Alzheimer’s disease(AD)is the most prevalent neurodegenerative disorder worldwide,causing dementia and affecting millions of individuals.One prominent characteristic in the brains of AD patients is glucose hypometabo...Alzheimer’s disease(AD)is the most prevalent neurodegenerative disorder worldwide,causing dementia and affecting millions of individuals.One prominent characteristic in the brains of AD patients is glucose hypometabolism.In the context of galactose metabolism,intracellular glucose levels are heightened.Galactose mutarotase(GALM)plays a crucial role in maintaining normal galactose metabolism by catalyzing the conversion ofβ-D-galactose intoα-D-galactose(α-D-G).The latter is then converted into glucose-6-phosphate,improving glucose metabolism levels.However,the involvement of GALM in AD progression is still unclear.In the present study,we found that the expression of GALM was significantly increased in AD patients and model mice.Genetic knockdown of GALM using adeno-associated virus did not change the expression of amyloid precursor protein(APP)and APP-cleaving enzymes including a disintegrin and metalloprotease 10(ADAM10),β-site APP-cleaving enzyme 1(BACE1),and presenilin-1(PS1).Interestingly,genetic overexpression of GALM reduced APP and Aβdeposition by increasing the maturation of ADAM10,although it did not alter the expression of BACE1 and PS1.Further electrophysiological and behavioral experiments showed that GALM overexpression significantly ameliorated the deficits in hippocampal CA1 long-term potentiation(LTP)and spatial learning and memory in AD model mice.Importantly,directα-D-G(20 mg/kg,i.p.)also inhibited Aβdeposition by increasing the maturation of ADAM10,thereby improving hippocampal CA1 LTP and spatial learning and memory in AD model mice.Taken together,our results indicate that GALM shifts APP processing towardsα-cleavage,preventing Aβgeneration by increasing the level of mature ADAM10.These findings indicate that GALM may be a potential therapeutic target for AD,andα-D-G has the potential to be used as a dietary supplement for the prevention and treatment of AD.展开更多
目的解离素金属蛋白酶10(Adisintegrin and metalloproteinase 10,ADAM10)是一种跨膜金属蛋白,其在胆管癌中的表达及主要功能尚不清楚。在本研究中,我们想探究ADAM10在胆管癌中的表达模式及可能的生物学作用。方法我们用GEPIA2分析ADAM1...目的解离素金属蛋白酶10(Adisintegrin and metalloproteinase 10,ADAM10)是一种跨膜金属蛋白,其在胆管癌中的表达及主要功能尚不清楚。在本研究中,我们想探究ADAM10在胆管癌中的表达模式及可能的生物学作用。方法我们用GEPIA2分析ADAM10在胆管癌中的表达谱。然后,我们进行qRT-PCR、蛋白质印迹、免疫组织化学染色来评估ADAM10的表达,讨论了ADAM10的表达与胆管癌患者的临床病理特征、癌症相关表型之间的相关性。此外,在体外我们检测了ADAM10的功能。结果在胆管癌中ADAM10表达显著升高,ADAM10低表达与胆管癌中的神经和血管侵袭显著相关,相对应地,低表达ADAM10水平的患者具有更低的生存率。结论ADAM10过表达促进肿瘤细胞凋亡。这些发现可能有助于开发胆管癌可能的治疗靶点以及早发生物标志物。展开更多
基金supported by grants from the National Natural Science Foundation of China(32371030,82371194,and 82071395)the Natural Science Foundation of Chongqing(CSTB2022NSCQ-LZX0010 and CSTB2024NSCQ-MSX0269)the CQMU Program for Youth Innovation in Future Medicine(W0044).
文摘Alzheimer’s disease(AD)is the most prevalent neurodegenerative disorder worldwide,causing dementia and affecting millions of individuals.One prominent characteristic in the brains of AD patients is glucose hypometabolism.In the context of galactose metabolism,intracellular glucose levels are heightened.Galactose mutarotase(GALM)plays a crucial role in maintaining normal galactose metabolism by catalyzing the conversion ofβ-D-galactose intoα-D-galactose(α-D-G).The latter is then converted into glucose-6-phosphate,improving glucose metabolism levels.However,the involvement of GALM in AD progression is still unclear.In the present study,we found that the expression of GALM was significantly increased in AD patients and model mice.Genetic knockdown of GALM using adeno-associated virus did not change the expression of amyloid precursor protein(APP)and APP-cleaving enzymes including a disintegrin and metalloprotease 10(ADAM10),β-site APP-cleaving enzyme 1(BACE1),and presenilin-1(PS1).Interestingly,genetic overexpression of GALM reduced APP and Aβdeposition by increasing the maturation of ADAM10,although it did not alter the expression of BACE1 and PS1.Further electrophysiological and behavioral experiments showed that GALM overexpression significantly ameliorated the deficits in hippocampal CA1 long-term potentiation(LTP)and spatial learning and memory in AD model mice.Importantly,directα-D-G(20 mg/kg,i.p.)also inhibited Aβdeposition by increasing the maturation of ADAM10,thereby improving hippocampal CA1 LTP and spatial learning and memory in AD model mice.Taken together,our results indicate that GALM shifts APP processing towardsα-cleavage,preventing Aβgeneration by increasing the level of mature ADAM10.These findings indicate that GALM may be a potential therapeutic target for AD,andα-D-G has the potential to be used as a dietary supplement for the prevention and treatment of AD.
文摘目的解离素金属蛋白酶10(Adisintegrin and metalloproteinase 10,ADAM10)是一种跨膜金属蛋白,其在胆管癌中的表达及主要功能尚不清楚。在本研究中,我们想探究ADAM10在胆管癌中的表达模式及可能的生物学作用。方法我们用GEPIA2分析ADAM10在胆管癌中的表达谱。然后,我们进行qRT-PCR、蛋白质印迹、免疫组织化学染色来评估ADAM10的表达,讨论了ADAM10的表达与胆管癌患者的临床病理特征、癌症相关表型之间的相关性。此外,在体外我们检测了ADAM10的功能。结果在胆管癌中ADAM10表达显著升高,ADAM10低表达与胆管癌中的神经和血管侵袭显著相关,相对应地,低表达ADAM10水平的患者具有更低的生存率。结论ADAM10过表达促进肿瘤细胞凋亡。这些发现可能有助于开发胆管癌可能的治疗靶点以及早发生物标志物。
