Alzheimer’s disease (AD) has been associated with cardiovascular and cerebrovascular risk factors (CVRFs) during middle age and later and is frequently accompanied by cerebrovascular pathology at death. An interaction between CVRFs and genetic variants might explain the pathogenesis. Genome-wide, gene by CVRF interaction analyses for AD, in 6568 patients and 8101 controls identified FMNL2 (p = 6.6 × 10^–7). A significant increase in FMNL2 expression was observed in the brains of patients with brain infarcts and AD pathology and was associated with amyloid and phosphorylated tau deposition. FMNL2 was also prominent in astroglia in AD among those with cerebrovascular pathology. Amyloid toxicity in zebrafish increased fmnl2a expression in astroglia with detachment of astroglial end feet from blood vessels. Knockdown of fmnl2a prevented gliovascular remodeling, reduced microglial activity and enhanced amyloidosis. APP/PS1dE9 AD mice also displayed increased Fmnl2 expression and reduced the gliovascular contacts independent of the gliotic response. Based on this work, we propose that FMNL2 regulates pathology-dependent plasticity of the blood–brain-barrier by controlling gliovascular interactions and stimulating the clearance of extracellular aggregates. Therefore, in AD cerebrovascular risk factors promote cerebrovascular pathology which in turn, interacts with FMNL2 altering the normal astroglial-vascular mechanisms underlying the clearance of amyloid and tau increasing their deposition in brain.

阿尔茨海默病（AD）与中年及以后的心血管和脑血管危险因素（CVRF）相关，并且在死亡时经常伴有脑血管病变。 CVRF 和遗传变异之间的相互作用可能可以解释发病机制。对 AD 进行全基因组 CVRF 相互作用分析，在 6568 名患者和 8101 名对照中发现了FMNL2 ( p = 6.6 × 10 ^–7 )。在脑梗塞和 AD 病理患者的大脑中观察到FMNL2表达显着增加，并且与淀粉样蛋白和磷酸化 tau 沉积相关。 FMNL2 在患有脑血管病变的 AD 患者的星形胶质细胞中也很突出。斑马鱼的淀粉样蛋白毒性增加了星形胶质细胞中fmnl2a 的表达，并导致星形胶质细胞末端脚与血管脱离。 fmnl2a的敲低可防止胶质血管重塑、小胶质细胞活性降低和淀粉样变性增强。 APP/PS1dE9 AD 小鼠还表现出Fmnl2表达增加和胶质血管接触减少，与胶质细胞反应无关。基于这项工作，我们提出 FMNL2 通过控制胶质血管相互作用和刺激细胞外聚集物的清除来调节血脑屏障的病理依赖性可塑性。因此，在 AD 中，脑血管危险因素会促进脑血管病理，而脑血管病理又与FMNL2相互作用，改变淀粉样蛋白和 tau 蛋白清除的正常星形胶质细胞血管机制，增加其在大脑中的沉积。