Presenilin 1 and presenilin 2 are widely expressed during brain development. Several mutations in these proteins have been associated with autosomal-dominant inherited forms of Alzheimer disease. Their expression is r...Presenilin 1 and presenilin 2 are widely expressed during brain development. Several mutations in these proteins have been associated with autosomal-dominant inherited forms of Alzheimer disease. Their expression is regulated by various cellular and extracellular factors, which change with age and sex. Both age and sex are key risk factors for Alzheimer’s disease, but the issue of whether the expression of presenilins is influenced by the sex during early postnatal development of the brain has been poorly investigated so far. In this study, we report that transcript levels of presenilins, and the subset of neurons expressing these proteins in various brain areas of the developing post-natal brain are different in male and female rats, suggesting that their function(s) may contribute to sexual dimorphism in the brain, both at morphological and functional levels.展开更多
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
Evidence from genetics and from analyzing cellular and animal models have converged to suggest links between neurodegenerative disorders of early and late life.Here,we summarize emerging links between the most common ...Evidence from genetics and from analyzing cellular and animal models have converged to suggest links between neurodegenerative disorders of early and late life.Here,we summarize emerging links between the most common late life neurodegenerative disease,Alzheimer’s disease,and the most common early life neurodegenerative diseases,neuronal ceroid lipofuscinoses.Genetic studies reported an overlap of clinically diagnosed Alzheimer’s disease and mutations in genes known to cause neuronal ceroid lipofuscinoses.Accumulating data strongly suggest dysfunction of intracellular trafficking mechanisms and the autophagy-endolysosome system in both types of neurodegenerative disorders.This suggests shared cytopathological processes underlying these different types of neurodegenerative diseases.A better understanding of the common mechanisms underlying the different diseases is important as this might lead to the identification of novel targets for therapeutic concepts,the transfer of therapeutic strategies from one disease to the other and therapeutic approaches tailored to patients with specific mutations.Here,we review dysfunctions of the endolysosomal autophagy pathway in Alzheimer’s disease and neuronal ceroid lipofuscinoses and summarize emerging etiologic and genetic overlaps.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
The mutation in the amyloid-beta precursor protein(APP)and presenilin genes(PSEN1 and PSEN2)cause autosomal dominant Alzheimer’s diease(ADAD)which is typically associated with early-onset familial Alzheimer’s diseas...The mutation in the amyloid-beta precursor protein(APP)and presenilin genes(PSEN1 and PSEN2)cause autosomal dominant Alzheimer’s diease(ADAD)which is typically associated with early-onset familial Alzheimer’s disease(FAD),however,the mechanism by which presenilin mutations cause memory disorders and neurodegeneration remains poorly understood.In the present study,using Presenilin-1 and Presenilin-2 double knockout mice(cDKO mice),we observed that the impaired spatial reference memory,spatial working memory and contextual fear memory in cDKO mice.Consistently,deficits of basal synaptic transmission and LTP formation,as well as down-regulation of PI3K/Akt signaling pathway at hippocampus in cDKO mice.Furthermore,we found the expression levels ofα7-nicotinic ACh receptors(α7nAChRs),NMDAR and AMPAR composition subunits,which related to synaptic plasticity and memory,were decreased at hippocampus in cDKO mice.Importantly,all above deficits could be reversed byα7nAChR agonist PHA-543613.Taken together,our results indicate that knockout of PS1 and PS2 can disrupt the function ofα7nAChR,thereby down-regulate activation of PI3K/Akt signaling pathway,reduce the synaptic expression levels of NMDAR and AMPAR composition subunits at hippocampus,consequently cause neuronal apoptosis,disrupt basal synaptic transmission and LTP formation at hippocampus,fi nally impair hippocampal-dependent memory.展开更多
文摘Presenilin 1 and presenilin 2 are widely expressed during brain development. Several mutations in these proteins have been associated with autosomal-dominant inherited forms of Alzheimer disease. Their expression is regulated by various cellular and extracellular factors, which change with age and sex. Both age and sex are key risk factors for Alzheimer’s disease, but the issue of whether the expression of presenilins is influenced by the sex during early postnatal development of the brain has been poorly investigated so far. In this study, we report that transcript levels of presenilins, and the subset of neurons expressing these proteins in various brain areas of the developing post-natal brain are different in male and female rats, suggesting that their function(s) may contribute to sexual dimorphism in the brain, both at morphological and functional levels.
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supported by the Deutsche Forschungsgemeinschaft(DFG,425373668,HE 3220/4-1)(to GH).
文摘Evidence from genetics and from analyzing cellular and animal models have converged to suggest links between neurodegenerative disorders of early and late life.Here,we summarize emerging links between the most common late life neurodegenerative disease,Alzheimer’s disease,and the most common early life neurodegenerative diseases,neuronal ceroid lipofuscinoses.Genetic studies reported an overlap of clinically diagnosed Alzheimer’s disease and mutations in genes known to cause neuronal ceroid lipofuscinoses.Accumulating data strongly suggest dysfunction of intracellular trafficking mechanisms and the autophagy-endolysosome system in both types of neurodegenerative disorders.This suggests shared cytopathological processes underlying these different types of neurodegenerative diseases.A better understanding of the common mechanisms underlying the different diseases is important as this might lead to the identification of novel targets for therapeutic concepts,the transfer of therapeutic strategies from one disease to the other and therapeutic approaches tailored to patients with specific mutations.Here,we review dysfunctions of the endolysosomal autophagy pathway in Alzheimer’s disease and neuronal ceroid lipofuscinoses and summarize emerging etiologic and genetic overlaps.
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The mutation in the amyloid-beta precursor protein(APP)and presenilin genes(PSEN1 and PSEN2)cause autosomal dominant Alzheimer’s diease(ADAD)which is typically associated with early-onset familial Alzheimer’s disease(FAD),however,the mechanism by which presenilin mutations cause memory disorders and neurodegeneration remains poorly understood.In the present study,using Presenilin-1 and Presenilin-2 double knockout mice(cDKO mice),we observed that the impaired spatial reference memory,spatial working memory and contextual fear memory in cDKO mice.Consistently,deficits of basal synaptic transmission and LTP formation,as well as down-regulation of PI3K/Akt signaling pathway at hippocampus in cDKO mice.Furthermore,we found the expression levels ofα7-nicotinic ACh receptors(α7nAChRs),NMDAR and AMPAR composition subunits,which related to synaptic plasticity and memory,were decreased at hippocampus in cDKO mice.Importantly,all above deficits could be reversed byα7nAChR agonist PHA-543613.Taken together,our results indicate that knockout of PS1 and PS2 can disrupt the function ofα7nAChR,thereby down-regulate activation of PI3K/Akt signaling pathway,reduce the synaptic expression levels of NMDAR and AMPAR composition subunits at hippocampus,consequently cause neuronal apoptosis,disrupt basal synaptic transmission and LTP formation at hippocampus,fi nally impair hippocampal-dependent memory.
