The E3 ubiquitin ligase,carboxyl terminus of heat shock protein 70(Hsp70)interacting protein(CHIP),also functions as a co-chaperone and plays a crucial role in the protein quality control system.In this study,we aimed...The E3 ubiquitin ligase,carboxyl terminus of heat shock protein 70(Hsp70)interacting protein(CHIP),also functions as a co-chaperone and plays a crucial role in the protein quality control system.In this study,we aimed to investigate the neuroprotective effect of overexpressed CHIP on Alzheimer’s disease.We used an adeno-associated virus vector that can cross the blood-brain barrier to mediate CHIP overexpression in APP/PS1 mouse brain.CHIP overexpression significantly ameliorated the performance of APP/PS1 mice in the Morris water maze and nest building tests,reduced amyloid-βplaques,and decreased the expression of both amyloid-βand phosphorylated tau.CHIP also alleviated the concentration of microglia and astrocytes around plaques.In APP/PS1 mice of a younger age,CHIP overexpression promoted an increase in ADAM10 expression and inhibitedβ-site APP cleaving enzyme 1,insulin degrading enzyme,and neprilysin expression.Levels of HSP70 and HSP40,which have functional relevance to CHIP,were also increased.Single nuclei transcriptome sequencing in the hippocampus of CHIP overexpressed mice showed that the lysosomal pathway and oligodendrocyte-related biological processes were up-regulated,which may also reflect a potential mechanism for the neuroprotective effect of CHIP.Our research shows that CHIP effectively reduces the behavior and pathological manifestations of APP/PS1 mice.Indeed,overexpression of CHIP could be a beneficial approach for the treatment of Alzheimer’s disease.展开更多
In patients with Alzheimer’s disease,gamma-glutamyl transferase 5(GGT5)expression has been observed to be downregulated in cerebrovascular endothelial cells.However,the functional role of GGT5 in the development of A...In patients with Alzheimer’s disease,gamma-glutamyl transferase 5(GGT5)expression has been observed to be downregulated in cerebrovascular endothelial cells.However,the functional role of GGT5 in the development of Alzheimer’s disease remains unclear.This study aimed to explore the effect of GGT5 on cognitive function and brain pathology in an APP/PS1 mouse model of Alzheimer’s disease,as well as the underlying mechanism.We observed a significant reduction in GGT5 expression in two in vitro models of Alzheimer’s disease(Aβ_(1-42)-treated hCMEC/D3 and bEnd.3 cells),as well as in the APP/PS1 mouse model.Additionally,injection of APP/PS1 mice with an adeno-associated virus encoding GGT5 enhanced hippocampal synaptic plasticity and mitigated cognitive deficits.Interestingly,increasing GGT5 expression in cerebrovascular endothelial cells reduced levels of both soluble and insoluble amyloid-βin the brains of APP/PS1 mice.This effect may be attributable to inhibition of the expression ofβ-site APP cleaving enzyme 1,which is mediated by nuclear factor-kappa B.Our findings demonstrate that GGT5 expression in cerebrovascular endothelial cells is inversely associated with Alzheimer’s disease pathogenesis,and that GGT5 upregulation mitigates cognitive deficits in APP/PS1 mice.These findings suggest that GGT5 expression in cerebrovascular endothelial cells is a potential therapeutic target and biomarker for Alzheimer’s disease.展开更多
Alzheimer's disease is a progressive neurological disorder characterized by cognitive decline and chronic inflammation within the brain.The ketogenic diet,a widely recognized therapeutic intervention for refractor...Alzheimer's disease is a progressive neurological disorder characterized by cognitive decline and chronic inflammation within the brain.The ketogenic diet,a widely recognized therapeutic intervention for refractory epilepsy,has recently been proposed as a potential treatment for a variety of neurological diseases,including Alzheimer's disease.However,the efficacy of ketogenic diet in treating Alzheimer's disease and the underlying mechanism remains unclear.The current investigation aimed to explore the effect of ketogenic diet on cognitive function and the underlying biological mechanisms in a mouse model of Alzheimer's disease.Male amyloid precursor protein/presenilin 1(APP/PS1)mice were randomly assigned to either a ketogenic diet or control diet group,and received their respective diets for a duration of 3 months.The findings show that ketogenic diet administration enhanced cognitive function,attenuated amyloid plaque formation and proinflammatory cytokine levels in APP/PS1 mice,and augmented the nuclear factor-erythroid 2-p45 derived factor 2/heme oxygenase-1 signaling pathway while suppressing the nuclear factor-kappa B pathway.Collectively,these data suggest that ketogenic diet may have a therapeutic potential in treating Alzheimer's disease by ameliorating the neurotoxicity associated with Aβ-induced inflammation.This study highlights the urgent need for further research into the use of ketogenic diet as a potential therapy for Alzheimer's disease.展开更多
Cognitive impairment is the main clinical manifestation of Alzheimer's disease(AD),and amyloid-β(AB)deposition and senile plaques are the characteristic neuropathological hallmarks in AD brains.This study aimed t...Cognitive impairment is the main clinical manifestation of Alzheimer's disease(AD),and amyloid-β(AB)deposition and senile plaques are the characteristic neuropathological hallmarks in AD brains.This study aimed to explore the effect and mechanism of tetrahydroxy stilbene glucoside(TSG)on cognitive function in APP/PS 1 mice during long-term administration.Here,we treated APP/PS1 model mice of AD with different doses of TSG(50 mg/kg and 100 mg/kg)for 5 to 17 months by gavage,and we further observed whether TSG could ameliorate the cognitive decline in APP/PS1 mice using behavioral tests,and investigated the possible mechanisms by immunohistochemistry and Western blotting.Our results showed that TSG treatment rescued the spatial and non-spatial learning and memory impairments of APP/PS1 mice at Morris water maze test and novel object recognition test.Furthermore,Aβ40/42 deposition in the cortex and hippocampus of APP/PS1 mice treated with TSG was significantly reduced compared to the wild type mice using the immunohistochemical technique.Finally,Western blotting showed that TSG primarily decreased the APP expression to avoid the Aβplaque deposition in the cortex and hippocampus of mice.These results reveal the beneficial effects of TSG in APP/PSI-AD mice,which may be associated with the reduction of Aβdeposits in the brain.展开更多
OBJECTIVE To study the protective effect of potassium 2-(l-hydroxypentyl)-benzoate(PHPB) on hippocampal neurons,synapses and dystrophic axons in APP/PS1 mice.METHODS Ten-month-old male APP/PS1 transgenic mice and age-...OBJECTIVE To study the protective effect of potassium 2-(l-hydroxypentyl)-benzoate(PHPB) on hippocampal neurons,synapses and dystrophic axons in APP/PS1 mice.METHODS Ten-month-old male APP/PS1 transgenic mice and age-matched wild-type mice were randomly divided into three groups:wild-type group(WT Con group,n=10),APP/PS1 group(Tg Con group,n=10) and PHPB treated APP/PS1 group(PHPB group,n=10).PHPB group received 30 mg · kg-1 PHPB by oral gavage once daily for 3 months.WT Con group and Tg Con group received the same volume of water.Three months later,mice were sacrificed for biochemical and pathological testing such as transmission electron microscopy,Golgi staining and Western boltting analysis.RESULTS Under the transmission electron microscope,most hippocampal neurons and subcel ular organel es in WT Con group exhibited normal morphology.However,the degenerative changes were observed in Tg Con group such as nuclear fragmentation,mitochondrial swelling,ribosomes detachment and autophagic vacuoles accumulation.The hippocampal synapses number and the thickness of postsynaptic density(PSD) were significantly decreased in Tg Con group compared with the WT Con group(P<0.05).After PHPB treatment,the degenerative changes in APP/PS1 mice were alleviated to some extent.The synapse number has been elevated significantly(P<0.05) and the PSD has been thickened as well.Golgi staining showed that the spine density of secondary and tertiary apical dendritic branches was significantly decreased in CA1 and DG areas of Tg Con group(P<0.05).Sholl analysis revealed a decrease of dendritic complexity in Tg Con group compared with WT Con group(P<0.05).These abnormalities were alleviated to some extent after PHPB treatment.Western blotting study showed that the protein levels of synaptic marker PSD-95 and synaptophysin were significantly decreased in the hippocampus of Tg Con group(P<0.05).A significant increase of PSD-95(P<0.05) and a slight increase of SYP were observed after the PHPB treatment.Besides,we found a significant increase in the ratio of LC3-Ⅱ/LC3-Ⅰ in Tg Con group compared with the WT Con group(P<0.01) and the relevant improvement after PHPB treatment(P<0.05),which showed the regulatory effect of PHPB on autophagy impairment.CONCLUSION PHPB showed protective effects on hippocampal neurons,synapses and dystrophic axons in APP/PS1 mice,which might help explain its role on cognitive improvement in Alzheimer disease treatment.展开更多
Phosphodiesterase-4(PDE4)has been demonstrated to be a promising target for treatment of Alzheimer’s disease(AD).Roflumilast(Rof),a potent PDE4 inhibitor,has been approved for treatment of chronic obstructive pulmona...Phosphodiesterase-4(PDE4)has been demonstrated to be a promising target for treatment of Alzheimer’s disease(AD).Roflumilast(Rof),a potent PDE4 inhibitor,has been approved for treatment of chronic obstructive pulmonary disease(COPD)in humans.Recent studies have shown that Rof improves cognition at doses that do not cause an emetic response,the major side-effect of PDE4 inhibitors.However,the effect of Rof on cognition associated with AD remains largely unknown.Here we examined the effects of Rof on behavioral dysfunction and the related mechanisms in APP/PS1 double transgenic mice,a widely used model for AD.Mice at 10 months of age were first tested in novel object recognition for memory.The recognition index in APP/PS1 mice was decreased compared to WT mice,which was reversed by Rof at 5 and 10 mg·kg-1.This was then verified in the Morris water-maze test.The escape latency during acquisition training was significantly longer and the entries into the target quadrant during the probe trial were much less compared to WT controls,these were also reversed by Rof.In the tail-suspension and forced-swimming tests,which measure depression-like behavior,APP/PS1 mice showed prolonged immobility time,which was reversed by Rof.In addition,the staining of HE and Nissl showed that Rof reduced the loss of neurons and neurocyte apoptosis in APP/PS1 mice.It also reversed the decreased ratio of Bcl-2/BAX and inhibited the increased expression of PDE4D in the cerebral cortex and hippocampus of APP/PS1 mice.Finally,Rof reversed the decreased levels of cAMP and expression of phosphorylated cAMP response element-binding protein(CREB)and brain derived neurotrophic factor(BDNF)in APP/PS1 mice.Overall,these results suggest that Rof not only improves learning and memory,but attenuates depression-like behavior in AD mice,likely via PDE4D/cAMP/CREB/BDNF signaling-mediated neuroprotection.Therefore,Rof can be a therapeutic agent for AD,in particular the comorbidity of memory deficits and depression.展开更多
Lamotrigine(LTG)is a widely used drug for the treatment of epilepsy.Emerging clinical evidence suggests that LTG may improve cognitive function in patients with Alzheimer’s disease.However,the underlying molecular me...Lamotrigine(LTG)is a widely used drug for the treatment of epilepsy.Emerging clinical evidence suggests that LTG may improve cognitive function in patients with Alzheimer’s disease.However,the underlying molecular mechanisms remain unclear.In this study,amyloid precursor protein/presenilin 1(APP/PS1)double transgenic mice were used as a model of Alzheimer’s disease.Five-month-old APP/PS1 mice were intragastrically administered 30 mg/kg LTG or vehicle once per day for 3 successive months.The cognitive functions of animals were assessed using Morris water maze.Hyperphosphorylated tau and markers of synapse and glial cells were detected by western blot assay.The cell damage in the brain was investigated using hematoxylin and eosin staining.The levels of amyloid-βand the concentrations of interleukin-1β,interleukin-6 and tumor necrosis factor-αin the brain were measured using enzyme-linked immunosorbent assay.Differentially expressed genes in the brain after LTG treatment were analyzed by high-throughput RNA sequencing and real-time polymerase chain reaction.We found that LTG substantially improved spatial cognitive deficits of APP/PS1 mice;alleviated damage to synapses and nerve cells in the brain;and reduced amyloid-βlevels,tau protein hyperphosphorylation,and inflammatory responses.High-throughput RNA sequencing revealed that the beneficial effects of LTG on Alzheimer’s disease-related neuropathologies may have been mediated by the regulation of Ptgds,Cd74,Map3k1,Fosb,and Spp1 expression in the brain.These findings revealed potential molecular mechanisms by which LTG treatment improved Alzheimer’s disease.Furthermore,these data indicate that LTG may be a promising therapeutic drug for Alzheimer’s disease.展开更多
[Objectives]To study the effect of human umbilical cord mesenchymal stem cells(hUC-MSCs)on GRP78/ATF4 pathway in APP/PS1 mice.[Methods]Twelve 6-month-old female APP/PS1 mice were randomly divided into model group(MOD,...[Objectives]To study the effect of human umbilical cord mesenchymal stem cells(hUC-MSCs)on GRP78/ATF4 pathway in APP/PS1 mice.[Methods]Twelve 6-month-old female APP/PS1 mice were randomly divided into model group(MOD,n=6)and human umbilical cord mesenchymal stem cell treatment group(MSC,n=6);six 6-month-old C57BL/6N mice were used as control group(CON,n=6).The mice in each group were treated with the fourth generation of human umbilical cord mesenchymal stem cells through tail vein.Four weeks later,the mice in each group were killed.The expression of GFP78 and ATF4 in the cortex of mice in each group was detected by Western blotting and real-time fluorescence quantitative PCR.[Results]The results of immunoblotting and real-time fluorescence quantitative PCR showed that the expression of GRP78 in MOD group was lower than that in CON group and the expression of ATF4 increased.The expression of GRP78 protein in MSC group was higher than that in MOD group,but the expression of ATF4 protein was lower.The results of real-time fluorescence quantitative PCR showed that the mRNA level of GRP78 decreased and the mRNA level of ATF4 increased in MOD group compared with CON group.The mRNA level of GRP78 in MSC group was higher than that in MOD group,while the mRNA level of ATF4 in MSC group was lower than that in MOD group.[Conclusions]Human umbilical cord mesenchymal stem cells can regulate the expression of GRP78/ATF4 pathway in APP/PSI mice,which may be related to the stress level of endoplasmic reticulum in the brain of APP/PS1 mice mediated by human umbilical cord mesenchymal stem cells.展开更多
Recent studies have suggested that abnormal acidification of lysosomes induces autophagic accumulation of amyloid-βin neurons,which is a key step in senile plaque formation.Therefore,resto ring normal lysosomal funct...Recent studies have suggested that abnormal acidification of lysosomes induces autophagic accumulation of amyloid-βin neurons,which is a key step in senile plaque formation.Therefore,resto ring normal lysosomal function and rebalancing lysosomal acidification in neurons in the brain may be a new treatment strategy for Alzheimer's disease.Microtubule acetylation/deacetylation plays a central role in lysosomal acidification.Here,we show that inhibiting the classic microtubule deacetylase histone deacetylase 6 with an histone deacetylase 6 shRNA or thehistone deacetylase 6 inhibitor valproic acid promoted lysosomal reacidification by modulating V-ATPase assembly in Alzheimer's disease.Fu rthermore,we found that treatment with valproic acid markedly enhanced autophagy.promoted clearance of amyloid-βaggregates,and ameliorated cognitive deficits in a mouse model of Alzheimer's disease.Our findings demonstrate a previously unknown neuroprotective mechanism in Alzheimer's disease,in which histone deacetylase 6 inhibition by valproic acid increases V-ATPase assembly and lysosomal acidification.展开更多
Behavioral experiments have demonstrated that long-term physical exercise can be beneficial for learning and memory dysfunction caused by neuroinflammation in Alzheimer's disease(AD).However,the molecular mechanis...Behavioral experiments have demonstrated that long-term physical exercise can be beneficial for learning and memory dysfunction caused by neuroinflammation in Alzheimer's disease(AD).However,the molecular mechanism remains poorly understood due to a lack of sufficient pertinent biochemical evidence.We investigated the potential effect of long-term physical exercise on cognition and hippocampal gene and protein expression changes in a transgenic AD mouse model.Following twenty weeks of treadmill exercise,transgenic AD mice showed improvement in cognitive functions and downregulation of Nod-like receptor protein 3(NLRP3)(p<0.01),interleukin-1beta(IL-1β)(p<0.05),and amyloid-β1-42(Aβ1-42)(p<0.05)expression levels.In addition,we observed significant reductions of microglial activation and hippocampal neuronal damage in the exercised AD mice(p<0.01),which might be a result of the downregulation of NLRP3-mediated signaling and neuroinflammatory responses.As neuronal damage due to inflammation might be a likely cause of AD-associated cognitive dysfunction.Our results suggested that the anti-inflammatory effects of exercise training involved downregulating the expression of key inflammatory factors and might play an important role in protecting hippocampal neurons against damage during the course of AD.展开更多
基金supported by the National Natural Science Foundation of China,Nos.91849115 and U1904207(to YX),81974211 and 82171247(to CS)Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences,No.2020-PT310-01(to YX).
文摘The E3 ubiquitin ligase,carboxyl terminus of heat shock protein 70(Hsp70)interacting protein(CHIP),also functions as a co-chaperone and plays a crucial role in the protein quality control system.In this study,we aimed to investigate the neuroprotective effect of overexpressed CHIP on Alzheimer’s disease.We used an adeno-associated virus vector that can cross the blood-brain barrier to mediate CHIP overexpression in APP/PS1 mouse brain.CHIP overexpression significantly ameliorated the performance of APP/PS1 mice in the Morris water maze and nest building tests,reduced amyloid-βplaques,and decreased the expression of both amyloid-βand phosphorylated tau.CHIP also alleviated the concentration of microglia and astrocytes around plaques.In APP/PS1 mice of a younger age,CHIP overexpression promoted an increase in ADAM10 expression and inhibitedβ-site APP cleaving enzyme 1,insulin degrading enzyme,and neprilysin expression.Levels of HSP70 and HSP40,which have functional relevance to CHIP,were also increased.Single nuclei transcriptome sequencing in the hippocampus of CHIP overexpressed mice showed that the lysosomal pathway and oligodendrocyte-related biological processes were up-regulated,which may also reflect a potential mechanism for the neuroprotective effect of CHIP.Our research shows that CHIP effectively reduces the behavior and pathological manifestations of APP/PS1 mice.Indeed,overexpression of CHIP could be a beneficial approach for the treatment of Alzheimer’s disease.
基金supported by STI2030-Major Projects,No.2021ZD 0201801(to JG)Shanxi Province Basic Research Program,No.20210302123429(to QS).
文摘In patients with Alzheimer’s disease,gamma-glutamyl transferase 5(GGT5)expression has been observed to be downregulated in cerebrovascular endothelial cells.However,the functional role of GGT5 in the development of Alzheimer’s disease remains unclear.This study aimed to explore the effect of GGT5 on cognitive function and brain pathology in an APP/PS1 mouse model of Alzheimer’s disease,as well as the underlying mechanism.We observed a significant reduction in GGT5 expression in two in vitro models of Alzheimer’s disease(Aβ_(1-42)-treated hCMEC/D3 and bEnd.3 cells),as well as in the APP/PS1 mouse model.Additionally,injection of APP/PS1 mice with an adeno-associated virus encoding GGT5 enhanced hippocampal synaptic plasticity and mitigated cognitive deficits.Interestingly,increasing GGT5 expression in cerebrovascular endothelial cells reduced levels of both soluble and insoluble amyloid-βin the brains of APP/PS1 mice.This effect may be attributable to inhibition of the expression ofβ-site APP cleaving enzyme 1,which is mediated by nuclear factor-kappa B.Our findings demonstrate that GGT5 expression in cerebrovascular endothelial cells is inversely associated with Alzheimer’s disease pathogenesis,and that GGT5 upregulation mitigates cognitive deficits in APP/PS1 mice.These findings suggest that GGT5 expression in cerebrovascular endothelial cells is a potential therapeutic target and biomarker for Alzheimer’s disease.
基金the National Natural Science Foundation of China,Nos.82171401,81971187(to SC)and 81971183(to YT)grants from Shanghai Municipal Science and Technology Major Project,No.2018SHZDZX05(to SC)Shanghai Municipal Education Commission,No.2017-01-07-00-01-E00046(to SC)。
文摘Alzheimer's disease is a progressive neurological disorder characterized by cognitive decline and chronic inflammation within the brain.The ketogenic diet,a widely recognized therapeutic intervention for refractory epilepsy,has recently been proposed as a potential treatment for a variety of neurological diseases,including Alzheimer's disease.However,the efficacy of ketogenic diet in treating Alzheimer's disease and the underlying mechanism remains unclear.The current investigation aimed to explore the effect of ketogenic diet on cognitive function and the underlying biological mechanisms in a mouse model of Alzheimer's disease.Male amyloid precursor protein/presenilin 1(APP/PS1)mice were randomly assigned to either a ketogenic diet or control diet group,and received their respective diets for a duration of 3 months.The findings show that ketogenic diet administration enhanced cognitive function,attenuated amyloid plaque formation and proinflammatory cytokine levels in APP/PS1 mice,and augmented the nuclear factor-erythroid 2-p45 derived factor 2/heme oxygenase-1 signaling pathway while suppressing the nuclear factor-kappa B pathway.Collectively,these data suggest that ketogenic diet may have a therapeutic potential in treating Alzheimer's disease by ameliorating the neurotoxicity associated with Aβ-induced inflammation.This study highlights the urgent need for further research into the use of ketogenic diet as a potential therapy for Alzheimer's disease.
基金supported by grants from the National Natural Science Foundation of China(No.81803537)the"Major New Drug Creation"of Major Science and Technology Project(No.2015ZX09101-016)+1 种基金Capital Science and Technology Leading Talent Training Project(No.Z191100006119017)Beijing Hospitals Authority Ascent Plan(No.DFL20190803)。
文摘Cognitive impairment is the main clinical manifestation of Alzheimer's disease(AD),and amyloid-β(AB)deposition and senile plaques are the characteristic neuropathological hallmarks in AD brains.This study aimed to explore the effect and mechanism of tetrahydroxy stilbene glucoside(TSG)on cognitive function in APP/PS 1 mice during long-term administration.Here,we treated APP/PS1 model mice of AD with different doses of TSG(50 mg/kg and 100 mg/kg)for 5 to 17 months by gavage,and we further observed whether TSG could ameliorate the cognitive decline in APP/PS1 mice using behavioral tests,and investigated the possible mechanisms by immunohistochemistry and Western blotting.Our results showed that TSG treatment rescued the spatial and non-spatial learning and memory impairments of APP/PS1 mice at Morris water maze test and novel object recognition test.Furthermore,Aβ40/42 deposition in the cortex and hippocampus of APP/PS1 mice treated with TSG was significantly reduced compared to the wild type mice using the immunohistochemical technique.Finally,Western blotting showed that TSG primarily decreased the APP expression to avoid the Aβplaque deposition in the cortex and hippocampus of mice.These results reveal the beneficial effects of TSG in APP/PSI-AD mice,which may be associated with the reduction of Aβdeposits in the brain.
基金National Natural Sciences Foundation of China(8147320081673420)CAMS InnovationFund for Medical Sciences (2017-I2M-2-004).
文摘OBJECTIVE To study the protective effect of potassium 2-(l-hydroxypentyl)-benzoate(PHPB) on hippocampal neurons,synapses and dystrophic axons in APP/PS1 mice.METHODS Ten-month-old male APP/PS1 transgenic mice and age-matched wild-type mice were randomly divided into three groups:wild-type group(WT Con group,n=10),APP/PS1 group(Tg Con group,n=10) and PHPB treated APP/PS1 group(PHPB group,n=10).PHPB group received 30 mg · kg-1 PHPB by oral gavage once daily for 3 months.WT Con group and Tg Con group received the same volume of water.Three months later,mice were sacrificed for biochemical and pathological testing such as transmission electron microscopy,Golgi staining and Western boltting analysis.RESULTS Under the transmission electron microscope,most hippocampal neurons and subcel ular organel es in WT Con group exhibited normal morphology.However,the degenerative changes were observed in Tg Con group such as nuclear fragmentation,mitochondrial swelling,ribosomes detachment and autophagic vacuoles accumulation.The hippocampal synapses number and the thickness of postsynaptic density(PSD) were significantly decreased in Tg Con group compared with the WT Con group(P<0.05).After PHPB treatment,the degenerative changes in APP/PS1 mice were alleviated to some extent.The synapse number has been elevated significantly(P<0.05) and the PSD has been thickened as well.Golgi staining showed that the spine density of secondary and tertiary apical dendritic branches was significantly decreased in CA1 and DG areas of Tg Con group(P<0.05).Sholl analysis revealed a decrease of dendritic complexity in Tg Con group compared with WT Con group(P<0.05).These abnormalities were alleviated to some extent after PHPB treatment.Western blotting study showed that the protein levels of synaptic marker PSD-95 and synaptophysin were significantly decreased in the hippocampus of Tg Con group(P<0.05).A significant increase of PSD-95(P<0.05) and a slight increase of SYP were observed after the PHPB treatment.Besides,we found a significant increase in the ratio of LC3-Ⅱ/LC3-Ⅰ in Tg Con group compared with the WT Con group(P<0.01) and the relevant improvement after PHPB treatment(P<0.05),which showed the regulatory effect of PHPB on autophagy impairment.CONCLUSION PHPB showed protective effects on hippocampal neurons,synapses and dystrophic axons in APP/PS1 mice,which might help explain its role on cognitive improvement in Alzheimer disease treatment.
基金This work was supported by research grants from National Natural Science Foundation of China(81773717 to HTZ81601229 and 81441111 to HW).
文摘Phosphodiesterase-4(PDE4)has been demonstrated to be a promising target for treatment of Alzheimer’s disease(AD).Roflumilast(Rof),a potent PDE4 inhibitor,has been approved for treatment of chronic obstructive pulmonary disease(COPD)in humans.Recent studies have shown that Rof improves cognition at doses that do not cause an emetic response,the major side-effect of PDE4 inhibitors.However,the effect of Rof on cognition associated with AD remains largely unknown.Here we examined the effects of Rof on behavioral dysfunction and the related mechanisms in APP/PS1 double transgenic mice,a widely used model for AD.Mice at 10 months of age were first tested in novel object recognition for memory.The recognition index in APP/PS1 mice was decreased compared to WT mice,which was reversed by Rof at 5 and 10 mg·kg-1.This was then verified in the Morris water-maze test.The escape latency during acquisition training was significantly longer and the entries into the target quadrant during the probe trial were much less compared to WT controls,these were also reversed by Rof.In the tail-suspension and forced-swimming tests,which measure depression-like behavior,APP/PS1 mice showed prolonged immobility time,which was reversed by Rof.In addition,the staining of HE and Nissl showed that Rof reduced the loss of neurons and neurocyte apoptosis in APP/PS1 mice.It also reversed the decreased ratio of Bcl-2/BAX and inhibited the increased expression of PDE4D in the cerebral cortex and hippocampus of APP/PS1 mice.Finally,Rof reversed the decreased levels of cAMP and expression of phosphorylated cAMP response element-binding protein(CREB)and brain derived neurotrophic factor(BDNF)in APP/PS1 mice.Overall,these results suggest that Rof not only improves learning and memory,but attenuates depression-like behavior in AD mice,likely via PDE4D/cAMP/CREB/BDNF signaling-mediated neuroprotection.Therefore,Rof can be a therapeutic agent for AD,in particular the comorbidity of memory deficits and depression.
基金supported by the National Natural Science Foundation of China, No. 81771140 (to YDZ)the Natural Science Foundation of Jiangsu Province of China, No. BK20201117 (to YDZ)Jiangsu “Six One Project” for Distinguished Medical Scholars of China, No. LGY2020013 (to TJ)
文摘Lamotrigine(LTG)is a widely used drug for the treatment of epilepsy.Emerging clinical evidence suggests that LTG may improve cognitive function in patients with Alzheimer’s disease.However,the underlying molecular mechanisms remain unclear.In this study,amyloid precursor protein/presenilin 1(APP/PS1)double transgenic mice were used as a model of Alzheimer’s disease.Five-month-old APP/PS1 mice were intragastrically administered 30 mg/kg LTG or vehicle once per day for 3 successive months.The cognitive functions of animals were assessed using Morris water maze.Hyperphosphorylated tau and markers of synapse and glial cells were detected by western blot assay.The cell damage in the brain was investigated using hematoxylin and eosin staining.The levels of amyloid-βand the concentrations of interleukin-1β,interleukin-6 and tumor necrosis factor-αin the brain were measured using enzyme-linked immunosorbent assay.Differentially expressed genes in the brain after LTG treatment were analyzed by high-throughput RNA sequencing and real-time polymerase chain reaction.We found that LTG substantially improved spatial cognitive deficits of APP/PS1 mice;alleviated damage to synapses and nerve cells in the brain;and reduced amyloid-βlevels,tau protein hyperphosphorylation,and inflammatory responses.High-throughput RNA sequencing revealed that the beneficial effects of LTG on Alzheimer’s disease-related neuropathologies may have been mediated by the regulation of Ptgds,Cd74,Map3k1,Fosb,and Spp1 expression in the brain.These findings revealed potential molecular mechanisms by which LTG treatment improved Alzheimer’s disease.Furthermore,these data indicate that LTG may be a promising therapeutic drug for Alzheimer’s disease.
基金Supported by Major Project of Basic Scientific Research in Chengde Medical University(KY202217).
文摘[Objectives]To study the effect of human umbilical cord mesenchymal stem cells(hUC-MSCs)on GRP78/ATF4 pathway in APP/PS1 mice.[Methods]Twelve 6-month-old female APP/PS1 mice were randomly divided into model group(MOD,n=6)and human umbilical cord mesenchymal stem cell treatment group(MSC,n=6);six 6-month-old C57BL/6N mice were used as control group(CON,n=6).The mice in each group were treated with the fourth generation of human umbilical cord mesenchymal stem cells through tail vein.Four weeks later,the mice in each group were killed.The expression of GFP78 and ATF4 in the cortex of mice in each group was detected by Western blotting and real-time fluorescence quantitative PCR.[Results]The results of immunoblotting and real-time fluorescence quantitative PCR showed that the expression of GRP78 in MOD group was lower than that in CON group and the expression of ATF4 increased.The expression of GRP78 protein in MSC group was higher than that in MOD group,but the expression of ATF4 protein was lower.The results of real-time fluorescence quantitative PCR showed that the mRNA level of GRP78 decreased and the mRNA level of ATF4 increased in MOD group compared with CON group.The mRNA level of GRP78 in MSC group was higher than that in MOD group,while the mRNA level of ATF4 in MSC group was lower than that in MOD group.[Conclusions]Human umbilical cord mesenchymal stem cells can regulate the expression of GRP78/ATF4 pathway in APP/PSI mice,which may be related to the stress level of endoplasmic reticulum in the brain of APP/PS1 mice mediated by human umbilical cord mesenchymal stem cells.
基金supported by the National Natural Science Foundation of China,No.82201582(to QT)Scientific and Technological Research Program of Chongqing Municipal Education Commission,No.KJQN202200457(to QT)+3 种基金General Project of Changqing Natural Science Foundation,No.cstc2021jcyjmsxmX0442(to ZL)CQMU Program for Youth Innovation in Future Medicine,No.W0044(to ZD and GH)Direct Research Project for PhD of Chongqing,No.CSTB2022BSXM-JCX0051(to ZL)the Project of the Top-Notch Talent Cultivation Program For the Graduate Students of Chongqing Medical University,No.BJRC202310(to CG)。
文摘Recent studies have suggested that abnormal acidification of lysosomes induces autophagic accumulation of amyloid-βin neurons,which is a key step in senile plaque formation.Therefore,resto ring normal lysosomal function and rebalancing lysosomal acidification in neurons in the brain may be a new treatment strategy for Alzheimer's disease.Microtubule acetylation/deacetylation plays a central role in lysosomal acidification.Here,we show that inhibiting the classic microtubule deacetylase histone deacetylase 6 with an histone deacetylase 6 shRNA or thehistone deacetylase 6 inhibitor valproic acid promoted lysosomal reacidification by modulating V-ATPase assembly in Alzheimer's disease.Fu rthermore,we found that treatment with valproic acid markedly enhanced autophagy.promoted clearance of amyloid-βaggregates,and ameliorated cognitive deficits in a mouse model of Alzheimer's disease.Our findings demonstrate a previously unknown neuroprotective mechanism in Alzheimer's disease,in which histone deacetylase 6 inhibition by valproic acid increases V-ATPase assembly and lysosomal acidification.
基金the Sports Medicine Key Laboratory of Sichuan Province/Sports Medicine Key Laboratory of State Sport General Administration(Grant No.2023-A015)the Innovative Project of Sports Medicine and Health Institute/Zheng Huaixian Bone and Trauma Research Institute(Grant No.CX21A02)the"14th Five Year Plan"Scientific Research and Innovation Team of Chengdu Sport University(Grant No.23CXTD02).
文摘Behavioral experiments have demonstrated that long-term physical exercise can be beneficial for learning and memory dysfunction caused by neuroinflammation in Alzheimer's disease(AD).However,the molecular mechanism remains poorly understood due to a lack of sufficient pertinent biochemical evidence.We investigated the potential effect of long-term physical exercise on cognition and hippocampal gene and protein expression changes in a transgenic AD mouse model.Following twenty weeks of treadmill exercise,transgenic AD mice showed improvement in cognitive functions and downregulation of Nod-like receptor protein 3(NLRP3)(p<0.01),interleukin-1beta(IL-1β)(p<0.05),and amyloid-β1-42(Aβ1-42)(p<0.05)expression levels.In addition,we observed significant reductions of microglial activation and hippocampal neuronal damage in the exercised AD mice(p<0.01),which might be a result of the downregulation of NLRP3-mediated signaling and neuroinflammatory responses.As neuronal damage due to inflammation might be a likely cause of AD-associated cognitive dysfunction.Our results suggested that the anti-inflammatory effects of exercise training involved downregulating the expression of key inflammatory factors and might play an important role in protecting hippocampal neurons against damage during the course of AD.
