The Experts below are selected from a list of 13056 Experts worldwide ranked by ideXlab platform
Jianping Jia - One of the best experts on this subject based on the ideXlab platform.
-
Two novel Presenilin-1 mutations (I249L and P433S) in early onset Chinese Alzheimer's pedigrees and their functional characterization
Biochemical and biophysical research communications, 2019Co-Authors: Luxi Shen, Longfei Jia, Wei Qin, Aihong Zhou, Yi Tang, Qi Wang, Jianping JiaAbstract:Abstract Clinical case study and functional characterization of the disease-associated Presenilin-1 (PSEN1) mutations may help reveal the roles of PSEN1 in the pathogenesis of Alzheimer's disease (AD). By mutation screening of PSEN1, Presenilin-2, and amyloid precursor protein genes in two Chinese Alzheimer's pedigrees, we identified two novel PSEN1 mutations, I249L and P433S. The two probands presented with progressive memory decline and subsequent psychiatric symptoms, with the age of onset at 54 and 34 years old, respectively. The effects of these two mutations on Presenilin-1 endoproteolysis and β-amyloid (Aβ) production were examined in SH-SY5Y neuroblastoma cells infected with lentiviruses expressing Presenilin-1 wild type (WT), I249L and P433S mutants. Both mutants showed increased Aβ42 levels and Aβ42/Aβ40 ratios. However, the I249L did not affect Presenilin-1 endoproteolysis or Aβ43 production, whereas the P433S mutant inhibited Presenilin-1 endoproteolysis and enhanced Aβ43 production. Our findings suggest that both I249L and P433S are pathogenic for early onset of AD by increasing Aβ42 production and Aβ42/Aβ40 ratios. Furthermore, P433S may contribute to the very early onset of AD by inhibiting PS1 endoproteolysis and enhancing the production of longer Aβ peptide Aβ43.
-
Val97Leu mutant Presenilin‐1 induces tau hyperphosphorylation and spatial memory deficit in mice and the underlying mechanisms
Journal of neurochemistry, 2012Co-Authors: Yue Wang, Zhe Cheng, Wei Qin, Jianping JiaAbstract:J. Neurochem. (2012) 121, 135–145. Abstract Although the pathological role of Presenilin-1 mutation in early onset familial Alzheimer’s disease has been widely studied, few focused on how the Presenilin-1 mutations result in memory impairment and tau hyperphosphorylation. In the present study, we expressed human Val97Leu mutant Presenilin-1, which is reported in Chinese pedigrees by our group, in transgenic mice and found that the mutant Presenilin-1 induced spatial memory deficit and tau hyperphosphorylation at PHF-1, pS199/202, pT231 and pS396 epitopes, but not at pS214 and pS422 epitopes. Pearson analysis showed that the memory deficit was only significantly correlated with tau phosphorylation level at PHF-1, pS199/202, pT231 and pS396 epitopes. Additionally, the hyperphosphorylated tau and tangle-like argentophilic structures were detected at CA3 and CA4, but not CA1, region of hippocampus, and we also found tangle-like structure and wizened degenerative neurons in frontal cortex. We demonstrated the tau hyperphosphorylation at the same epitopes in N2a cells expressing the mutant Presenilin-1, which is caused by inhibition of phosphoinositol-3 kinase/Akt and activation of glycogen synthase kinase-3 specifically. Our data demonstrated that human Val97Leu mutant Presenilin-1 causes spatial memory deficit in mice and increases tau phosphorylation level in glycogen synthase kinase-3-dependent manner.
-
Chinese Presenilin-1 V97L mutation enhanced Abeta42 levels in SH-SY5Y neuroblastoma cells.
Neuroscience letters, 2006Co-Authors: Boyan Fang, Longfei Jia, Jianping JiaAbstract:Presenilin-1 gene mutations have been proven to be associated with the majority of early-onset familial Alzheimer's disease (FAD). There have been, however, no systematic studies of Presenilin-1 gene mutation in FAD in China so far. We found a novel Val-->Leu missense mutation at codon 97 (Val97Leu) of the Presenilin-1 gene in a Chinese FAD pedigree. To verify whether this mutation is pathologically functional, we established mutation type and wild type Presenilin-1 gene stably transfected cell lines (human neuroblastoma SH-SY5Y cells) to detect beta-amyloid (Abeta) concentrations using ELISA and radioimmunity methods. We also examined levels of beta-amyloid precursor protein cleaving enzyme (BACE) and amyloid precursor protein (APP) to explore their impact upon beta-amyloid production. Our results showed that Abeta42 concentration was significantly enhanced at 48h when compared to that at 24h in the mutant type cells. At 48h Abeta42 levels in the V97L mutants was also found to be elevated significantly, both intracellularly and extracellularly when compared to wild and mock transfected cells. The total Abeta in either group did not alter, consistent with unchanged BACE and APP expression levels. Our data reveal that the Presenilin-1 V97L variant can elevate Abeta42 levels both intracellularly and extracellularly, and was a potentially pathogenic mutation for this Chinese FAD pedigree. It also suggests that there are common mechanisms in the pathogenesis of FAD between Chinese and other ethnic populations, although their gene mutation sites are different.
-
Chinese Presenilin-1 V97L mutation enhanced Aβ42 levels in SH-SY5Y neuroblastoma cells
Neuroscience Letters, 2006Co-Authors: Boyan Fang, Longfei Jia, Jianping JiaAbstract:Abstract Presenilin-1 gene mutations have been proven to be associated with the majority of early-onset familial Alzheimer's disease (FAD). There have been, however, no systematic studies of Presenilin-1 gene mutation in FAD in China so far. We found a novel Val → Leu missense mutation at codon 97 (Val97Leu) of the Presenilin-1 gene in a Chinese FAD pedigree. To verify whether this mutation is pathologically functional, we established mutation type and wild type Presenilin-1 gene stably transfected cell lines (human neuroblastoma SH-SY5Y cells) to detect β-amyloid (Aβ) concentrations using ELISA and radioimmunity methods. We also examined levels of β-amyloid precursor protein cleaving enzyme (BACE) and amyloid precursor protein (APP) to explore their impact upon β-amyloid production. Our results showed that Aβ42 concentration was significantly enhanced at 48 h when compared to that at 24 h in the mutant type cells. At 48 h Aβ42 levels in the V97L mutants was also found to be elevated significantly, both intracellularly and extracellularly when compared to wild and mock transfected cells. The total Aβ in either group did not alter, consistent with unchanged BACE and APP expression levels. Our data reveal that the Presenilin-1 V97L variant can elevate Aβ42 levels both intracellularly and extracellularly, and was a potentially pathogenic mutation for this Chinese FAD pedigree. It also suggests that there are common mechanisms in the pathogenesis of FAD between Chinese and other ethnic populations, although their gene mutation sites are different.
Dennis J. Selkoe - One of the best experts on this subject based on the ideXlab platform.
-
Presenilin-1 exists in both pre- and post-Golgi compartments and recycles via COPI-coated membranes
Traffic (Copenhagen Denmark), 2003Co-Authors: Marloes Réchards, Dennis J. Selkoe, Weiming Xia, Viola Oorschot, Judith KlumpermanAbstract:Presenilin-1 is involved in intramembrane proteolysis of various proteins, but its intracellular site of action has remained elusive. Here, we determined by quantitative immunogold-electron microscopy that Presenilin-1 in Chinese hamster ovary cells is present in pre-Golgi compartments as well as at the plasma membrane and endosomes. Notably, a high percentage of Presenilin-1 resides in COPI-coated membranes between the endoplasmic reticulum and the Golgi complex, indicating significant recycling to the endoplasmic reticulum. By contrast, the inactive aspartate mutant Presenilin-1(D257A) is relatively excluded from COPI-coated membranes, concomitant with increased post-Golgi levels. These data provide critical evidence for the scenario that the complex containing Presenilin-1 can serve as gamma-secretase at the plasma membrane or endosomes and suggest a role for COPI-mediated retrograde transport in regulating post-Golgi levels of Presenilin-1.
-
two transmembrane aspartates in Presenilin 1 required for Presenilin endoproteolysis and gamma secretase activity
Nature, 1999Co-Authors: Beth L Ostaszewski, Michael S Wolfe, Thekla S Diehl, Taylor W Kimberly, Dennis J. SelkoeAbstract:Accumulation of the amyloid-β protein (Aβ) in the cerebral cortex is an early and invariant event in the pathogenesis of Alzheimer's disease. The final step in the generation of Aβ from the β-amyloid precursor protein is an apparently intramembranous proteolysis by the elusive γ-secretase(s)1. The most common cause of familial Alzheimer's disease is mutation of the genes encoding Presenilins 1 and 2, which alters γ-secretase activity to increase the production of the highly amyloidogenic Aβ42 isoform2. Moreover, deletion of Presenilin-1 in mice greatly reduces γ-secretase activity3, indicating that Presenilin-1 mediates most of this proteolytic event. Here we report that mutation of either of two conserved transmembrane (TM) aspartate residues in Presenilin-1, Asp 257 (in TM6) and Asp 385 (in TM7), substantially reduces Aβ production and increases the amounts of the carboxy-terminal fragments of β-amyloid precursor protein that are the substrates of γ-secretase. We observed these effects in three different cell lines as well as in cell-free microsomes. Either of the Asp → Ala mutations also prevented the normal endoproteolysis of Presenilin-1 in the TM6 → TM7 cytoplasmic loop. In a functional Presenilin-1 variant (carrying a deletion in exon 9) that is associated with familial Alzheimer's disease and which does not require this cleavage4, the Asp 385 → Ala mutation still inhibited γ-secretase activity. Our results indicate that the two transmembrane aspartate residues are critical for both Presenilin-1 endoproteolysis and γ-secretase activity, and suggest that Presenilin 1 is either a unique diaspartyl cofactor for γ-secretase or is itself γ-secretase, an autoactivated intramembranous aspartyl protease.
-
Two transmembrane aspartates in Presenilin-1 required for Presenilin endoproteolysis and gamma-secretase activity.
Nature, 1999Co-Authors: Michael S Wolfe, Weiming Xia, Beth L Ostaszewski, Thekla S Diehl, W. Taylor Kimberly, Dennis J. SelkoeAbstract:Accumulation of the amyloid-beta protein (Abeta) in the cerebral cortex is an early and invariant event in the pathogenesis of Alzheimer's disease. The final step in the generation of Abeta from the beta-amyloid precursor protein is an apparently intramembranous proteolysis by the elusive gamma-secretase(s). The most common cause of familial Alzheimer's disease is mutation of the genes encoding Presenilins 1 and 2, which alters gamma-secretase activity to increase the production of the highly amyloidogenic Abeta42 isoform. Moreover, deletion of Presenilin-1 in mice greatly reduces gamma-secretase activity, indicating that Presenilin-1 mediates most of this proteolytic event. Here we report that mutation of either of two conserved transmembrane (TM) aspartate residues in Presenilin-1, Asp 257 (in TM6) and Asp 385 (in TM7), substantially reduces Abeta production and increases the amounts of the carboxy-terminal fragments of beta-amyloid precursor protein that are the substrates of gamma-secretase. We observed these effects in three different cell lines as well as in cell-free microsomes. Either of the Asp --> Ala mutations also prevented the normal endoproteolysis of Presenilin-1 in the TM6 --> TM7 cytoplasmic loop. In a functional Presenilin-1 variant (carrying a deletion in exon 9) that is associated with familial Alzheimer's disease and which does not require this cleavage, the Asp 385 --> Ala mutation still inhibited gamma-secretase activity. Our results indicate that the two transmembrane aspartate residues are critical for both Presenilin-1 endoproteolysis and gamma-secretase activity, and suggest that Presenilin 1 is either a unique diaspartyl cofactor for gamma-secretase or is itself gamma-secretase, an autoactivated intramembranous aspartyl protease.
-
Protein Topology of Presenilin 1
Neuron, 1996Co-Authors: Andrew Doan, Gopal Thinakaran, David R. Borchelt, Hilda H. Slunt, Tamara Ratovitsky, Marcia B. Podlisny, Dennis J. Selkoe, Mary Seeger, Sam Gandy, Donald L. PriceAbstract:Abstract Mutations in a gene encoding a multitransmembrane protein, termed Presenilin 1 (PS1), are causative in the majority of early-onset cases of AD. To determine the topology of PS1, we utilized two strategies: first, we tested whether putative transmembranes are sufficient to export a protease-sensitive substrate across a lipid bilayer; and second, we examined the binding of antibodies to specific PS1 epitopes in cultured cells selectively permeabilized with the pore-forming toxin, streptolysin-O. We document that the "loop," N-terminal, and C-terminal domains of PS1 are oriented toward the cytoplasm.
Magdolna Pákáski - One of the best experts on this subject based on the ideXlab platform.
-
Presenilin-1 and the amyloid precursor protein are transported bidirectionally in the sciatic nerve of adult rat
Neurochemistry international, 2002Co-Authors: Henrietta Papp, Magdolna Pákáski, Peter KasaAbstract:Abstract The amyloid precursor protein (APP) and Presenilin-1 (PS-1) are not only of importance for the normal functioning of the various neurons, but also play central roles in the pathogenesis of Alzheimer’s disease (AD). Through the use of immunohistochemical and Western blot techniques, the bidirectional axonal transport of these proteins has been demonstrated in the sciatic nerve of adult rat. Double-ligation of the sciatic nerve for 6, 12 or 24 h was observed to cause a progressive accumulation of the 45 kDa Presenilin-1 holoprotein and APPs with molecular masses of 116 and 94 kDa on both sites of the ligature. It is concluded that the functions of Presenilin-1 and APPs are not restricted to the neuronal perikarya: they may carry information in both directions, from the cell body to the axon terminals and vice versa.
-
Presenilin-1 and its N-terminal and C-terminal fragments are transported in the sciatic nerve of rat.
Brain Research, 2001Co-Authors: Peter Kasa, Henrietta Papp, Magdolna PákáskiAbstract:The axonal transport of Presenilin-1 was investigated in a spinal cord-sciatic nerve-neuromuscular junction model system in the rat. The technique of unilateral sciatic nerve ligation, using double ligatures, was combined with immunohistochemical staining and Western blotting to examine the axonal transport of the protein. Immunohistochemical studies involving the use of polyclonal antibodies for either the N-terminal or the C-terminal domain of Presenilin-1 furnished evidence that both fragments may be present not only in the neuronal cell bodies, but also in the motoric and sensory axons and the motoric axon terminals at the neuromuscular junctions. After double ligation of the sciatic nerve for 6, 12 or 24 h, progressive immunostaining of Presenilin-1 occurred above the upper ligature and to a lesser extent below the lower ligature. Double staining of the sciatic nerve for Presenilin-1 and for amyloid precursor protein revealed overlapping immunoreactivity. Western blotting confirmed the accumulation of the approximately 20-kDa C-terminal and approximately 25-kDa N-terminal fragments and the full-length 45-kDa holoprotein of Presenilin-1 both above and below the ligature. It is concluded that besides the larger amounts of C-terminal and N-terminal fragments, a smaller quantity of intact Presenilin-1 may be present and conveyed bidirectionally in the sciatic nerve of the rat. These results lend further support to the suggestion that Presenilin-1 may leave the trans-Golgi network and be found in the axons and axon terminals of the various neurons.
Peter Kasa - One of the best experts on this subject based on the ideXlab platform.
-
Presenilin-1 and the amyloid precursor protein are transported bidirectionally in the sciatic nerve of adult rat
Neurochemistry international, 2002Co-Authors: Henrietta Papp, Magdolna Pákáski, Peter KasaAbstract:Abstract The amyloid precursor protein (APP) and Presenilin-1 (PS-1) are not only of importance for the normal functioning of the various neurons, but also play central roles in the pathogenesis of Alzheimer’s disease (AD). Through the use of immunohistochemical and Western blot techniques, the bidirectional axonal transport of these proteins has been demonstrated in the sciatic nerve of adult rat. Double-ligation of the sciatic nerve for 6, 12 or 24 h was observed to cause a progressive accumulation of the 45 kDa Presenilin-1 holoprotein and APPs with molecular masses of 116 and 94 kDa on both sites of the ligature. It is concluded that the functions of Presenilin-1 and APPs are not restricted to the neuronal perikarya: they may carry information in both directions, from the cell body to the axon terminals and vice versa.
-
Presenilin-1 and its N-terminal and C-terminal fragments are transported in the sciatic nerve of rat.
Brain Research, 2001Co-Authors: Peter Kasa, Henrietta Papp, Magdolna PákáskiAbstract:The axonal transport of Presenilin-1 was investigated in a spinal cord-sciatic nerve-neuromuscular junction model system in the rat. The technique of unilateral sciatic nerve ligation, using double ligatures, was combined with immunohistochemical staining and Western blotting to examine the axonal transport of the protein. Immunohistochemical studies involving the use of polyclonal antibodies for either the N-terminal or the C-terminal domain of Presenilin-1 furnished evidence that both fragments may be present not only in the neuronal cell bodies, but also in the motoric and sensory axons and the motoric axon terminals at the neuromuscular junctions. After double ligation of the sciatic nerve for 6, 12 or 24 h, progressive immunostaining of Presenilin-1 occurred above the upper ligature and to a lesser extent below the lower ligature. Double staining of the sciatic nerve for Presenilin-1 and for amyloid precursor protein revealed overlapping immunoreactivity. Western blotting confirmed the accumulation of the approximately 20-kDa C-terminal and approximately 25-kDa N-terminal fragments and the full-length 45-kDa holoprotein of Presenilin-1 both above and below the ligature. It is concluded that besides the larger amounts of C-terminal and N-terminal fragments, a smaller quantity of intact Presenilin-1 may be present and conveyed bidirectionally in the sciatic nerve of the rat. These results lend further support to the suggestion that Presenilin-1 may leave the trans-Golgi network and be found in the axons and axon terminals of the various neurons.
Michael S Wolfe - One of the best experts on this subject based on the ideXlab platform.
-
two transmembrane aspartates in Presenilin 1 required for Presenilin endoproteolysis and gamma secretase activity
Nature, 1999Co-Authors: Beth L Ostaszewski, Michael S Wolfe, Thekla S Diehl, Taylor W Kimberly, Dennis J. SelkoeAbstract:Accumulation of the amyloid-β protein (Aβ) in the cerebral cortex is an early and invariant event in the pathogenesis of Alzheimer's disease. The final step in the generation of Aβ from the β-amyloid precursor protein is an apparently intramembranous proteolysis by the elusive γ-secretase(s)1. The most common cause of familial Alzheimer's disease is mutation of the genes encoding Presenilins 1 and 2, which alters γ-secretase activity to increase the production of the highly amyloidogenic Aβ42 isoform2. Moreover, deletion of Presenilin-1 in mice greatly reduces γ-secretase activity3, indicating that Presenilin-1 mediates most of this proteolytic event. Here we report that mutation of either of two conserved transmembrane (TM) aspartate residues in Presenilin-1, Asp 257 (in TM6) and Asp 385 (in TM7), substantially reduces Aβ production and increases the amounts of the carboxy-terminal fragments of β-amyloid precursor protein that are the substrates of γ-secretase. We observed these effects in three different cell lines as well as in cell-free microsomes. Either of the Asp → Ala mutations also prevented the normal endoproteolysis of Presenilin-1 in the TM6 → TM7 cytoplasmic loop. In a functional Presenilin-1 variant (carrying a deletion in exon 9) that is associated with familial Alzheimer's disease and which does not require this cleavage4, the Asp 385 → Ala mutation still inhibited γ-secretase activity. Our results indicate that the two transmembrane aspartate residues are critical for both Presenilin-1 endoproteolysis and γ-secretase activity, and suggest that Presenilin 1 is either a unique diaspartyl cofactor for γ-secretase or is itself γ-secretase, an autoactivated intramembranous aspartyl protease.
-
Two transmembrane aspartates in Presenilin-1 required for Presenilin endoproteolysis and gamma-secretase activity.
Nature, 1999Co-Authors: Michael S Wolfe, Weiming Xia, Beth L Ostaszewski, Thekla S Diehl, W. Taylor Kimberly, Dennis J. SelkoeAbstract:Accumulation of the amyloid-beta protein (Abeta) in the cerebral cortex is an early and invariant event in the pathogenesis of Alzheimer's disease. The final step in the generation of Abeta from the beta-amyloid precursor protein is an apparently intramembranous proteolysis by the elusive gamma-secretase(s). The most common cause of familial Alzheimer's disease is mutation of the genes encoding Presenilins 1 and 2, which alters gamma-secretase activity to increase the production of the highly amyloidogenic Abeta42 isoform. Moreover, deletion of Presenilin-1 in mice greatly reduces gamma-secretase activity, indicating that Presenilin-1 mediates most of this proteolytic event. Here we report that mutation of either of two conserved transmembrane (TM) aspartate residues in Presenilin-1, Asp 257 (in TM6) and Asp 385 (in TM7), substantially reduces Abeta production and increases the amounts of the carboxy-terminal fragments of beta-amyloid precursor protein that are the substrates of gamma-secretase. We observed these effects in three different cell lines as well as in cell-free microsomes. Either of the Asp --> Ala mutations also prevented the normal endoproteolysis of Presenilin-1 in the TM6 --> TM7 cytoplasmic loop. In a functional Presenilin-1 variant (carrying a deletion in exon 9) that is associated with familial Alzheimer's disease and which does not require this cleavage, the Asp 385 --> Ala mutation still inhibited gamma-secretase activity. Our results indicate that the two transmembrane aspartate residues are critical for both Presenilin-1 endoproteolysis and gamma-secretase activity, and suggest that Presenilin 1 is either a unique diaspartyl cofactor for gamma-secretase or is itself gamma-secretase, an autoactivated intramembranous aspartyl protease.