Little genomic support for cyclophilin A-matrix metalloproteinase-9 pathway as a therapeutic target for cognitive impairment in APOE4 carriers
Little genomic support for cyclophilin A-matrix metalloproteinase-9 pathway as a therapeutic target for cognitive impairment in APOE4 carriers
复制标题
亲环蛋白 A-基质金属蛋白酶-9 通路作为 APOE4 携带者认知障碍的治疗靶点的基因组支持很少
DOI：
10.1101/2021.04.22.21255729
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Anderson E
中科院分区：
文献类型：
--
作者：
Anderson E
阻止阿尔茨海默病病理进展的治疗靶点是缺乏的。最近的证据表明，APOE4，而不是APOE3，激活亲环蛋白- a基质金属蛋白酶-9 （CypA-MMP9）途径，导致血脑屏障（BBB）加速分解，从而引起神经元和突触功能障碍。此外，在APOE4敲入小鼠中，阻断CypA-MMP9通路可恢复血脑屏障的完整性，并随后使神经元和突触功能正常化。因此，CypA被认为是治疗APOE4介导的神经血管损伤及其导致的神经元功能障碍和变性的潜在靶点。如果有基因组证据支持，药物靶点通过临床试验的几率就会大大增加。通过对人类进行双样本孟德尔随机化和多基因风险评分分析，我们发现很少有证据表明CypA或MMP9会影响阿尔茨海默病或认知障碍的风险。这使人们怀疑它们是否可能代表人类APOE4携带者认知障碍的有效药物靶点。
Therapeutic targets for halting the progression of Alzheimer’s disease pathology are lacking. Recent evidence suggests that APOE4, but not APOE3, activates the Cyclophilin-A matrix metalloproteinase-9 (CypA-MMP9) pathway, leading to an accelerated breakdown of the blood–brain barrier (BBB) and thereby causing neuronal and synaptic dysfunction. Furthermore, blockade of the CypA-MMP9 pathway in APOE4 knock-in mice restores BBB integrity and subsequently normalizes neuronal and synaptic function. Thus, CypA has been suggested as a potential target for treating APOE4 mediated neurovascular injury and the resulting neuronal dysfunction and degeneration. The odds of drug targets passing through clinical trials are greatly increased if they are supported by genomic evidence. We found little evidence to suggest that CypA or MMP9 affects the risk of Alzheimer’s disease or cognitive impairment using two-sample Mendelian randomization and polygenic risk score analysis in humans. This casts doubt on whether they are likely to represent effective drug targets for cognitive impairment in human APOE4 carriers.