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
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
Triggering receptor expressed on myeloid cells-like 2(TREML2)is a newly identified susceptibility gene for Alzheimer's disease(AD).It encodes a microglial inflammation-associated receptor.To date,the potential rol...Triggering receptor expressed on myeloid cells-like 2(TREML2)is a newly identified susceptibility gene for Alzheimer's disease(AD).It encodes a microglial inflammation-associated receptor.To date,the potential role of mic roglial TREML2 in neuroinflammation in the context of AD remains unclear.In this study,APP/PS1 mice were used to investigate the dynamic changes of TREML2 levels in brain during AD progression.In addition,lipopolysaccharide(LPS)stimulation of primary microglia as well as a lentivirus-mediated TREML2 overexpression and knockdown were employed to explore the role of TREML2 in neuroinflammation in the context of AD.Our res ults show that TREML2 levels gradually increased in the brains of AP P/PS1 mice during disease progression.LPS stimulation of primary microglia led to the release of inflammato ry cytokines including interleukin-1β,inte rleukin-6,and tumor necrosis factor-a in the culture medium.The LPS-induced mic roglial release of inflammatory cytokines was enhanced by TREML2 overexpression and was attenuated by TREML2 knoc kdown.LPS increased the levels of mic roglial M1-type polarization marker inducible nitric oxide synthase.This effect was enhanced by TREML2 overexpression and ameliorated by TREML2 knockdown.Furthermore,the levels of microglial M2-type polarization markers CD206 and ARG1 in the primary microglia were reduced by TREML2 overexpression and elevated by TREML2 knockdown.LPS stimulation increased the levels of NLRP3 in primary microglia.The LPS-induced increase in NLRP3 was further elevated by TREML2 overexpression and alleviated by TREML2 knockdown.In summary,this study provides the first evidence that TREML2 modulates inflammation by regulating microglial polarization and NLRP3 inflammasome activation.These findings reveal the mechanisms by which TREML2 regulates microglial inflammation and suggest that TREML2 inhibition may represent a novel therapeutic strategy for AD.展开更多
Memory deficits with aging are related to the neurodegeneration in the brain, including a reduction in arginine vasopressin(AVP) in the brain of patients with Alzheimer’s disease(AD). AVP(4-8), different from its pre...Memory deficits with aging are related to the neurodegeneration in the brain, including a reduction in arginine vasopressin(AVP) in the brain of patients with Alzheimer’s disease(AD). AVP(4-8), different from its precursor AVP, plays memory enhancement roles in the CNS without peripheral side-effects. However, it is not clear whether AVP(4-8) can improve cognitive behaviors and synaptic plasticity in the APP/PS1 mouse model of AD. Here, we investigated for the first time the neuroprotective effects of AVP(4-8) on memory behaviors and in vivo long-term potentiation(LTP) in APP/PS1-AD mice.The results showed that:(1) APP/PS1-AD mice had lower spontaneous alternation in the Y-maze than wild-type(WT) mice, and this was significantly reversed by AVP(4-8);(2) the prolonged escape latency of APP/PS1-AD mice in the Morris water maze was significantly decreased by AVP(4-8), and the decreased swimming time in target quadrant recovered significantly after AVP(4-8) treatment;(3) in vivo hippocampal LTP induced by high-frequency stimulation had a significant deficit in the AD mice, and this was partly rescued by AVP(4-8);(4) AVP(4-8)significantly up-regulated the expression levels of postsynaptic density 95(PSD95) and nerve growth factor(NGF)in the hippocampus of AD mice. These results reveal the beneficial effects of AVP(4-8) in APP/PS1-AD mice,showing that the intranasal administration of AVP(4-8)effectively improved the working memory and long-term spatial memory of APP/PS1-AD mice, which may be associated with the elevation of PSD95 and NGF levels in the brain and the maintenance of hippocampal synaptic plasticity.展开更多
Fine particulate matter(PM_(2.5))is associated with increased risks of Alzheimer's disease(AD),yet the toxicological mechanisms of PM_(2.5)promoting AD remain unclear.In this study,wildtype and APP/PS1 transgenic ...Fine particulate matter(PM_(2.5))is associated with increased risks of Alzheimer's disease(AD),yet the toxicological mechanisms of PM_(2.5)promoting AD remain unclear.In this study,wildtype and APP/PS1 transgenic mice(AD mice)were exposed to either filtered air(FA)or PM_(2.5)for eight weeks with a real-world exposure system in Taiyuan,China(mean PM_(2.5)concentration in the cage was 61μg/m~3).We found that PM_(2.5)exposure could remarkably aggravate AD mice's ethological and brain ultrastructural damage,along with the elevation of the pro-inflammatory cytokines(IL-6 and TNF-α),Aβ-42 and ACh E levels and the decline of Ch AT levels in the brains.Based on high-throughput sequencing results,some differentially expressed(DE)m RNAs and DE mi RNAs in the brains of AD mice after PM_(2.5)exposure were screened.Using RT-q PCR,seven DE mi RNAs(mmu-mi R-193b-5p,122b-5p,466h-3p,10b-5p,1895,384–5p,and 6412)and six genes(Pcdhgb8,Unc13b,Robo3,Prph,Pter,and Tbata)were evidenced the and verified.Two mi RNA-target gene pairs(mi R-125b-Pcdhgb8 pair and mi R-466h-3p-IL-17Rα/TGF-βR2/Aβ-42/ACh E pairs)were demonstrated that they were more related to PM_(2.5)-induced brain injury.Results of Gene Ontology(GO)pathways and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathways predicted that synaptic and postsynaptic regulation,axon guidance,Wnt,MAPK,and m TOR pathways might be the possible regulatory mechanisms associated with pathological response.These revealed that PM_(2.5)-elevated pro-inflammatory cytokine levels and PM_(2.5)-altered neurotransmitter levels in AD mice could be the important causes of brain damage and proposed the promising mi RNA and m RNA biomarkers and potential mi RNA-m RNA interaction networks of PM_(2.5)-promoted AD.展开更多
Autophagy has been reported to play a dual"double-edged sword"role in the occurrence and development of Alzheimer's disease(AD).To assess the relationship between AD and autophagy,the dynamic changes of ...Autophagy has been reported to play a dual"double-edged sword"role in the occurrence and development of Alzheimer's disease(AD).To assess the relationship between AD and autophagy,the dynamic changes of autophagic flux in the brain of postmortem AD patients,animal models and cell models were studied.The results showed that in AD patients,LC3 was accumulated in large amount,but the expression of Lamp1 and CTSB decreased,and the co-expression of LC3 and CTSB decreased.In the brain of APP/PS1 double transgenic mice,autophagosomes(APs)and autolysosomes(ALs)accumulation occur with the deposition of senile plaques(SPs),and the levels of lysosomal markers CTSB and Lamp1 protein decreased significantly.In the brain of APP/PS1/LC3 triple transgenic mice,the number of APs increased with the age of mice,but the number of ALs did not increase accordingly.展开更多
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.
基金supported by the National Natural Science Foundation of china,No.81974156(to TJ)the Natural Science Foundation of Jiangsu Province,No.BK20201117(to YDZ)。
文摘Triggering receptor expressed on myeloid cells-like 2(TREML2)is a newly identified susceptibility gene for Alzheimer's disease(AD).It encodes a microglial inflammation-associated receptor.To date,the potential role of mic roglial TREML2 in neuroinflammation in the context of AD remains unclear.In this study,APP/PS1 mice were used to investigate the dynamic changes of TREML2 levels in brain during AD progression.In addition,lipopolysaccharide(LPS)stimulation of primary microglia as well as a lentivirus-mediated TREML2 overexpression and knockdown were employed to explore the role of TREML2 in neuroinflammation in the context of AD.Our res ults show that TREML2 levels gradually increased in the brains of AP P/PS1 mice during disease progression.LPS stimulation of primary microglia led to the release of inflammato ry cytokines including interleukin-1β,inte rleukin-6,and tumor necrosis factor-a in the culture medium.The LPS-induced mic roglial release of inflammatory cytokines was enhanced by TREML2 overexpression and was attenuated by TREML2 knoc kdown.LPS increased the levels of mic roglial M1-type polarization marker inducible nitric oxide synthase.This effect was enhanced by TREML2 overexpression and ameliorated by TREML2 knockdown.Furthermore,the levels of microglial M2-type polarization markers CD206 and ARG1 in the primary microglia were reduced by TREML2 overexpression and elevated by TREML2 knockdown.LPS stimulation increased the levels of NLRP3 in primary microglia.The LPS-induced increase in NLRP3 was further elevated by TREML2 overexpression and alleviated by TREML2 knockdown.In summary,this study provides the first evidence that TREML2 modulates inflammation by regulating microglial polarization and NLRP3 inflammasome activation.These findings reveal the mechanisms by which TREML2 regulates microglial inflammation and suggest that TREML2 inhibition may represent a novel therapeutic strategy for AD.
基金the National Natural Science Foundation of China(31471080)the Scientific Program for“Sanjin Scholars”of Shanxi Province,Shanxi“1331 Project”Key Subjects Construction(1331KSC)Science Foundation for Excellent Young Scholars of Shanxi Province,China(201801D211005)。
文摘Memory deficits with aging are related to the neurodegeneration in the brain, including a reduction in arginine vasopressin(AVP) in the brain of patients with Alzheimer’s disease(AD). AVP(4-8), different from its precursor AVP, plays memory enhancement roles in the CNS without peripheral side-effects. However, it is not clear whether AVP(4-8) can improve cognitive behaviors and synaptic plasticity in the APP/PS1 mouse model of AD. Here, we investigated for the first time the neuroprotective effects of AVP(4-8) on memory behaviors and in vivo long-term potentiation(LTP) in APP/PS1-AD mice.The results showed that:(1) APP/PS1-AD mice had lower spontaneous alternation in the Y-maze than wild-type(WT) mice, and this was significantly reversed by AVP(4-8);(2) the prolonged escape latency of APP/PS1-AD mice in the Morris water maze was significantly decreased by AVP(4-8), and the decreased swimming time in target quadrant recovered significantly after AVP(4-8) treatment;(3) in vivo hippocampal LTP induced by high-frequency stimulation had a significant deficit in the AD mice, and this was partly rescued by AVP(4-8);(4) AVP(4-8)significantly up-regulated the expression levels of postsynaptic density 95(PSD95) and nerve growth factor(NGF)in the hippocampus of AD mice. These results reveal the beneficial effects of AVP(4-8) in APP/PS1-AD mice,showing that the intranasal administration of AVP(4-8)effectively improved the working memory and long-term spatial memory of APP/PS1-AD mice, which may be associated with the elevation of PSD95 and NGF levels in the brain and the maintenance of hippocampal synaptic plasticity.
基金supported by the National Natural Science Foundation of China(No.91843301)the Hundred Talents Program of Shanxi Province in China,and the Hong Kong Research Grants Council Research Matching Scheme(RMGS2019-1-12,RMGS-2019-1-15)。
文摘Fine particulate matter(PM_(2.5))is associated with increased risks of Alzheimer's disease(AD),yet the toxicological mechanisms of PM_(2.5)promoting AD remain unclear.In this study,wildtype and APP/PS1 transgenic mice(AD mice)were exposed to either filtered air(FA)or PM_(2.5)for eight weeks with a real-world exposure system in Taiyuan,China(mean PM_(2.5)concentration in the cage was 61μg/m~3).We found that PM_(2.5)exposure could remarkably aggravate AD mice's ethological and brain ultrastructural damage,along with the elevation of the pro-inflammatory cytokines(IL-6 and TNF-α),Aβ-42 and ACh E levels and the decline of Ch AT levels in the brains.Based on high-throughput sequencing results,some differentially expressed(DE)m RNAs and DE mi RNAs in the brains of AD mice after PM_(2.5)exposure were screened.Using RT-q PCR,seven DE mi RNAs(mmu-mi R-193b-5p,122b-5p,466h-3p,10b-5p,1895,384–5p,and 6412)and six genes(Pcdhgb8,Unc13b,Robo3,Prph,Pter,and Tbata)were evidenced the and verified.Two mi RNA-target gene pairs(mi R-125b-Pcdhgb8 pair and mi R-466h-3p-IL-17Rα/TGF-βR2/Aβ-42/ACh E pairs)were demonstrated that they were more related to PM_(2.5)-induced brain injury.Results of Gene Ontology(GO)pathways and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathways predicted that synaptic and postsynaptic regulation,axon guidance,Wnt,MAPK,and m TOR pathways might be the possible regulatory mechanisms associated with pathological response.These revealed that PM_(2.5)-elevated pro-inflammatory cytokine levels and PM_(2.5)-altered neurotransmitter levels in AD mice could be the important causes of brain damage and proposed the promising mi RNA and m RNA biomarkers and potential mi RNA-m RNA interaction networks of PM_(2.5)-promoted AD.
文摘Autophagy has been reported to play a dual"double-edged sword"role in the occurrence and development of Alzheimer's disease(AD).To assess the relationship between AD and autophagy,the dynamic changes of autophagic flux in the brain of postmortem AD patients,animal models and cell models were studied.The results showed that in AD patients,LC3 was accumulated in large amount,but the expression of Lamp1 and CTSB decreased,and the co-expression of LC3 and CTSB decreased.In the brain of APP/PS1 double transgenic mice,autophagosomes(APs)and autolysosomes(ALs)accumulation occur with the deposition of senile plaques(SPs),and the levels of lysosomal markers CTSB and Lamp1 protein decreased significantly.In the brain of APP/PS1/LC3 triple transgenic mice,the number of APs increased with the age of mice,but the number of ALs did not increase accordingly.
