claudio russo - Academia.edu (original) (raw)
Papers by claudio russo
Journal of Biological Chemistry, 2007
The amyloid precursor protein (APP) and the presenilins 1 and 2 are genetically linked to the dev... more The amyloid precursor protein (APP) and the presenilins 1 and 2 are genetically linked to the development of familial Alzheimer disease. APP is a single-pass transmembrane protein and precursor of fibrillar and toxic amyloid- peptides, which are considered responsible for Alzheimer disease neurodegeneration. Presenilins are multipass membrane proteins, involved in the enzymatic cleavage of APP and other signaling receptors and transducers. The role of APP and presenilins in Alzheimer disease development seems to be related to the formation of amyloid- peptides; however, their physiological function, reciprocal interaction, and molecular mechanisms leading to neurodegeneration are unclear. APP and presenilins are also involved in multiple interactions with intracellular proteins, the significance of which is under investigation. Among the different APP-interacting proteins, we focused our interest on the GRB2 adaptor protein, which connects cell surface receptors to intracellular signaling pathways. In this study we provide evidence by co-immunoprecipitation experiments, confocal and electron microscopy, and by fluorescence resonance energy transfer experiments that both APP and presenilin1 interact with GRB2 in vesicular structures at the centrosome of the cell. The final target for these interactions is ERK1,2, which is activated in mitotic centrosomes in a PS1-and APP-dependent manner. These data suggest that both APP and presenilin1 can be part of a common signaling pathway that regulates ERK1,2 and the cell cycle.
Proceedings of The National Academy of Sciences, 1998
We have characterized the interaction between apolipoprotein E (apoE) and amyloid  peptide (A) ... more We have characterized the interaction between apolipoprotein E (apoE) and amyloid  peptide (A) in the soluble fraction of the cerebral cortex of Alzheimer's disease (AD) and control subjects. Western blot analysis with specific antibodies identified in both groups a complex composed of the full-length apoE and A peptides ending at residues 40 and 42. The apoE-A soluble aggregate is less stable in AD brains than in controls, when treated with the anionic detergent SDS. The complex is present in significantly higher quantity in control than in AD brains, whereas in the insoluble fraction an inverse correlation has previously been reported. Moreover, in the AD subjects the A bound to apoE is more sensitive to protease digestion than is the unbound A. Taken together, our results indicate that in normal brains apoE efficiently binds and sequesters A, preventing its aggregation. In AD, the impaired apoE-A binding leads to the critical accumulation of A, facilitating plaque formation.
Brain Research Reviews, 2005
The amyloid precursor protein (APP) is an ubiquitous receptor-like molecule involved in the patho... more The amyloid precursor protein (APP) is an ubiquitous receptor-like molecule involved in the pathogenesis of Alzheimer's disease that generates beta-amyloid peptides and causes plaque formation. APP and some of its C-terminal proteolytic fragments (CTFs) have also been shown to be in the center of a complex protein-protein network, where selective phosphorylation of APP C-terminus may regulate the interaction with cytosolic phosphotyrosine binding (PTB) domain or Src homology 2 (SH2) domain containing proteins involved in cell signaling. We have recently described an interaction between tyrosine-phosphorylated CTFs and ShcA adaptor protein which is highly enhanced in AD brain, and a new interaction between APP and the adaptor protein Grb2 both in human brain and in neuroblastoma cultured cells. These data suggest a possible role in cell signaling for APP and its CTFs, in a manner similar to that previously reported for other receptors, through a tightly regulated coupling with intracellular adaptors to control the signaling of the cell. In this review, we discuss the significance of these novel findings for AD development.
Neurobiology of Disease, 2001
The carboxy-terminal fragments (CTFs) of the amyloid precursor protein (APP) are considered -amy... more The carboxy-terminal fragments (CTFs) of the amyloid precursor protein (APP) are considered -amyloid (A) precursors as well as molecular species that are both amyloidogenic and neurotoxic by themselves in vitro or in animal models. However the CTFs' role in the pathogenesis of Alzheimer's disease (AD) is however relatively unexplored in human brain. In this study, we analyzed CTFs extracted from brains of subjects with AD, non-AD control, and Down's syndrome (DS) cases. Our data indicate that: (i) In fetal DS brains CTFs levels are increased in comparison to age-matched control, suggesting that the enhanced CTFs formation is important for the early occurrence of plaque deposition in DS. There is no significant difference in CTFs level is present between AD and age-matched control cases. (ii) CTFs modified at their N-terminus appear to be the direct precursors of likewise N-terminally modified A peptides, which constitute the most abundant species in AD and DS plaques. This observation suggests that N-truncated A peptides are rather formed directly at -secretase level and not through a progressive proteolysis of full-length A1-40/42. (iii) Among the differently cleaved CTFs, only the 22-and 12.5-kDa polypeptides are tyrosine phosphorylated in both AD and control brains while the full-length APP and the CTFs migrating below the 12.5-kDa marker are not phosphorylated, suggesting that some APP and CTFs are processed through regulated pathways. This study provides further evidence that in human brain CTFs constitute a molecular species directly involved in AD pathogenesis and in the development of the AD-like pathology in DS subjects.
Febs Letters, 1997
Water-soluble amyloid ß-peptides (sAß), ending at residue 42, precede amyloid plaques in Down's s... more Water-soluble amyloid ß-peptides (sAß), ending at residue 42, precede amyloid plaques in Down's syndrome (DS). Here we report that sAß consists of the full-length Aßi 42 and peptides truncated and modified by cyclization of the N-terminal glutamates, Aß 3(pE) _ 42 and Aß 11(pE ) 42 . The Aß 3(pE) _ 42 peptide is the most abundant form of sAß in Alzheimer's disease (AD) brains. In DS, sAß 3 ( pE ) 42 concentration increases with age and the peptide becomes a dominant species in the presence of plaques. Both pyroglutamate-modified peptides and the fulllength Aß form a stable aggregate that is water soluble. The findings point to a crucial role of the aggregated and modified sAß in the plaque formation and pathogenesis of AD.
Journal of Biological Chemistry, 2007
The amyloid precursor protein (APP) and the presenilins 1 and 2 are genetically linked to the dev... more The amyloid precursor protein (APP) and the presenilins 1 and 2 are genetically linked to the development of familial Alzheimer disease. APP is a single-pass transmembrane protein and precursor of fibrillar and toxic amyloid- peptides, which are considered responsible for Alzheimer disease neurodegeneration. Presenilins are multipass membrane proteins, involved in the enzymatic cleavage of APP and other signaling receptors and transducers. The role of APP and presenilins in Alzheimer disease development seems to be related to the formation of amyloid- peptides; however, their physiological function, reciprocal interaction, and molecular mechanisms leading to neurodegeneration are unclear. APP and presenilins are also involved in multiple interactions with intracellular proteins, the significance of which is under investigation. Among the different APP-interacting proteins, we focused our interest on the GRB2 adaptor protein, which connects cell surface receptors to intracellular signaling pathways. In this study we provide evidence by co-immunoprecipitation experiments, confocal and electron microscopy, and by fluorescence resonance energy transfer experiments that both APP and presenilin1 interact with GRB2 in vesicular structures at the centrosome of the cell. The final target for these interactions is ERK1,2, which is activated in mitotic centrosomes in a PS1-and APP-dependent manner. These data suggest that both APP and presenilin1 can be part of a common signaling pathway that regulates ERK1,2 and the cell cycle.
Proceedings of The National Academy of Sciences, 1998
We have characterized the interaction between apolipoprotein E (apoE) and amyloid  peptide (A) ... more We have characterized the interaction between apolipoprotein E (apoE) and amyloid  peptide (A) in the soluble fraction of the cerebral cortex of Alzheimer's disease (AD) and control subjects. Western blot analysis with specific antibodies identified in both groups a complex composed of the full-length apoE and A peptides ending at residues 40 and 42. The apoE-A soluble aggregate is less stable in AD brains than in controls, when treated with the anionic detergent SDS. The complex is present in significantly higher quantity in control than in AD brains, whereas in the insoluble fraction an inverse correlation has previously been reported. Moreover, in the AD subjects the A bound to apoE is more sensitive to protease digestion than is the unbound A. Taken together, our results indicate that in normal brains apoE efficiently binds and sequesters A, preventing its aggregation. In AD, the impaired apoE-A binding leads to the critical accumulation of A, facilitating plaque formation.
Brain Research Reviews, 2005
The amyloid precursor protein (APP) is an ubiquitous receptor-like molecule involved in the patho... more The amyloid precursor protein (APP) is an ubiquitous receptor-like molecule involved in the pathogenesis of Alzheimer's disease that generates beta-amyloid peptides and causes plaque formation. APP and some of its C-terminal proteolytic fragments (CTFs) have also been shown to be in the center of a complex protein-protein network, where selective phosphorylation of APP C-terminus may regulate the interaction with cytosolic phosphotyrosine binding (PTB) domain or Src homology 2 (SH2) domain containing proteins involved in cell signaling. We have recently described an interaction between tyrosine-phosphorylated CTFs and ShcA adaptor protein which is highly enhanced in AD brain, and a new interaction between APP and the adaptor protein Grb2 both in human brain and in neuroblastoma cultured cells. These data suggest a possible role in cell signaling for APP and its CTFs, in a manner similar to that previously reported for other receptors, through a tightly regulated coupling with intracellular adaptors to control the signaling of the cell. In this review, we discuss the significance of these novel findings for AD development.
Neurobiology of Disease, 2001
The carboxy-terminal fragments (CTFs) of the amyloid precursor protein (APP) are considered -amy... more The carboxy-terminal fragments (CTFs) of the amyloid precursor protein (APP) are considered -amyloid (A) precursors as well as molecular species that are both amyloidogenic and neurotoxic by themselves in vitro or in animal models. However the CTFs' role in the pathogenesis of Alzheimer's disease (AD) is however relatively unexplored in human brain. In this study, we analyzed CTFs extracted from brains of subjects with AD, non-AD control, and Down's syndrome (DS) cases. Our data indicate that: (i) In fetal DS brains CTFs levels are increased in comparison to age-matched control, suggesting that the enhanced CTFs formation is important for the early occurrence of plaque deposition in DS. There is no significant difference in CTFs level is present between AD and age-matched control cases. (ii) CTFs modified at their N-terminus appear to be the direct precursors of likewise N-terminally modified A peptides, which constitute the most abundant species in AD and DS plaques. This observation suggests that N-truncated A peptides are rather formed directly at -secretase level and not through a progressive proteolysis of full-length A1-40/42. (iii) Among the differently cleaved CTFs, only the 22-and 12.5-kDa polypeptides are tyrosine phosphorylated in both AD and control brains while the full-length APP and the CTFs migrating below the 12.5-kDa marker are not phosphorylated, suggesting that some APP and CTFs are processed through regulated pathways. This study provides further evidence that in human brain CTFs constitute a molecular species directly involved in AD pathogenesis and in the development of the AD-like pathology in DS subjects.
Febs Letters, 1997
Water-soluble amyloid ß-peptides (sAß), ending at residue 42, precede amyloid plaques in Down's s... more Water-soluble amyloid ß-peptides (sAß), ending at residue 42, precede amyloid plaques in Down's syndrome (DS). Here we report that sAß consists of the full-length Aßi 42 and peptides truncated and modified by cyclization of the N-terminal glutamates, Aß 3(pE) _ 42 and Aß 11(pE ) 42 . The Aß 3(pE) _ 42 peptide is the most abundant form of sAß in Alzheimer's disease (AD) brains. In DS, sAß 3 ( pE ) 42 concentration increases with age and the peptide becomes a dominant species in the presence of plaques. Both pyroglutamate-modified peptides and the fulllength Aß form a stable aggregate that is water soluble. The findings point to a crucial role of the aggregated and modified sAß in the plaque formation and pathogenesis of AD.
Journal of Biological Chemistry, 2007
The amyloid precursor protein (APP) and the presenilins 1 and 2 are genetically linked to the dev... more The amyloid precursor protein (APP) and the presenilins 1 and 2 are genetically linked to the development of familial Alzheimer disease. APP is a single-pass transmembrane protein and precursor of fibrillar and toxic amyloid- peptides, which are considered responsible for Alzheimer disease neurodegeneration. Presenilins are multipass membrane proteins, involved in the enzymatic cleavage of APP and other signaling receptors and transducers. The role of APP and presenilins in Alzheimer disease development seems to be related to the formation of amyloid- peptides; however, their physiological function, reciprocal interaction, and molecular mechanisms leading to neurodegeneration are unclear. APP and presenilins are also involved in multiple interactions with intracellular proteins, the significance of which is under investigation. Among the different APP-interacting proteins, we focused our interest on the GRB2 adaptor protein, which connects cell surface receptors to intracellular signaling pathways. In this study we provide evidence by co-immunoprecipitation experiments, confocal and electron microscopy, and by fluorescence resonance energy transfer experiments that both APP and presenilin1 interact with GRB2 in vesicular structures at the centrosome of the cell. The final target for these interactions is ERK1,2, which is activated in mitotic centrosomes in a PS1-and APP-dependent manner. These data suggest that both APP and presenilin1 can be part of a common signaling pathway that regulates ERK1,2 and the cell cycle.
Proceedings of The National Academy of Sciences, 1998
We have characterized the interaction between apolipoprotein E (apoE) and amyloid  peptide (A) ... more We have characterized the interaction between apolipoprotein E (apoE) and amyloid  peptide (A) in the soluble fraction of the cerebral cortex of Alzheimer's disease (AD) and control subjects. Western blot analysis with specific antibodies identified in both groups a complex composed of the full-length apoE and A peptides ending at residues 40 and 42. The apoE-A soluble aggregate is less stable in AD brains than in controls, when treated with the anionic detergent SDS. The complex is present in significantly higher quantity in control than in AD brains, whereas in the insoluble fraction an inverse correlation has previously been reported. Moreover, in the AD subjects the A bound to apoE is more sensitive to protease digestion than is the unbound A. Taken together, our results indicate that in normal brains apoE efficiently binds and sequesters A, preventing its aggregation. In AD, the impaired apoE-A binding leads to the critical accumulation of A, facilitating plaque formation.
Brain Research Reviews, 2005
The amyloid precursor protein (APP) is an ubiquitous receptor-like molecule involved in the patho... more The amyloid precursor protein (APP) is an ubiquitous receptor-like molecule involved in the pathogenesis of Alzheimer's disease that generates beta-amyloid peptides and causes plaque formation. APP and some of its C-terminal proteolytic fragments (CTFs) have also been shown to be in the center of a complex protein-protein network, where selective phosphorylation of APP C-terminus may regulate the interaction with cytosolic phosphotyrosine binding (PTB) domain or Src homology 2 (SH2) domain containing proteins involved in cell signaling. We have recently described an interaction between tyrosine-phosphorylated CTFs and ShcA adaptor protein which is highly enhanced in AD brain, and a new interaction between APP and the adaptor protein Grb2 both in human brain and in neuroblastoma cultured cells. These data suggest a possible role in cell signaling for APP and its CTFs, in a manner similar to that previously reported for other receptors, through a tightly regulated coupling with intracellular adaptors to control the signaling of the cell. In this review, we discuss the significance of these novel findings for AD development.
Neurobiology of Disease, 2001
The carboxy-terminal fragments (CTFs) of the amyloid precursor protein (APP) are considered -amy... more The carboxy-terminal fragments (CTFs) of the amyloid precursor protein (APP) are considered -amyloid (A) precursors as well as molecular species that are both amyloidogenic and neurotoxic by themselves in vitro or in animal models. However the CTFs' role in the pathogenesis of Alzheimer's disease (AD) is however relatively unexplored in human brain. In this study, we analyzed CTFs extracted from brains of subjects with AD, non-AD control, and Down's syndrome (DS) cases. Our data indicate that: (i) In fetal DS brains CTFs levels are increased in comparison to age-matched control, suggesting that the enhanced CTFs formation is important for the early occurrence of plaque deposition in DS. There is no significant difference in CTFs level is present between AD and age-matched control cases. (ii) CTFs modified at their N-terminus appear to be the direct precursors of likewise N-terminally modified A peptides, which constitute the most abundant species in AD and DS plaques. This observation suggests that N-truncated A peptides are rather formed directly at -secretase level and not through a progressive proteolysis of full-length A1-40/42. (iii) Among the differently cleaved CTFs, only the 22-and 12.5-kDa polypeptides are tyrosine phosphorylated in both AD and control brains while the full-length APP and the CTFs migrating below the 12.5-kDa marker are not phosphorylated, suggesting that some APP and CTFs are processed through regulated pathways. This study provides further evidence that in human brain CTFs constitute a molecular species directly involved in AD pathogenesis and in the development of the AD-like pathology in DS subjects.
Febs Letters, 1997
Water-soluble amyloid ß-peptides (sAß), ending at residue 42, precede amyloid plaques in Down's s... more Water-soluble amyloid ß-peptides (sAß), ending at residue 42, precede amyloid plaques in Down's syndrome (DS). Here we report that sAß consists of the full-length Aßi 42 and peptides truncated and modified by cyclization of the N-terminal glutamates, Aß 3(pE) _ 42 and Aß 11(pE ) 42 . The Aß 3(pE) _ 42 peptide is the most abundant form of sAß in Alzheimer's disease (AD) brains. In DS, sAß 3 ( pE ) 42 concentration increases with age and the peptide becomes a dominant species in the presence of plaques. Both pyroglutamate-modified peptides and the fulllength Aß form a stable aggregate that is water soluble. The findings point to a crucial role of the aggregated and modified sAß in the plaque formation and pathogenesis of AD.
Journal of Biological Chemistry, 2007
The amyloid precursor protein (APP) and the presenilins 1 and 2 are genetically linked to the dev... more The amyloid precursor protein (APP) and the presenilins 1 and 2 are genetically linked to the development of familial Alzheimer disease. APP is a single-pass transmembrane protein and precursor of fibrillar and toxic amyloid- peptides, which are considered responsible for Alzheimer disease neurodegeneration. Presenilins are multipass membrane proteins, involved in the enzymatic cleavage of APP and other signaling receptors and transducers. The role of APP and presenilins in Alzheimer disease development seems to be related to the formation of amyloid- peptides; however, their physiological function, reciprocal interaction, and molecular mechanisms leading to neurodegeneration are unclear. APP and presenilins are also involved in multiple interactions with intracellular proteins, the significance of which is under investigation. Among the different APP-interacting proteins, we focused our interest on the GRB2 adaptor protein, which connects cell surface receptors to intracellular signaling pathways. In this study we provide evidence by co-immunoprecipitation experiments, confocal and electron microscopy, and by fluorescence resonance energy transfer experiments that both APP and presenilin1 interact with GRB2 in vesicular structures at the centrosome of the cell. The final target for these interactions is ERK1,2, which is activated in mitotic centrosomes in a PS1-and APP-dependent manner. These data suggest that both APP and presenilin1 can be part of a common signaling pathway that regulates ERK1,2 and the cell cycle.
Proceedings of The National Academy of Sciences, 1998
We have characterized the interaction between apolipoprotein E (apoE) and amyloid  peptide (A) ... more We have characterized the interaction between apolipoprotein E (apoE) and amyloid  peptide (A) in the soluble fraction of the cerebral cortex of Alzheimer's disease (AD) and control subjects. Western blot analysis with specific antibodies identified in both groups a complex composed of the full-length apoE and A peptides ending at residues 40 and 42. The apoE-A soluble aggregate is less stable in AD brains than in controls, when treated with the anionic detergent SDS. The complex is present in significantly higher quantity in control than in AD brains, whereas in the insoluble fraction an inverse correlation has previously been reported. Moreover, in the AD subjects the A bound to apoE is more sensitive to protease digestion than is the unbound A. Taken together, our results indicate that in normal brains apoE efficiently binds and sequesters A, preventing its aggregation. In AD, the impaired apoE-A binding leads to the critical accumulation of A, facilitating plaque formation.
Brain Research Reviews, 2005
The amyloid precursor protein (APP) is an ubiquitous receptor-like molecule involved in the patho... more The amyloid precursor protein (APP) is an ubiquitous receptor-like molecule involved in the pathogenesis of Alzheimer's disease that generates beta-amyloid peptides and causes plaque formation. APP and some of its C-terminal proteolytic fragments (CTFs) have also been shown to be in the center of a complex protein-protein network, where selective phosphorylation of APP C-terminus may regulate the interaction with cytosolic phosphotyrosine binding (PTB) domain or Src homology 2 (SH2) domain containing proteins involved in cell signaling. We have recently described an interaction between tyrosine-phosphorylated CTFs and ShcA adaptor protein which is highly enhanced in AD brain, and a new interaction between APP and the adaptor protein Grb2 both in human brain and in neuroblastoma cultured cells. These data suggest a possible role in cell signaling for APP and its CTFs, in a manner similar to that previously reported for other receptors, through a tightly regulated coupling with intracellular adaptors to control the signaling of the cell. In this review, we discuss the significance of these novel findings for AD development.
Neurobiology of Disease, 2001
The carboxy-terminal fragments (CTFs) of the amyloid precursor protein (APP) are considered -amy... more The carboxy-terminal fragments (CTFs) of the amyloid precursor protein (APP) are considered -amyloid (A) precursors as well as molecular species that are both amyloidogenic and neurotoxic by themselves in vitro or in animal models. However the CTFs' role in the pathogenesis of Alzheimer's disease (AD) is however relatively unexplored in human brain. In this study, we analyzed CTFs extracted from brains of subjects with AD, non-AD control, and Down's syndrome (DS) cases. Our data indicate that: (i) In fetal DS brains CTFs levels are increased in comparison to age-matched control, suggesting that the enhanced CTFs formation is important for the early occurrence of plaque deposition in DS. There is no significant difference in CTFs level is present between AD and age-matched control cases. (ii) CTFs modified at their N-terminus appear to be the direct precursors of likewise N-terminally modified A peptides, which constitute the most abundant species in AD and DS plaques. This observation suggests that N-truncated A peptides are rather formed directly at -secretase level and not through a progressive proteolysis of full-length A1-40/42. (iii) Among the differently cleaved CTFs, only the 22-and 12.5-kDa polypeptides are tyrosine phosphorylated in both AD and control brains while the full-length APP and the CTFs migrating below the 12.5-kDa marker are not phosphorylated, suggesting that some APP and CTFs are processed through regulated pathways. This study provides further evidence that in human brain CTFs constitute a molecular species directly involved in AD pathogenesis and in the development of the AD-like pathology in DS subjects.
Febs Letters, 1997
Water-soluble amyloid ß-peptides (sAß), ending at residue 42, precede amyloid plaques in Down's s... more Water-soluble amyloid ß-peptides (sAß), ending at residue 42, precede amyloid plaques in Down's syndrome (DS). Here we report that sAß consists of the full-length Aßi 42 and peptides truncated and modified by cyclization of the N-terminal glutamates, Aß 3(pE) _ 42 and Aß 11(pE ) 42 . The Aß 3(pE) _ 42 peptide is the most abundant form of sAß in Alzheimer's disease (AD) brains. In DS, sAß 3 ( pE ) 42 concentration increases with age and the peptide becomes a dominant species in the presence of plaques. Both pyroglutamate-modified peptides and the fulllength Aß form a stable aggregate that is water soluble. The findings point to a crucial role of the aggregated and modified sAß in the plaque formation and pathogenesis of AD.