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
亲环素A-基质金属蛋白酶-9通路作为APOE 4携带者认知障碍治疗靶点的基因组支持很少。
DOI：
10.1038/s41598-022-05225-8
复制
发表时间：
2022-01-20
影响因子：
4.6
通讯作者：
Davies NM
中科院分区：
文献类型：
--
作者：
Anderson EL;Williams DM;Walker VM;Davies NM
缺乏用于停止阿尔茨海默病病理学进展的治疗靶点。最近的证据表明，APOE 4，而不是APOE 3，激活亲环素-A基质金属蛋白酶-9（CypA-MMP 9）途径，导致血脑屏障（BBB）的加速破坏，从而引起神经元和突触功能障碍。此外，在APOE 4敲入小鼠中阻断CypA-MMP 9通路可恢复BBB完整性，随后使神经元和突触功能正常化。因此，CypA被认为是治疗APOE 4介导的神经血管损伤和由此产生的神经元功能障碍和变性的潜在靶点。如果有基因组证据的支持，药物靶点通过临床试验的几率会大大增加。我们在人类中使用双样本孟德尔随机化和多基因风险评分分析，几乎没有证据表明CypA或MMP 9影响阿尔茨海默病或认知障碍的风险。这让人怀疑它们是否可能代表人类APOE 4携带者认知障碍的有效药物靶标。
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.
登录
查看更多内容
DOI：
10.1186/alzrt44
发表时间：
2010-06-24
期刊：
Alzheimer's research & therapy
影响因子：
--
作者：
Stomrud E;Björkqvist M;Janciauskiene S;Minthon L;Hansson O
通讯作者：
Hansson O
影响因子：
4
作者：
Mroczko, Barbara;Groblewska, Magdalena;Lewczuk, Piotr
通讯作者：
Lewczuk, Piotr
影响因子：
8.3
作者：
Adair, JC;Charlie, J;Rosenberg, GA
通讯作者：
Rosenberg, GA
影响因子：
2.4
作者：
Babenko VN;Afonnikov DA;Ignatieva EV;Klimov AV;Gusev FE;Rogaev EI
通讯作者：
Rogaev EI
影响因子：
4
作者：
Hernandes-Alejandro, Mario;Montano, Sarita;Luna-Munoz, Jose
通讯作者：
Luna-Munoz, Jose