模型并不完全相关，在漫长且成本高昂的药物研发过程结束时，治疗试验是检验这些不同假说的唯一途径。
