Ample clinical evidence suggests a high incidence of cardiovascular events in Alzheimer’s disease(AD),although neither precise etiology nor effective treatment is available.This study was designed to evaluate cardiac...Ample clinical evidence suggests a high incidence of cardiovascular events in Alzheimer’s disease(AD),although neither precise etiology nor effective treatment is available.This study was designed to evaluate cardiac function in AD patients and APP/PS1 mutant mice,along with circulating levels of melatonin,mitochondrial aldehyde dehydrogenase(ALDH2)and autophagy.AD patients and APP/PS1 mice displayed cognitive and myocardial deficits,low levels of circulating melatonin,ALDH2 activity,and autophagy,ultrastructural,geometric(cardiac atrophy and interstitial fibrosis)and functional(reduced fractional shortening and cardiomyocyte contraction)anomalies,mitochondrial injury,cytosolic mtDNA buildup,apoptosis,and suppressed autophagy and mitophagy.APP/PS1 mutation downregulated cyclic GMP-AMP synthase(cGAS)and stimulator of interferon genes(STING)levels and TBK1 phosphorylation,while promoting Aβaccumulation.Treatment with melatonin overtly ameliorated unfavorable APP/PS1-induced changes in cardiac geometry and function,apoptosis,mitochondrial integrity,cytosolic mtDNA accumulation(using both immunocytochemistry and qPCR),mitophagy,and cGAS-STING-TBK1 signaling,although these benefits were absent in APP/PS1/ALDH2−/−mice.In vitro evidence indicated that melatonin attenuated APP/PS1-induced suppression of mitophagy and cardiomyocyte function,and the effect was negated by the nonselective melatonin receptor blocker luzindole,inhibitors or RNA interference of cGAS,STING,TBK1,and autophagy.Our data collectively established a correlation among cardiac dysfunction,low levels of melatonin,ALDH2 activity,and autophagy in AD patients,with compelling support in APP/PS1 mice,in which melatonin rescued myopathic changes by promoting cGAS-STING-TBK1 signaling and mitophagy via an ALDH2-dependent mechanism.展开更多
MicroRNA alterations have been reported in patients with Alzheimer＇s disease （AD） and AD mouse models. We now report that miR-206 is upregulated in the hippocampal tissue, cerebrospinal fluid, and plasma of embryon...MicroRNA alterations have been reported in patients with Alzheimer＇s disease （AD） and AD mouse models. We now report that miR-206 is upregulated in the hippocampal tissue, cerebrospinal fluid, and plasma of embryonic APP/PS1 transgenic mice. The increased miR-206 downregulates the expression of brain-derived neurotrophic factor （BDNF）. BDNF is neuroprotective against cell death after various insults, but in embryonic and newborn APP/PS1 mice it is decreased. Thus, a specific microRNA alteration may contribute to AD pathology by downregulating BDNF.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
The APPSwe/PSEN1 dE9（APP/PS1） transgenic mouse model is an Alzheimer＇s disease mouse model exhibiting symptoms of dementia, and is commonly used to explore pathological changes in the development of Alzheimer＇s di...The APPSwe/PSEN1 dE9（APP/PS1） transgenic mouse model is an Alzheimer＇s disease mouse model exhibiting symptoms of dementia, and is commonly used to explore pathological changes in the development of Alzheimer＇s disease. Previous clinical autopsy and imaging studies suggest that Alzheimer＇s disease patients have white matter and oligodendrocyte damage, but the underlying mechanisms of these have not been revealed. Therefore, the present study used APP/PS1 mice to assess cognitive change, myelin loss, and corresponding changes in oligodendrocytes, and to explore the underlying mechanisms. Morris water maze tests were performed to evaluate cognitive change in APP/PS1 mice and normal C57 BL/6 mice aged 3 and 6 months. Luxol fast blue staining of the corpus callosum and quantitative reverse transcription-polymerase chain reaction（q RT-PCR） for myelin basic protein（MBP） mRNA were carried out to quantify myelin damage. Immunohistochemistry staining for NG2 and qRT-PCR for monocarboxylic acid transporter 1（MCT1） mRNA were conducted to assess corresponding changes in oligodendrocytes. Our results demonstrate that compared with C57 BL/6 mice, there was a downregulation of MBP mRNA in APP/PS1 mice aged 3 months. This became more obvious in APP/PS1 mice aged 6 months accompanied by other abnormalities such as prolonged escape latency in the Morris water maze test, shrinkage of the corpus callosum, upregulation of NG2-immunoreactive cells, and downregulation of MCT1 mRNA. These findings indicate that the involvement of early demyelination at 3 months and the oligodendrocyte dysfunction at 6 months in APP/PS1 mice are in association with Alzheimer＇s disease pathogenesis.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
基金supported in part by grants from the National Key R&D Program of China(2017YFA0506000)National Natural Science Foundation of China(91749128)the Shannxi Province Key Science and Natural Project(2019JQ-704).
文摘Ample clinical evidence suggests a high incidence of cardiovascular events in Alzheimer’s disease(AD),although neither precise etiology nor effective treatment is available.This study was designed to evaluate cardiac function in AD patients and APP/PS1 mutant mice,along with circulating levels of melatonin,mitochondrial aldehyde dehydrogenase(ALDH2)and autophagy.AD patients and APP/PS1 mice displayed cognitive and myocardial deficits,low levels of circulating melatonin,ALDH2 activity,and autophagy,ultrastructural,geometric(cardiac atrophy and interstitial fibrosis)and functional(reduced fractional shortening and cardiomyocyte contraction)anomalies,mitochondrial injury,cytosolic mtDNA buildup,apoptosis,and suppressed autophagy and mitophagy.APP/PS1 mutation downregulated cyclic GMP-AMP synthase(cGAS)and stimulator of interferon genes(STING)levels and TBK1 phosphorylation,while promoting Aβaccumulation.Treatment with melatonin overtly ameliorated unfavorable APP/PS1-induced changes in cardiac geometry and function,apoptosis,mitochondrial integrity,cytosolic mtDNA accumulation(using both immunocytochemistry and qPCR),mitophagy,and cGAS-STING-TBK1 signaling,although these benefits were absent in APP/PS1/ALDH2−/−mice.In vitro evidence indicated that melatonin attenuated APP/PS1-induced suppression of mitophagy and cardiomyocyte function,and the effect was negated by the nonselective melatonin receptor blocker luzindole,inhibitors or RNA interference of cGAS,STING,TBK1,and autophagy.Our data collectively established a correlation among cardiac dysfunction,low levels of melatonin,ALDH2 activity,and autophagy in AD patients,with compelling support in APP/PS1 mice,in which melatonin rescued myopathic changes by promoting cGAS-STING-TBK1 signaling and mitophagy via an ALDH2-dependent mechanism.
基金supported by a National Natural Science Foundation of China(91132718)
文摘MicroRNA alterations have been reported in patients with Alzheimer＇s disease （AD） and AD mouse models. We now report that miR-206 is upregulated in the hippocampal tissue, cerebrospinal fluid, and plasma of embryonic APP/PS1 transgenic mice. The increased miR-206 downregulates the expression of brain-derived neurotrophic factor （BDNF）. BDNF is neuroprotective against cell death after various insults, but in embryonic and newborn APP/PS1 mice it is decreased. Thus, a specific microRNA alteration may contribute to AD pathology by downregulating BDNF.
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supported by the National Natural Science Foundation of China,No.81371395the Liaoning Scientific and Technological Preferential Finance for Returned Overseas 2015 of China,No.[2015]125+2 种基金the Natural Science Foundation of Liaoning Province of China,No.20170541021,2015020547a grant from the Shenyang Science Technology Project,No.F16-206-9-12the China Post-doctoral Science Foundation,No.2015M581375
文摘The APPSwe/PSEN1 dE9（APP/PS1） transgenic mouse model is an Alzheimer＇s disease mouse model exhibiting symptoms of dementia, and is commonly used to explore pathological changes in the development of Alzheimer＇s disease. Previous clinical autopsy and imaging studies suggest that Alzheimer＇s disease patients have white matter and oligodendrocyte damage, but the underlying mechanisms of these have not been revealed. Therefore, the present study used APP/PS1 mice to assess cognitive change, myelin loss, and corresponding changes in oligodendrocytes, and to explore the underlying mechanisms. Morris water maze tests were performed to evaluate cognitive change in APP/PS1 mice and normal C57 BL/6 mice aged 3 and 6 months. Luxol fast blue staining of the corpus callosum and quantitative reverse transcription-polymerase chain reaction（q RT-PCR） for myelin basic protein（MBP） mRNA were carried out to quantify myelin damage. Immunohistochemistry staining for NG2 and qRT-PCR for monocarboxylic acid transporter 1（MCT1） mRNA were conducted to assess corresponding changes in oligodendrocytes. Our results demonstrate that compared with C57 BL/6 mice, there was a downregulation of MBP mRNA in APP/PS1 mice aged 3 months. This became more obvious in APP/PS1 mice aged 6 months accompanied by other abnormalities such as prolonged escape latency in the Morris water maze test, shrinkage of the corpus callosum, upregulation of NG2-immunoreactive cells, and downregulation of MCT1 mRNA. These findings indicate that the involvement of early demyelination at 3 months and the oligodendrocyte dysfunction at 6 months in APP/PS1 mice are in association with Alzheimer＇s disease pathogenesis.
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.
