scholarly journals Apoptotic Activities of Wild-Type and Alzheimer's Disease-Related Mutant Presenilins in Drosophila melanogaster

1999 ◽  
Vol 146 (6) ◽  
pp. 1351-1364 ◽  
Author(s):  
Yihong Ye ◽  
Mark E. Fortini
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Drosophila Melanogaster ◽  
Genetic Model ◽  
Cell Types ◽  
Notch Receptor ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
Loss Of Function ◽  
Wild Type

Mutant human presenilins cause early-onset familial Alzheimer's disease and render cells susceptible to apoptosis in cultured cell models. We show that loss of presenilin function in Drosophila melanogaster increases levels of apoptosis in developing tissues. Moreover, overexpression of presenilin causes apoptotic and neurogenic phenotypes resembling those of Presenilin loss-of-function mutants, suggesting that presenilin exerts a dominant negative effect when expressed at high levels. In Drosophila S2 cells, Psn overexpression leads to reduced Notch receptor synthesis affecting levels of the intact ∼300-kD precursor and its ∼120-kD processed COOH-terminal derivatives. Presenilin-induced apoptosis is cell autonomous and can be blocked by constitutive Notch activation, suggesting that the increased cell death is due to a developmental mechanism that eliminates improperly specified cell types. We describe a genetic model in which the apoptotic activities of wild-type and mutant presenilins can be assessed, and we find that Alzheimer's disease-linked mutant presenilins are less effective at inducing apoptosis than wild-type presenilin.

scholarly journals Dominant negative effect of the loss-of-function γ-secretase mutants on the wild-type enzyme through heterooligomerization

2017 ◽  
Vol 114 (48) ◽  
pp. 12731-12736 ◽  
Author(s):  
Rui Zhou ◽  
Guanghui Yang ◽  
Yigong Shi
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protease Activity ◽  
Underlying Mechanism ◽  
Dominant Negative ◽  
Presenilin 1 ◽  
Dominant Negative Effect ◽  
Loss Of Function ◽  
Negative Effect

γ-secretase is an intramembrane protease complex consisting of nicastrin, presenilin-1/2, APH-1a/b, and Pen-2. Hydrolysis of the 99-residue transmembrane fragment of amyloid precursor protein (APP-C99) by γ-secretase produces β-amyloid (Aβ) peptides. Pathogenic mutations in PSEN1 and PSEN2, which encode the catalytic subunit presenilin-1/2 of γ-secretase, lead to familial Alzheimer’s disease in an autosomal dominant manner. However, the underlying mechanism of how the mutant PSEN gene may affect the function of the WT allele remains to be elucidated. Here we report that each of the loss-of-function γ-secretase variants that carries a PSEN1 mutation suppresses the protease activity of the WT γ-secretase on Aβ production. Each of these γ-secretase variants forms a stable oligomer with the WT γ-secretase in vitro in the presence of the detergent CHAPSO {3-[(3-cholamidopropyl)dimethylammonio]-2-hydroxy-1-propanesulfonate}, but not digitonin. Importantly, robust protease activity of γ-secretase is detectable in the presence of CHAPSO, but not digitonin. These experimental observations suggest a dominant negative effect of the γ-secretase, in which the protease activity of WT γ-secretase is suppressed by the loss-of-function γ-secretase variants through hetero-oligomerization. The relevance of this finding to the genesis of Alzheimer’s disease is critically evaluated.

scholarly journals Adrenergic mechanisms of myocardium contractility regulation in genetic model of Alzheimer’s disease

2015 ◽  
Vol 96 (1) ◽  
pp. 50-55 ◽  
Author(s):  
A V Leushina ◽  
L F Nurullin ◽  
E O Petukhova ◽  
A L Zefirov ◽  
M A Mukhamedyarov
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transgenic Mice ◽  
Adrenergic Receptors ◽  
Myocardial Contractility ◽  
Genetic Model ◽  
Immunofluorescent Staining ◽  
Wild Type ◽  
Adrenergic Mechanisms ◽  
Model Of Alzheimer’S Disease

Aim. Study is aimed to investigate contractility impairments and receptor mechanisms of adrenergic regulation of myocardium inotropic function in Alzheimer’s disease model on transgenic mice.Methods. Experiments were performed on isolated preparations of atria and ventricles myocardium of mice. Transgenic mice of B6C3-Tg(APP695)85Dbo Tg(PSENI)85Dbo genotype were used as animal model of Alzheimer’s disease. Contractile responses of myocardium were registered by conventional myographic technique in isometric conditions. To evaluate the expression of adrenergic receptors, immunofluorescence staining of myocardium with specific antibodies was performed.Results. Transgenic mice showed not only a decreased effect of norepinephrine on myocardium inotropic function but also the inversion of the effect of norepinephrine - the use of 10-5-10-4 M of norepinephrine decreased myocardium inotropic function. Immunofluorescent staining showed decrease of expression of β1- and especially β2-adrenergic receptors ventricular myocardium of transgenic mice comparing to wild type mice. Adrenergic deregulation was registered in ventricles, but not in atria. The features of adrenergic regulatory mechanisms of myocardial contractility in transgenic APP/PS1 mice aged 8-10 months are specific, although somewhat similar to wild type mice aged 8-10 months, and are evidently due to Alzheimer’s disease. The inversion of norepinephrine inotropic effect (from positive to negative) may be explained by switching the intracellular cascade pathway of β2-adrenergic receptors effects to another type of G-protein.Conclusion. The results indicate that peripheral adrenergic mechanisms of myocardial contractility regulation are impaired in studied transgenic mice model of Alzheimer’s disease. Obtained data widen our understanding of Alzheimer’s disease pathogenesis, as well as our conception of relations between cardiovascular diseases and neurodegeneration.

scholarly journals Alzheimer's disease BIN1 coding variants increase intracellular Aβ by interfering with BACE1 recycling

2021 ◽  
Author(s):  
Catarina Perdigão ◽  
Mariana A Barata ◽  
Tatiana Burrinha ◽  
Claudia Guimas Almeida
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Beta Amyloid ◽  
Early Endosome ◽  
Dominant Negative Effect ◽  
Causal Mechanism ◽  
Wild Type ◽  
Endocytic Recycling ◽  
Early Endosomes ◽  
Coding Variants

Genetics identified BIN1 as the second most important risk locus associated with late-onset Alzheimer's disease after APOE4. Here we show the consequences of two coding variants in BIN1 (rs754834233 and rs138047593), both in terms of intracellular beta-amyloid accumulation (iAbeta) and early endosome enlargement, two interrelated early cytopathological Alzheimer's disease phenotypes, supporting their association with LOAD risk. We previously found that Bin1 deficiency potentiates beta-amyloid production by decreasing BACE1 recycling and enlarging early endosomes. Here, we demonstrate that the expression of the two LOAD mutant forms of Bin1 did not rescue the iAbeta accumulation and early endosome enlargement induced by Bin1 knockdown and recovered by wild-type Bin1. The LOAD coding variants reduced Bin1 interaction with BACE1 likely causing a dominant-negative effect since Bin1 mutants, but not wild-type Bin1, overexpression increased iAbeta42 due to defective BACE1 recycling and accumulation in early endosomes. Endocytic recycling of transferrin was similarly affected by Bin1 wild-type and mutants, indicating that Bin1 is a general regulator of endocytic recycling. These data show that the LOAD mutations in Bin1 lead to a loss of function, suggesting that endocytic recycling defects are an early causal mechanism of Alzheimer's disease.

Decreased cerebral Irp-1B limits impact of social isolation in wild type and Alzheimer's disease modeled in Drosophila melanogaster

2018 ◽  
Vol 17 (5) ◽  
pp. e12451 ◽  
Author(s):  
C. Ruland ◽  
J. Berlandi ◽  
K. Eikmeier ◽  
T. Weinert ◽  
F. J. Lin ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Drosophila Melanogaster ◽  
Social Isolation ◽  
Wild Type

scholarly journals Brain transcriptome analysis reveals subtle effects on mitochondrial function and iron homeostasis of mutations in the SORL1 gene implicated in early onset familial Alzheimer’s disease

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Karissa Barthelson ◽  
Stephen Martin Pederson ◽  
Morgan Newman ◽  
Michael Lardelli
Keyword(s):  
Gene Expression ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Onset ◽  
Iron Homeostasis ◽  
Enrichment Analysis ◽  
Loss Of Function ◽  
Wild Type ◽  
Expression Of Genes ◽  
Insight Into

Abstract To prevent or delay the onset of Alzheimer’s disease (AD), we must understand its molecular basis. The great majority of AD cases arise sporadically with a late onset after 65 years of age (LOAD). However, rare familial cases of AD can occur due to dominant mutations in a small number of genes that cause an early onset prior to 65 years of age (EOfAD). As EOfAD and LOAD share similar pathologies and disease progression, analysis of EOfAD genetic models may give insight into both subtypes of AD. Sortilin-related receptor 1 (SORL1) is genetically associated with both EOfAD and LOAD and provides a unique opportunity to investigate the relationships between both forms of AD. Currently, the role of SORL1 mutations in AD pathogenesis is unclear. To understand the molecular consequences of SORL1 mutation, we performed targeted mutagenesis of the orthologous gene in zebrafish. We generated an EOfAD-like mutation, V1482Afs, and a putatively null mutation, to investigate whether EOfAD-like mutations in sorl1 display haploinsufficiency by acting through loss-of-function mechanisms. We performed mRNA-sequencing on whole brains, comparing wild type fish with their siblings heterozygous for EOfAD-like or putatively loss-of-function mutations in sorl1, or transheterozygous for these mutations. Differential gene expression analysis identified a small number of differentially expressed genes due to the sorl1 genotypes. We also performed enrichment analysis on all detectable genes to obtain a more complete view on changes to gene expression by performing three methods of gene set enrichment analysis, then calculated an overall significance value using the harmonic mean p-value. This identified subtle effects on expression of genes involved in energy production, mRNA translation and mTORC1 signalling in both the EOfAD-like and null mutant brains, implying that these effects are due to sorl1 haploinsufficiency. Surprisingly, we also observed changes to expression of genes occurring only in the EOfAD-mutation carrier brains, suggesting gain-of-function effects. Transheterozygosity for the EOfAD-like and null mutations (i.e. lacking wild type sorl1), caused apparent effects on iron homeostasis and other transcriptome changes distinct from the single-mutation heterozygous fish. Our results provide insight into the possible early brain molecular effects of an EOfAD mutation in human SORL1. Differential effects of heterozygosity and complete loss of normal SORL1 expression are revealed.

scholarly journals Homozygote loss-of-function variants in the human COCH gene underlie hearing loss

2020 ◽  
Author(s):  
Nada Danial-Farran ◽  
Elena Chervinsky ◽  
Prathamesh Thangaraj Nadar-Ponniah ◽  
Eran Cohen Barak ◽  
Shahar Taiber ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Autosomal Dominant ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
Loss Of Function ◽  
Wild Type ◽  
Cos7 Cell ◽  
Gene Encoding ◽  
Negative Effect ◽  
Syndromic Hearing Loss

AbstractSince 1999, the COCH gene encoding cochlin, has been linked to the autosomal dominant non-syndromic hearing loss, DFNA9, with or without vestibular abnormalities. The hearing impairment associated with the variants affecting gene function has been attributed to a dominant-negative effect. Mutant cochlin was seen to accumulate intracellularly, with the formation of aggregates both inside and outside the cells, in contrast to the wild-type cochlin that is normally secreted. While an additional recessive variant in the COCH gene (DFNB110) has recently been reported, the mechanism of the loss-of-function (LOF) effect of the COCH gene product remains unknown. In this study, we used COS7 cell lines to investigate the consequences of a novel homozygous frameshift variant on RNA transcription, and on cochlin translation. Our results indicate a LOF effect of the variant and a major decrease in cochlin translation. This data has a dramatic impact on the accuracy of genetic counseling for both heterozygote and homozygote carriers of LOF variants in COCH.

scholarly journals Brain transcriptome analysis reveals subtle effects on mitochondrial function and iron homeostasis of mutations in the SORL1 gene implicated in early onset familial Alzheimer’s disease

2020 ◽  
Author(s):  
Karissa Barthelson ◽  
Stephen Martin Pederson ◽  
Morgan Newman ◽  
Michael Lardelli
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Onset ◽  
Iron Homeostasis ◽  
Mrna Translation ◽  
Complete Loss ◽  
Loss Of Function ◽  
Wild Type ◽  
Expression Of Genes ◽  
Insight Into

AbstractBackgroundTo prevent or delay the onset of Alzheimer’s disease (AD), we must understand its molecular basis. The great majority of AD cases arise sporadically with a late onset after 65 years of age (LOAD). However, rare familial cases of AD can occur due to dominant mutations in a small number of genes that cause an early onset prior to 65 years of age (EOfAD). As EOfAD and LOAD share similar pathologies and disease progression, analysis of EOfAD genetic models may give insight into both subtypes of AD. Sortilin-related receptor 1 (SORL1) is genetically associated with both EOfAD and LOAD and provides a unique opportunity to investigate the relationships between both forms of AD. Currently, the role of SORL1 mutations in AD pathogenesis is unclear.MethodsTo understand the molecular consequences of SORL1 mutation, we performed targeted mutagenesis of the orthologous gene in zebrafish. We generated an EOfAD-like mutation, V1482Afs, and a putatively null mutation, to investigate whether EOfAD-like mutations in sorl1 display haploinsufficiency by acting through loss-of-function mechanisms. We performed mRNA-sequencing on whole brains comparing normal (wild type) fish with their siblings heterozygous for EOfAD-like or complete loss-of-function mutations in sorl1 or transheterozygous for these mutations. Differential gene expression and gene set enrichment analyses identified, respectively, changes in young adult zebrafish brain transcriptomes, and putative effects on neural subcellular functions.ResultsWe identified subtle effects on expression of genes involved in energy production, mRNA translation and mTORC1 signalling in both the EOfAD-like and null mutant brains, implying that these effects are due to sorl1 haploinsufficiency. Surprisingly, we also observed changes to expression of genes occurring only in the EOfAD-mutation carrier brains, suggesting gain-of-function effects. Transheterozygosity for the EOfAD-like and null mutations (i.e. lacking wild type sorl1), caused apparent effects on iron homeostasis and other transcriptome changes distinct from the single-mutation heterozygous fish.ConclusionsOur results provide insight into the possible early brain molecular effects of an EOfAD mutation in human SORL1. Differential effects of heterozygosity and complete loss of normal SORL1 expression are revealed.

Effect Of Nhexane Extract Of Caryota No Seed On Markers Of Neurodegeneration And Fecundity In Drosophila Melanogaster

2020 ◽  
Vol 6 (5) ◽  
pp. 1-7
Author(s):  
Chinonye A Maduagwuna ◽  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Drosophila Melanogaster ◽  
Neurodegenerative Diseases ◽  
Cognitive Functions ◽  
The Elderly ◽  
Common Cause ◽  
Chronic Neuroinflammation

Study background: Chronic neuroinflammation is a common emerging hallmark of several neurodegenerative diseases. Alzheimer’s Disease (AD) is the most common cause of dementia among the elderly and is characterized by loss of memory and other cognitive functions.

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