We reviewed recent major clinical trials with investigational drugs for the treatment of subjects with neurodegenerative diseases caused by inheritance of gene mutations or associated with genetic risk factors.Specifi...We reviewed recent major clinical trials with investigational drugs for the treatment of subjects with neurodegenerative diseases caused by inheritance of gene mutations or associated with genetic risk factors.Specifically,we discussed randomized clinical trials in subjects with Alzheimer's disease,Huntington's disease and amyotrophic lateral sclerosis bearing pathogenic gene mutations,and glucocerebrosidase-associated Parkinson's disease.Learning potential lessons to improve future therapeutic approaches is the aim of this review.Two long-term,controlled trials on three anti-β-amyloid monoclonal antibodies(solanezumab,gantenerumab and crenezumab)in subjects carrying Alzheimer's disease-linked mutated genes encoding for amyloid precursor protein or presenilin 1 or presenilin 2 failed to show cognitive or functional benefits.A major trial on tominersen,an antisense oligonucleotide designed to reduce the production of the huntingtin protein in subjects with Huntington's disease,was prematurely interrupted because the drug failed to show higher efficacy than placebo and,at highest doses,led to worsened outcomes.A 28-week trial of tofersen,an antisense oligonucleotide for superoxide dismutase 1 in patients with amyotrophic lateral sclerosis with superoxide dismutase 1 gene mutations failed to show significant beneficial effects but the 1-year open label extension of this study indicated better clinical and functional outcomes in the group with early tofersen therapy.A trial of venglustat,a potent and brain-penetrant glucosylceramide synthase inhibitor,in Parkinson's disease subjects with heterozygous glucocerebrosidase gene mutations revealed worsened clinical and cognitive performance of patients on the enzyme inhibitor compared to placebo.We concluded that clinical trials in neurodegenerative diseases with a genetic basis should test monoclonal antibodies,antisense oligonucleotides or gene editing directed against the mutated enzyme or the mutated substrate without dramatically affecting physiological wild-type variants.展开更多
In a previous study,we found that long non-coding genes in Alzheimer’s disease(AD)are a result of endogenous gene disorders caused by the recruitment of microRNA(miRNA)and mRNA,and that miR-200a-3p and other represen...In a previous study,we found that long non-coding genes in Alzheimer’s disease(AD)are a result of endogenous gene disorders caused by the recruitment of microRNA(miRNA)and mRNA,and that miR-200a-3p and other representative miRNAs can mediate cognitive impairment and thus serve as new biomarkers for AD.In this study,we investigated the abnormal expression of miRNA and mRNA and the pathogenesis of AD at the epigenetic level.To this aim,we performed RNA sequencing and an integrative analysis of the cerebral cortex of the widely used amyloid precursor protein and presenilin-1 double transgenic mouse model of AD.Overall,129 mRNAs and 68 miRNAs were aberrantly expressed.Among these,eight down-regulated miRNAs and seven up-regulated miRNAs appeared as promising noninvasive biomarkers and therapeutic targets.The main enriched signaling pathways involved mitogen-activated kinase protein,phosphatidylinositol 3-kinase-protein kinase B,mechanistic target of rapamycin kinase,forkhead box O,and autophagy.An miRNA-mRNA network between dysregulated miRNAs and corresponding target genes connected with AD progression was also constructed.These miRNAs and mRNAs are potential biomarkers and therapeutic targets for new treatment strategies,early diagnosis,and prevention of AD.The present results provide a novel perspective on the role of miRNAs and mRNAs in AD.This study was approved by the Experimental Animal Care and Use Committee of Institute of Medicinal Biotechnology of Beijing,China(approval No.IMB-201909-D6)on September 6,2019.展开更多
The presenilin genes(PSEN1 and PSEN2)are mainly responsible for causing early-onset familial Alzheimer’s disease,harboring~300 causative mutations,and representing~90%of all mutations associated with a very aggressiv...The presenilin genes(PSEN1 and PSEN2)are mainly responsible for causing early-onset familial Alzheimer’s disease,harboring~300 causative mutations,and representing~90%of all mutations associated with a very aggressive disease form.Presenilin 1 is the catalytic core of theγ-secretase complex that conducts the intramembranous proteolytic excision of multiple transmembrane proteins like the amyloid precursor protein,Notch-1,N-and E-cadherin,LRP,Syndecan,Delta,Jagged,CD44,ErbB4,and Nectin1a.Presenilin 1 plays an essential role in neural progenitor maintenance,neurogenesis,neurite outgrowth,synaptic function,neuronal function,myelination,and plasticity.Therefore,an imbalance caused by mutations in presenilin 1/γ-secretase might cause aberrant signaling,synaptic dysfunction,memory impairment,and increased Aβ42/Aβ40 ratio,contributing to neurodegeneration during the initial stages of Alzheimer’s disease pathogenesis.This review focuses on the neuronal differentiation dysregulation mediated by PSEN1 mutations in Alzheimer’s disease.Furthermore,we emphasize the importance of Alzheimer’s disease-induced pluripotent stem cells models in analyzing PSEN1 mutations implication over the early stages of the Alzheimer’s disease pathogenesis throughout neuronal differentiation impairment.展开更多
Mutations in presenilin 1(PS1)gene are closely associated with the early onset of familial Alzheimer’s disease(EOFAD).The fusion genes,GFP-PS1(recombinant plasmid pEGFP-C1-PS1)and PS1-GFP(recombinant plasmid pEGFP-N2...Mutations in presenilin 1(PS1)gene are closely associated with the early onset of familial Alzheimer’s disease(EOFAD).The fusion genes,GFP-PS1(recombinant plasmid pEGFP-C1-PS1)and PS1-GFP(recombinant plasmid pEGFP-N2-PS1)were constructed to study the subcellular localization of PS1 holoprotein.Recombinant plasmids were transiently transfected into two cell lines,HEK293 and CHO,respectively,using the green fluorescence from GFP(green fluorescence protein)as the PS1 localization signal.Then,we observed green fluorescence with a SPOT II(Olympus,BH2)and CONFOCAL microscope(Olympus,FV300)under 488 nm.The results show that PS1 located on the nuclear envelope.A few can be found on the cellular membrane and in the cytosol in a non-homogeneous distribution.展开更多
Background Two novel presenilin 1 （PS1） mutations, V97L and A136G, were recently found to be involved in the early-onset of Alzheimer＇s disease in two Chinese families. This research aimed to verity their pathologi...Background Two novel presenilin 1 （PS1） mutations, V97L and A136G, were recently found to be involved in the early-onset of Alzheimer＇s disease in two Chinese families. This research aimed to verity their pathological effects. Methods The human neuroblastoma SH-SY5Y cells stably transfected with these two Chinese presenilin 1 mutations were established to explore whether they are sensitive to, or influenced by, serum deprivation and protected by insulin-like growth factor-1 （IGF-1）. Apoptosis rate, glucose uptake of the cells and the expression of glucose transport protein 1 （GLUT1） on cell membranes were examined. Results The V97L or A136G mutants significantly decreased the cells viability and increased the apoptosis rate when compare to PSlwt and mock transfected cells. IGF-1 was found to improve the viability of these two kinds of mutant cells significantly, and to show a protective effect for the mutants when they were treated with trophic deprivation. The glucose uptake of each transfected cell line increased to about 25% after IGF-1 treatment, GLUT1 expression on the cell membrane increased modestly by about 15%-20%. Conclusions Enhanced sensitivity to trophic withdrawal in the cells transfected with the two Chinese PS1 mutations may contribute to the neuron apoptosis, IGF-1 provided a protective effect to cells, possibly through an enhanced glucose transport and mitochondrial activities.展开更多
Objective To evaluate the association of apolipoprotein E (apoE) and presenilin 1 (PS 1) gene polymorphism with late onset Alzheimer's disease (AD) Methods A case control study was undertaken to detect ...Objective To evaluate the association of apolipoprotein E (apoE) and presenilin 1 (PS 1) gene polymorphism with late onset Alzheimer's disease (AD) Methods A case control study was undertaken to detect the polymorphism of apoE and PS 1 by polymerase chain reaction and digestion with the endonucleases of BspL Ⅰ, Hha Ⅰ and BamH Ⅰ Results The frequencies of apoE ε3/4 genotype and ε4 allele in late onset AD (n=42) were significantly higher than those of age matched controls ( P <0 05) The frequencies of the apoE intron 1 enhancer (IE1) G/G genotype and G allele in late onset AD were also significantly higher than those in controls ( P <0 05) The frequencies of the PS 1 1/1 genotype but not the 1 allele in AD were significantly higher than those in controls ( P <0 05) The apoE ε4 allele was associated with a tripling of risk for late onset AD compared with that with no ε4 allele (odds ratio: 2 932) Homozygosity of the G allele in IE1 and 1/1 genotype in PS 1 was associated with a doubling of risk for late onset AD, and odds ratios were 2 223 and 2 066, respectively When the apoE ε4 was controlled, the association between the IE1 G/G genotype AD was no longer statistically significant ( P >0 05) We sequenced the exon 4 of apoE in patients with late onset AD, and found no other genetic polymorphism or mutation except for apoE ε4 and IE1 G alleles associated with AD Conclusion apoE ε4 gene appears to be the strongest gene risk factor for late onset AD and its apparent association between the IE1 G/G genotype and late onset AD is a consequence of the association between the ε4 and IE1 G/G genotype The PS 1/1 genotype is weakly associated with late onset AD展开更多
文摘We reviewed recent major clinical trials with investigational drugs for the treatment of subjects with neurodegenerative diseases caused by inheritance of gene mutations or associated with genetic risk factors.Specifically,we discussed randomized clinical trials in subjects with Alzheimer's disease,Huntington's disease and amyotrophic lateral sclerosis bearing pathogenic gene mutations,and glucocerebrosidase-associated Parkinson's disease.Learning potential lessons to improve future therapeutic approaches is the aim of this review.Two long-term,controlled trials on three anti-β-amyloid monoclonal antibodies(solanezumab,gantenerumab and crenezumab)in subjects carrying Alzheimer's disease-linked mutated genes encoding for amyloid precursor protein or presenilin 1 or presenilin 2 failed to show cognitive or functional benefits.A major trial on tominersen,an antisense oligonucleotide designed to reduce the production of the huntingtin protein in subjects with Huntington's disease,was prematurely interrupted because the drug failed to show higher efficacy than placebo and,at highest doses,led to worsened outcomes.A 28-week trial of tofersen,an antisense oligonucleotide for superoxide dismutase 1 in patients with amyotrophic lateral sclerosis with superoxide dismutase 1 gene mutations failed to show significant beneficial effects but the 1-year open label extension of this study indicated better clinical and functional outcomes in the group with early tofersen therapy.A trial of venglustat,a potent and brain-penetrant glucosylceramide synthase inhibitor,in Parkinson's disease subjects with heterozygous glucocerebrosidase gene mutations revealed worsened clinical and cognitive performance of patients on the enzyme inhibitor compared to placebo.We concluded that clinical trials in neurodegenerative diseases with a genetic basis should test monoclonal antibodies,antisense oligonucleotides or gene editing directed against the mutated enzyme or the mutated substrate without dramatically affecting physiological wild-type variants.
基金This study was supported by the National Natural Science Foundation of China(General Program),No.81673411the United Fund Project of National Natural Science Foundation of China,No.U1803281+1 种基金Young Medical Talents Award Project of Chinese Academy of Medical Sciences,No.2018RC350013Chinese Academy of Medical Sciences Innovation Project for Medical Science,No.2017-I2M-1-016(all to RL).
文摘In a previous study,we found that long non-coding genes in Alzheimer’s disease(AD)are a result of endogenous gene disorders caused by the recruitment of microRNA(miRNA)and mRNA,and that miR-200a-3p and other representative miRNAs can mediate cognitive impairment and thus serve as new biomarkers for AD.In this study,we investigated the abnormal expression of miRNA and mRNA and the pathogenesis of AD at the epigenetic level.To this aim,we performed RNA sequencing and an integrative analysis of the cerebral cortex of the widely used amyloid precursor protein and presenilin-1 double transgenic mouse model of AD.Overall,129 mRNAs and 68 miRNAs were aberrantly expressed.Among these,eight down-regulated miRNAs and seven up-regulated miRNAs appeared as promising noninvasive biomarkers and therapeutic targets.The main enriched signaling pathways involved mitogen-activated kinase protein,phosphatidylinositol 3-kinase-protein kinase B,mechanistic target of rapamycin kinase,forkhead box O,and autophagy.An miRNA-mRNA network between dysregulated miRNAs and corresponding target genes connected with AD progression was also constructed.These miRNAs and mRNAs are potential biomarkers and therapeutic targets for new treatment strategies,early diagnosis,and prevention of AD.The present results provide a novel perspective on the role of miRNAs and mRNAs in AD.This study was approved by the Experimental Animal Care and Use Committee of Institute of Medicinal Biotechnology of Beijing,China(approval No.IMB-201909-D6)on September 6,2019.
基金supported by the Consejo Nacional de Ciencia y Tecnología Scholarship 711893(to MAH)and 711874(to EER)。
文摘The presenilin genes(PSEN1 and PSEN2)are mainly responsible for causing early-onset familial Alzheimer’s disease,harboring~300 causative mutations,and representing~90%of all mutations associated with a very aggressive disease form.Presenilin 1 is the catalytic core of theγ-secretase complex that conducts the intramembranous proteolytic excision of multiple transmembrane proteins like the amyloid precursor protein,Notch-1,N-and E-cadherin,LRP,Syndecan,Delta,Jagged,CD44,ErbB4,and Nectin1a.Presenilin 1 plays an essential role in neural progenitor maintenance,neurogenesis,neurite outgrowth,synaptic function,neuronal function,myelination,and plasticity.Therefore,an imbalance caused by mutations in presenilin 1/γ-secretase might cause aberrant signaling,synaptic dysfunction,memory impairment,and increased Aβ42/Aβ40 ratio,contributing to neurodegeneration during the initial stages of Alzheimer’s disease pathogenesis.This review focuses on the neuronal differentiation dysregulation mediated by PSEN1 mutations in Alzheimer’s disease.Furthermore,we emphasize the importance of Alzheimer’s disease-induced pluripotent stem cells models in analyzing PSEN1 mutations implication over the early stages of the Alzheimer’s disease pathogenesis throughout neuronal differentiation impairment.
文摘Mutations in presenilin 1(PS1)gene are closely associated with the early onset of familial Alzheimer’s disease(EOFAD).The fusion genes,GFP-PS1(recombinant plasmid pEGFP-C1-PS1)and PS1-GFP(recombinant plasmid pEGFP-N2-PS1)were constructed to study the subcellular localization of PS1 holoprotein.Recombinant plasmids were transiently transfected into two cell lines,HEK293 and CHO,respectively,using the green fluorescence from GFP(green fluorescence protein)as the PS1 localization signal.Then,we observed green fluorescence with a SPOT II(Olympus,BH2)and CONFOCAL microscope(Olympus,FV300)under 488 nm.The results show that PS1 located on the nuclear envelope.A few can be found on the cellular membrane and in the cytosol in a non-homogeneous distribution.
基金This work was supported by National Natural Science Foundation of China （No. 30370494 and 30470615）, National Basic Research 973 Program （No. 2006CB500700）.
文摘Background Two novel presenilin 1 （PS1） mutations, V97L and A136G, were recently found to be involved in the early-onset of Alzheimer＇s disease in two Chinese families. This research aimed to verity their pathological effects. Methods The human neuroblastoma SH-SY5Y cells stably transfected with these two Chinese presenilin 1 mutations were established to explore whether they are sensitive to, or influenced by, serum deprivation and protected by insulin-like growth factor-1 （IGF-1）. Apoptosis rate, glucose uptake of the cells and the expression of glucose transport protein 1 （GLUT1） on cell membranes were examined. Results The V97L or A136G mutants significantly decreased the cells viability and increased the apoptosis rate when compare to PSlwt and mock transfected cells. IGF-1 was found to improve the viability of these two kinds of mutant cells significantly, and to show a protective effect for the mutants when they were treated with trophic deprivation. The glucose uptake of each transfected cell line increased to about 25% after IGF-1 treatment, GLUT1 expression on the cell membrane increased modestly by about 15%-20%. Conclusions Enhanced sensitivity to trophic withdrawal in the cells transfected with the two Chinese PS1 mutations may contribute to the neuron apoptosis, IGF-1 provided a protective effect to cells, possibly through an enhanced glucose transport and mitochondrial activities.
文摘Objective To evaluate the association of apolipoprotein E (apoE) and presenilin 1 (PS 1) gene polymorphism with late onset Alzheimer's disease (AD) Methods A case control study was undertaken to detect the polymorphism of apoE and PS 1 by polymerase chain reaction and digestion with the endonucleases of BspL Ⅰ, Hha Ⅰ and BamH Ⅰ Results The frequencies of apoE ε3/4 genotype and ε4 allele in late onset AD (n=42) were significantly higher than those of age matched controls ( P <0 05) The frequencies of the apoE intron 1 enhancer (IE1) G/G genotype and G allele in late onset AD were also significantly higher than those in controls ( P <0 05) The frequencies of the PS 1 1/1 genotype but not the 1 allele in AD were significantly higher than those in controls ( P <0 05) The apoE ε4 allele was associated with a tripling of risk for late onset AD compared with that with no ε4 allele (odds ratio: 2 932) Homozygosity of the G allele in IE1 and 1/1 genotype in PS 1 was associated with a doubling of risk for late onset AD, and odds ratios were 2 223 and 2 066, respectively When the apoE ε4 was controlled, the association between the IE1 G/G genotype AD was no longer statistically significant ( P >0 05) We sequenced the exon 4 of apoE in patients with late onset AD, and found no other genetic polymorphism or mutation except for apoE ε4 and IE1 G alleles associated with AD Conclusion apoE ε4 gene appears to be the strongest gene risk factor for late onset AD and its apparent association between the IE1 G/G genotype and late onset AD is a consequence of the association between the ε4 and IE1 G/G genotype The PS 1/1 genotype is weakly associated with late onset AD
