Loss of Lipid Carrier ApoE Exacerbates Brain Glial and Inflammatory Responses after Lysosomal GBA1 Inhibition.
Loss of Lipid Carrier ApoE Exacerbates Brain Glial and Inflammatory Responses after Lysosomal GBA1 Inhibition.
复制标题
作者：
严密调控和高度适应性的脂类代谢和转运途径对于维持脑细胞脂类平衡和应对脂类和炎症应激以保护大脑功能和健康至关重要。脂质调节基因APOE和GBA1的缺陷是路易体痴呆和相关痴呆综合征最显著的遗传风险因素。与单一变异携带者相比，同时携带APOE4和GBA1变异的帕金森病患者认知能力下降速度更快。为了研究脑ApoE和GBA1之间的功能相互作用，在WT和ApoE缺陷小鼠体内进行了GBA1抑制试验。实验证明，由GBA1抑制引起的糖脂应激在WT小鼠中诱导了与运动和痴呆障碍相关的几个大脑区域的ApoE表达。ApoE-KO小鼠ApoE缺失可导致糖脂应激后补体C1q升高、反应性小胶质细胞增多和星形胶质细胞增多。从机制上讲，GBA1抑制分别引发细胞表面和细胞内脂质转运蛋白ABCA1和NPC1的增加。有趣的是，小鼠体内NPC1的缺失也引发了脑部载脂蛋白E水平的升高。这些新数据表明，在体内，脑ApoE、GBA1和NPC1的功能是相互关联的，ApoE的去除或减少可能会损害大脑功能。这些结果为脑内载脂蛋白E对脂质负荷增加的适应性反应提供了重要的见解。
Tightly regulated and highly adaptive lipid metabolic and transport pathways are critical to maintaining brain cellular lipid homeostasis and responding to lipid and inflammatory stress to preserve brain function and health. Deficits in the lipid handling genes APOE and GBA1 are the most significant genetic risk factors for Lewy body dementia and related dementia syndromes. Parkinson’s disease patients who carry both APOE4 and GBA1 variants have accelerated cognitive decline compared to single variant carriers. To investigate functional interactions between brain ApoE and GBA1, in vivo GBA1 inhibition was tested in WT versus ApoE-deficient mice. The experiments demonstrated glycolipid stress caused by GBA1 inhibition in WT mice induced ApoE expression in several brain regions associated with movement and dementia disorders. The absence of ApoE in ApoE-KO mice amplified complement C1q elevations, reactive microgliosis and astrocytosis after glycolipid stress. Mechanistically, GBA1 inhibition triggered increases in cell surface and intracellular lipid transporters ABCA1 and NPC1, respectively. Interestingly, the absence of NPC1 in mice also triggered elevations of brain ApoE levels. These new data show that brain ApoE, GBA1 and NPC1 functions are interconnected in vivo, and that the removal or reduction of ApoE would likely be detrimental to brain function. These results provide important insights into brain ApoE adaptive responses to increased lipid loads.
登录
查看更多内容
影响因子：
3.5
作者：
Hughes MP;Smith DA;Morris L;Fletcher C;Colaco A;Huebecker M;Tordo J;Palomar N;Massaro G;Henckaerts E;Waddington SN;Platt FM;Rahim AA
通讯作者：
Rahim AA
影响因子：
32.4
作者：
Hammond, Timothy R.;Dufort, Connor;Stevens, Beth
通讯作者：
Stevens, Beth
影响因子：
6
作者：
Farmer, Brandon C.;Kluemper, Jude;Johnson, Lance A.
通讯作者：
Johnson, Lance A.
影响因子：
4.8
作者：
Kaya E;Smith DA;Smith C;Morris L;Bremova-Ertl T;Cortina-Borja M;Fineran P;Morten KJ;Poulton J;Boland B;Spencer J;Strupp M;Platt FM
通讯作者：
Platt FM
影响因子：
6.1
作者：
Huang, Yadong;Mahley, Robert W.
通讯作者：
Mahley, Robert W.