Enhancing the activity ofα-secretase has emerged as a potential therapeutic strategy for treating Alzheimer’s disease(AD).The exploration of small molecules that can enhance α-secretase activity and their mechanism...Enhancing the activity ofα-secretase has emerged as a potential therapeutic strategy for treating Alzheimer’s disease(AD).The exploration of small molecules that can enhance α-secretase activity and their mechanisms provides insights for future AD treatments and the development of novel activators.In this study,ADAM10,a major α-secretase,is used as a model and is bound with the ligands(−)-epigallocatechin-3-gallate(EGCG)and ferulic acid(FA)in a 1:2 ratio(ADAM10:EGCG/FA=1:2/2)and equimolar ratio(ADAM10:EGCG:FA=1:1:1)to investigate the effects on ADAM10 activation and reveal the synergistic mechanism of the EGCG and FA combi-nation.The activity of ADAM10 was enhanced by the combination of EGCG and FA,compared to that achieved with EGCG or FA alone,where EGCG plays a dominant role,whereas FA plays a supportive role.The combined use of EGCG induces strong hydrophobic interactions between ADAM10 and FA,causing FA to dissociate from the S1 domain,thereby preventing the inhibition of ADAM10 activity by pure FA.The presence of FA allows EGCG to bind more precisely within the active cavity of ADAM10,thereby increasing the binding strength.Overall,the combination of EGCG and FA significantly increased the distance between the S1 domain and the cysteine-rich C-terminus,further opening up the cavity containing the active sites,consequently exposing more active sites and enhancing the activity of ADAM10.展开更多
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
基金supported by the Natural Science Foundation of Shan-dong Province,China(Grant No.:ZR2022MB073).
文摘Enhancing the activity ofα-secretase has emerged as a potential therapeutic strategy for treating Alzheimer’s disease(AD).The exploration of small molecules that can enhance α-secretase activity and their mechanisms provides insights for future AD treatments and the development of novel activators.In this study,ADAM10,a major α-secretase,is used as a model and is bound with the ligands(−)-epigallocatechin-3-gallate(EGCG)and ferulic acid(FA)in a 1:2 ratio(ADAM10:EGCG/FA=1:2/2)and equimolar ratio(ADAM10:EGCG:FA=1:1:1)to investigate the effects on ADAM10 activation and reveal the synergistic mechanism of the EGCG and FA combi-nation.The activity of ADAM10 was enhanced by the combination of EGCG and FA,compared to that achieved with EGCG or FA alone,where EGCG plays a dominant role,whereas FA plays a supportive role.The combined use of EGCG induces strong hydrophobic interactions between ADAM10 and FA,causing FA to dissociate from the S1 domain,thereby preventing the inhibition of ADAM10 activity by pure FA.The presence of FA allows EGCG to bind more precisely within the active cavity of ADAM10,thereby increasing the binding strength.Overall,the combination of EGCG and FA significantly increased the distance between the S1 domain and the cysteine-rich C-terminus,further opening up the cavity containing the active sites,consequently exposing more active sites and enhancing the activity of ADAM10.
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.
