The Experts below are selected from a list of 114 Experts worldwide ranked by ideXlab platform
Joseph El Khoury - One of the best experts on this subject based on the ideXlab platform.
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heterozygous cx3cr1 deficiency in microglia restores neuronal β amyloid clearance pathways and slows progression of alzheimer s like disease in ps1 app mice
Frontiers in Immunology, 2019Co-Authors: Suzanne E Hickman, Elizabeth Katherine Allison, Uwanda Coleman, Nathan David Kingerygallagher, Joseph El KhouryAbstract:CX3CR1 is a chemokine receptor expressed on microglia that binds Fractalkine (CX3CL1) and regulates microglial recruitment to sites of neuroinflammation. Full deletion of CX3CR1 in mouse models of Alzheimer’s disease have opposing effects on amyloid-β and tau pathologies raising concerns about the benefits of targeting CX3CR1 for treatment of this disease. Since most therapies achieve only partial blockade of their targets, we investigated the effects of partial CX3CR1 deficiency on the development and progression of amyloid-β deposition in the PS1-APP Alzheimer’s mouse model. We generated PS1-APP mice heterozygous for CX3CR1 (PS1-APP-CX3CR1+/-) and analyzed these mice for Alzheimer’s-like pathology. We found that partial CX3CR1 deficiency was associated with a significant reduction in Aβ levels and in senile-like plaque load in the brain as compared with age-matched PS1-APP mice. Reduced Aβ level in the brain was associated with improved cognitive function. Levels of the neuronal-expressed Aβ-degrading enzymes Insulysin and matrix metalloproteinase 9, which are reduced in the brains of regular PS1-APP mice, were significantly higher in PS1-APP-CX3CR1+/- mice. Our data indicate that lowering CX3CR1 levels or partially inhibiting its activity in the brain may be a therapeutic strategy to increase neuronal Aβ clearance, reduce Aβ levels and delay progression of Alzheimer’s-Like disease. Our findings also suggest a novel pathway where microglial CX3CR1 can regulates gene expression in neurons.
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microglial dysfunction and defective β amyloid clearance pathways in aging alzheimer s disease mice
The Journal of Neuroscience, 2008Co-Authors: Suzanne E Hickman, Elizabeth Katherine Allison, Joseph El KhouryAbstract:Early microglial accumulation in Alzheimer9s disease (AD) delays disease progression by promoting clearance of β-amyloid (Aβ) before formation of senile plaques. However, persistent Aβ accumulation despite increasing microglial numbers suggests that the ability of microglia to clear Aβ may decrease with age and progression of AD pathology. To determine the effects of aging and Aβ deposition on microglial ability to clear Aβ, we used quantitative PCR to analyze gene expression in freshly isolated adult microglia from 1.5-, 3-, 8-, and 14-month-old transgenic PS1-APP mice, an established mouse model of AD, and from their nontransgenic littermates. We found that microglia from old PS1-APP mice, but not from younger mice, have a twofold to fivefold decrease in expression of the Aβ-binding scavenger receptors scavenger receptor A (SRA), CD36, and RAGE (receptor for advanced-glycosylation endproducts), and the Aβ-degrading enzymes Insulysin, neprilysin, and MMP9, compared with their littermate controls. In contrast, PS1-APP microglia had a 2.5-fold increase in the proinflammatory cytokines IL-1β (interleukin-1β) and tumor necrosis factor α (TNFα), suggesting that there is an inverse correlation between cytokine production and Aβ clearance. In support of this possibility, we found that incubation of cultured N9 mouse microglia with TNFα decreased the expression of SRA and CD36 and reduced Aβ uptake. Our data indicate that, although early microglial recruitment promotes Aβ clearance and is neuroprotective in AD, as disease progresses, proinflammatory cytokines produced in response to Aβ deposition downregulate genes involved in Aβ clearance and promote Aβ accumulation, therefore contributing to neurodegeneration. Antiinflammatory therapy for AD should take this dichotomous microglial role into consideration.
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microglial dysfunction and defective β amyloid clearance pathways in aging alzheimer s disease mice
The Journal of Neuroscience, 2008Co-Authors: Suzanne E Hickman, Elizabeth Katherine Allison, Joseph El KhouryAbstract:Early microglial accumulation in Alzheimer's disease (AD) delays disease progression by promoting clearance of beta-amyloid (Abeta) before formation of senile plaques. However, persistent Abeta accumulation despite increasing microglial numbers suggests that the ability of microglia to clear Abeta may decrease with age and progression of AD pathology. To determine the effects of aging and Abeta deposition on microglial ability to clear Abeta, we used quantitative PCR to analyze gene expression in freshly isolated adult microglia from 1.5-, 3-, 8-, and 14-month-old transgenic PS1-APP mice, an established mouse model of AD, and from their nontransgenic littermates. We found that microglia from old PS1-APP mice, but not from younger mice, have a twofold to fivefold decrease in expression of the Abeta-binding scavenger receptors scavenger receptor A (SRA), CD36, and RAGE (receptor for advanced-glycosylation endproducts), and the Abeta-degrading enzymes Insulysin, neprilysin, and MMP9, compared with their littermate controls. In contrast, PS1-APP microglia had a 2.5-fold increase in the proinflammatory cytokines IL-1beta (interleukin-1beta) and tumor necrosis factor alpha (TNFalpha), suggesting that there is an inverse correlation between cytokine production and Abeta clearance. In support of this possibility, we found that incubation of cultured N9 mouse microglia with TNFalpha decreased the expression of SRA and CD36 and reduced Abeta uptake. Our data indicate that, although early microglial recruitment promotes Abeta clearance and is neuroprotective in AD, as disease progresses, proinflammatory cytokines produced in response to Abeta deposition downregulate genes involved in Abeta clearance and promote Abeta accumulation, therefore contributing to neurodegeneration. Antiinflammatory therapy for AD should take this dichotomous microglial role into consideration.
Louis B Hersh - One of the best experts on this subject based on the ideXlab platform.
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Identification of the Allosteric Regulatory Site of
2011Co-Authors: Nicholas Noinaj, Eun Suk Song, Louis B Hersh, Sonia K Bhasin, Kirsten E Scoggin, Maria A Juliano, David W RodgersAbstract:Background: Insulin degrading enzyme (IDE) is responsible for the metabolism of insulin and plays a role in clearance of the Ab peptide associated with Alzheimer’s disease. Unlike most proteolytic enzymes, IDE, which consists of four structurally related domains and exists primarily as a dimer, exhibits allosteric kinetics, being activated by both small substrate peptides and polyphosphates such as ATP. Principal Findings: The crystal structure of a catalytically compromised mutant of IDE has electron density for peptide ligands bound at the active site in domain 1 and a distal site in domain 2. Mutating residues in the distal site eliminates allosteric kinetics and activation by a small peptide, as well as greatly reducing activation by ATP, demonstrating that this site plays a key role in allostery. Comparison of the peptide bound IDE structure (using a low activity E111F IDE mutant) with unliganded wild type IDE shows a change in the interface between two halves of the clamshell-like molecule, which may enhance enzyme activity by altering the equilibrium between closed and open conformations. In addition, changes in the dimer interface suggest a basis for communication between subunits. Conclusions/Significance: Our findings indicate that a region remote from the active site mediates allosteric activation of Insulysin by peptides. Activation may involve a small conformational change that weakens the interface between two halve
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substrate activation of insulin degrading enzyme Insulysin a potential target for drug development
Journal of Biological Chemistry, 2003Co-Authors: Eun Suk Song, Luiz Juliano, Maria Aparecida Juliano, Louis B HershAbstract:The rate of the insulin-degrading enzyme (IDE)-catalyzed hydrolysis of the fluorogenic substrate 2-aminobenzoyl-GGFLRKHGQ-ethylenediamine-2,4-dinitrophenyl is increased 2-7-fold by other peptide substrates but not by peptide non-substrates. This increased rate is attributed to a decrease in Km with little effect on Vmax. An approximately 2.5-fold increase in the rate of amyloid beta peptide hydrolysis is produced by dynorphin B-9. However, with insulin as substrate, dynorphin B-9 is inhibitory. Immunoprecipitation of differentially tagged IDE and gel filtration analysis were used to show that IDE exists as a mixture of dimers and tetramers. The equilibrium between dimer and tetramer is concentration-dependent, with the dimer the more active form. Bradykinin shifted the equilibrium toward dimer. Activation of substrate hydrolysis is not seen with a mixed dimer of IDE containing one active subunit and one subunit that is catalytically inactive and deficient in substrate binding. On the other hand, a mixed dimer containing one active subunit and one subunit that is catalytically inactive but binds substrate with normal affinity is activated by peptides. These findings suggest that peptides bind to one subunit of IDE and induce a conformational change that shifts the equilibrium to the more active dimer as well as activates the adjacent subunit. The selective activation of IDE toward amyloid beta peptide relative to insulin suggests the potential for development of compounds that increase IDE activity toward amyloid beta peptide as a therapeutic intervention for the treatment of Alzheimer's disease.
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amyloid β peptide levels in brain are inversely correlated with Insulysin activity levels in vivo
Proceedings of the National Academy of Sciences of the United States of America, 2003Co-Authors: Bonnie C Miller, Louis B Hersh, Elizabeth A Eckman, Kumar Sambamurti, Nicole Dobbs, Martin K Chow, Christopher B Eckman, Dwain L ThieleAbstract:Abstract Factors that elevate amyloid-β (Aβ) peptide levels are associated with an increased risk for Alzheimer's disease. Insulysin has been identified as one of several proteases potentially involved in Aβ degradation based on its hydrolysis of Aβ peptides in vitro. In this study, in vivo levels of brain Aβ40 and Aβ42 peptides were found to be increased significantly (1.6- and 1.4-fold, respectively) in an Insulysin-deficient gene-trap mouse model. A 6-fold increase in the level of the γ-secretase-generated C-terminal fragment of the Aβ precursor protein in the Insulysin-deficient mouse also was found. In mice heterozygous for the Insulysin gene trap, in which Insulysin activity levels were decreased ≈50%, brain Aβ peptides were increased to levels intermediate between those in wild-type mice and homozygous Insulysin gene-trap mice that had no detectable Insulysin activity. These findings indicate that there is an inverse correlation between in vivo Insulysin activity levels and brain Aβ peptide levels and suggest that modulation of Insulysin activity may alter the risk for Alzheimer's disease.
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Identification of the allosteric regulatory site of Insulysin.
Public Library of Science (PLoS), 2026Co-Authors: Nicholas Noinaj, Eun Suk Song, Louis B Hersh, Luiz Juliano, Sonia K Bhasin, Kirsten E Scoggin, Maria A Juliano, David W RodgersAbstract:Insulin degrading enzyme (IDE) is responsible for the metabolism of insulin and plays a role in clearance of the Aβ peptide associated with Alzheimer's disease. Unlike most proteolytic enzymes, IDE, which consists of four structurally related domains and exists primarily as a dimer, exhibits allosteric kinetics, being activated by both small substrate peptides and polyphosphates such as ATP.The crystal structure of a catalytically compromised mutant of IDE has electron density for peptide ligands bound at the active site in domain 1 and a distal site in domain 2. Mutating residues in the distal site eliminates allosteric kinetics and activation by a small peptide, as well as greatly reducing activation by ATP, demonstrating that this site plays a key role in allostery. Comparison of the peptide bound IDE structure (using a low activity E111F IDE mutant) with unliganded wild type IDE shows a change in the interface between two halves of the clamshell-like molecule, which may enhance enzyme activity by altering the equilibrium between closed and open conformations. In addition, changes in the dimer interface suggest a basis for communication between subunits.Our findings indicate that a region remote from the active site mediates allosteric activation of Insulysin by peptides. Activation may involve a small conformational change that weakens the interface between two halves of the enzyme
Suzanne E Hickman - One of the best experts on this subject based on the ideXlab platform.
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heterozygous cx3cr1 deficiency in microglia restores neuronal β amyloid clearance pathways and slows progression of alzheimer s like disease in ps1 app mice
Frontiers in Immunology, 2019Co-Authors: Suzanne E Hickman, Elizabeth Katherine Allison, Uwanda Coleman, Nathan David Kingerygallagher, Joseph El KhouryAbstract:CX3CR1 is a chemokine receptor expressed on microglia that binds Fractalkine (CX3CL1) and regulates microglial recruitment to sites of neuroinflammation. Full deletion of CX3CR1 in mouse models of Alzheimer’s disease have opposing effects on amyloid-β and tau pathologies raising concerns about the benefits of targeting CX3CR1 for treatment of this disease. Since most therapies achieve only partial blockade of their targets, we investigated the effects of partial CX3CR1 deficiency on the development and progression of amyloid-β deposition in the PS1-APP Alzheimer’s mouse model. We generated PS1-APP mice heterozygous for CX3CR1 (PS1-APP-CX3CR1+/-) and analyzed these mice for Alzheimer’s-like pathology. We found that partial CX3CR1 deficiency was associated with a significant reduction in Aβ levels and in senile-like plaque load in the brain as compared with age-matched PS1-APP mice. Reduced Aβ level in the brain was associated with improved cognitive function. Levels of the neuronal-expressed Aβ-degrading enzymes Insulysin and matrix metalloproteinase 9, which are reduced in the brains of regular PS1-APP mice, were significantly higher in PS1-APP-CX3CR1+/- mice. Our data indicate that lowering CX3CR1 levels or partially inhibiting its activity in the brain may be a therapeutic strategy to increase neuronal Aβ clearance, reduce Aβ levels and delay progression of Alzheimer’s-Like disease. Our findings also suggest a novel pathway where microglial CX3CR1 can regulates gene expression in neurons.
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microglial dysfunction and defective β amyloid clearance pathways in aging alzheimer s disease mice
The Journal of Neuroscience, 2008Co-Authors: Suzanne E Hickman, Elizabeth Katherine Allison, Joseph El KhouryAbstract:Early microglial accumulation in Alzheimer9s disease (AD) delays disease progression by promoting clearance of β-amyloid (Aβ) before formation of senile plaques. However, persistent Aβ accumulation despite increasing microglial numbers suggests that the ability of microglia to clear Aβ may decrease with age and progression of AD pathology. To determine the effects of aging and Aβ deposition on microglial ability to clear Aβ, we used quantitative PCR to analyze gene expression in freshly isolated adult microglia from 1.5-, 3-, 8-, and 14-month-old transgenic PS1-APP mice, an established mouse model of AD, and from their nontransgenic littermates. We found that microglia from old PS1-APP mice, but not from younger mice, have a twofold to fivefold decrease in expression of the Aβ-binding scavenger receptors scavenger receptor A (SRA), CD36, and RAGE (receptor for advanced-glycosylation endproducts), and the Aβ-degrading enzymes Insulysin, neprilysin, and MMP9, compared with their littermate controls. In contrast, PS1-APP microglia had a 2.5-fold increase in the proinflammatory cytokines IL-1β (interleukin-1β) and tumor necrosis factor α (TNFα), suggesting that there is an inverse correlation between cytokine production and Aβ clearance. In support of this possibility, we found that incubation of cultured N9 mouse microglia with TNFα decreased the expression of SRA and CD36 and reduced Aβ uptake. Our data indicate that, although early microglial recruitment promotes Aβ clearance and is neuroprotective in AD, as disease progresses, proinflammatory cytokines produced in response to Aβ deposition downregulate genes involved in Aβ clearance and promote Aβ accumulation, therefore contributing to neurodegeneration. Antiinflammatory therapy for AD should take this dichotomous microglial role into consideration.
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microglial dysfunction and defective β amyloid clearance pathways in aging alzheimer s disease mice
The Journal of Neuroscience, 2008Co-Authors: Suzanne E Hickman, Elizabeth Katherine Allison, Joseph El KhouryAbstract:Early microglial accumulation in Alzheimer's disease (AD) delays disease progression by promoting clearance of beta-amyloid (Abeta) before formation of senile plaques. However, persistent Abeta accumulation despite increasing microglial numbers suggests that the ability of microglia to clear Abeta may decrease with age and progression of AD pathology. To determine the effects of aging and Abeta deposition on microglial ability to clear Abeta, we used quantitative PCR to analyze gene expression in freshly isolated adult microglia from 1.5-, 3-, 8-, and 14-month-old transgenic PS1-APP mice, an established mouse model of AD, and from their nontransgenic littermates. We found that microglia from old PS1-APP mice, but not from younger mice, have a twofold to fivefold decrease in expression of the Abeta-binding scavenger receptors scavenger receptor A (SRA), CD36, and RAGE (receptor for advanced-glycosylation endproducts), and the Abeta-degrading enzymes Insulysin, neprilysin, and MMP9, compared with their littermate controls. In contrast, PS1-APP microglia had a 2.5-fold increase in the proinflammatory cytokines IL-1beta (interleukin-1beta) and tumor necrosis factor alpha (TNFalpha), suggesting that there is an inverse correlation between cytokine production and Abeta clearance. In support of this possibility, we found that incubation of cultured N9 mouse microglia with TNFalpha decreased the expression of SRA and CD36 and reduced Abeta uptake. Our data indicate that, although early microglial recruitment promotes Abeta clearance and is neuroprotective in AD, as disease progresses, proinflammatory cytokines produced in response to Abeta deposition downregulate genes involved in Abeta clearance and promote Abeta accumulation, therefore contributing to neurodegeneration. Antiinflammatory therapy for AD should take this dichotomous microglial role into consideration.
Hersh L. B. - One of the best experts on this subject based on the ideXlab platform.
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ATP effects on insulin-degrading enzyme are mediated primarily through its triphosphate moiety
Amer Soc Biochemistry Molecular Biology Inc, 2004Co-Authors: Song E. S., Juliano, Maria Aparecida [unifesp], Juliano, Luiz [unifesp], Fried M. G., Wagner S. L., Hersh L. B.Abstract:It has been reported previously that ATP inhibits the Insulysin reaction (Camberos, M. C., Perez, A. A., Udrisar, D. P., Wanderley, M. I., and Cresto, J. C. ( 2001) Exp. Biol. Med. 226, 334-341). We report here that with 2-aminobenzoyl-GGFLRKHGQ-ethylenediamine-2,4-dinitrophenyl as substrate, ATP and other nucleotides increase the rate >20-fold in Tris buffer. There is no specificity with respect to the nucleotide; however, ATP is more effective than ADP, which is more effective than AMP. Triphosphate itself was as effective as ATP, indicating it is this moiety that is responsible for activation. the binding of triphosphate was shown to be at a site distinct from the active site, thus acting as a noncompetitive activator. With the physiological substrates insulin and amyloid beta peptide, nucleotides and triphosphate were without effect. However, with small physiological peptides such as bradykinin and dynorphin B-9, ATP and triphosphate increased the rate of hydrolysis similar to10-fold. Triphosphate and ATP shifted the oligomeric state of the enzyme from primarily dimer-tetramers to a monomer. These data suggest the presence of an allosteric regulatory site on Insulysin that may shift its specificity toward small peptide substrates
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ATP effects on insulin-degrading enzyme are mediated primarily through its triphosphate moiety
'American Society for Biochemistry & Molecular Biology (ASBMB)', 2004Co-Authors: Song E. S., Fried M. G., Wagner S. L., Juliano Luiz, Juliano, Maria Aparecida, Hersh L. B.Abstract:It has been reported previously that ATP inhibits the Insulysin reaction (Camberos, M. C., Perez, A. A., Udrisar, D. P., Wanderley, M. I., and Cresto, J. C. ( 2001) Exp. Biol. Med. 226, 334-341). We report here that with 2-aminobenzoyl-GGFLRKHGQ-ethylenediamine-2,4-dinitrophenyl as substrate, ATP and other nucleotides increase the rate >20-fold in Tris buffer. There is no specificity with respect to the nucleotide; however, ATP is more effective than ADP, which is more effective than AMP. Triphosphate itself was as effective as ATP, indicating it is this moiety that is responsible for activation. the binding of triphosphate was shown to be at a site distinct from the active site, thus acting as a noncompetitive activator. With the physiological substrates insulin and amyloid beta peptide, nucleotides and triphosphate were without effect. However, with small physiological peptides such as bradykinin and dynorphin B-9, ATP and triphosphate increased the rate of hydrolysis similar to10-fold. Triphosphate and ATP shifted the oligomeric state of the enzyme from primarily dimer-tetramers to a monomer. These data suggest the presence of an allosteric regulatory site on Insulysin that may shift its specificity toward small peptide substrates.Univ Kentucky, Coll Med, Dept Mol & Cellular Biochem, Lexington, KY 40536 USAEscola Paulista Med, Dept Biophys, BR-04023900 São Paulo, BrazilNeurogenet Inc, La Jolla, CA 92037 USAEscola Paulista Med, Dept Biophys, BR-04023900 São Paulo, BrazilWeb of Scienc
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Analysis of the subsite specificity of rat Insulysin using fluorogenic peptide substrates
Amer Soc Biochemistry Molecular Biology Inc, 2001Co-Authors: Song E. S., Juliano, Maria Aparecida [unifesp], Juliano, Luiz [unifesp], Mukherjee A., St Pyrek J., Goodman J. P., Hersh L. B.Abstract:Recombinant rat Insulysin was shown to cleave the internally quenched fluorogenic peptide 2-aminobenzyl-GGFLRKVGQ-ethylenediamine-2,4-dinitrophenol at the R-K bond, exhibiting a K-m of 13 muM and a V-max of 2.6 mu mol min(-1) mg(-1). Derivatives of this peptide in which the P-2 leucine or the P-2' valine were replaced with other residues were used to probe the subsite specificity of the enzyme. Varying the P-2 residue produced a l-fold range in K-m and a 7-fold range in k(cat). the nature of the P-2 residue had a significant effect on the site of cleavage. Leucine, isoleucine, valine, and aspartate produced cleavage at the R-K bond, Asparagine produced 36% cleavage at the N-R bond and 64% cleavage at the RK bond, whereas with alanine or serine the A-R and S-R bonds were the major cleavage sites. With tyrosine, phenylalanine, methionine, or histidine representing the varied residue X, cleavages at F-X, X-R, and RK were seen, whereas with tryptophan equal cleavage occurred at the F-W and W-R bonds. Variable P-2' residues produce less of a change in both K-m and k(cat) and have little influence on the cleavage site. Exceptions are phenylalanine, tyrosine, leucine, and isoleucine, which in addition to producing cleavage at the RK bond, produce significant cleavage at the GR bond. Alanine and tyrosine were unique in producing cleavage at the F-L bond. Taken together, these data suggest that Insulysin specificity is directed toward the amino side of hydrophobic and basic residues and that the enzyme has an extended substrate binding site
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Analysis of the subsite specificity of rat Insulysin using fluorogenic peptide substrates
'American Society for Biochemistry & Molecular Biology (ASBMB)', 2001Co-Authors: Song E. S., Juliano Luiz, Juliano, Maria Aparecida, Mukherjee A., St Pyrek J., Goodman J. P., Hersh L. B.Abstract:Recombinant rat Insulysin was shown to cleave the internally quenched fluorogenic peptide 2-aminobenzyl-GGFLRKVGQ-ethylenediamine-2,4-dinitrophenol at the R-K bond, exhibiting a K-m of 13 muM and a V-max of 2.6 mu mol min(-1) mg(-1). Derivatives of this peptide in which the P-2 leucine or the P-2' valine were replaced with other residues were used to probe the subsite specificity of the enzyme. Varying the P-2 residue produced a l-fold range in K-m and a 7-fold range in k(cat). the nature of the P-2 residue had a significant effect on the site of cleavage. Leucine, isoleucine, valine, and aspartate produced cleavage at the R-K bond, Asparagine produced 36% cleavage at the N-R bond and 64% cleavage at the RK bond, whereas with alanine or serine the A-R and S-R bonds were the major cleavage sites. With tyrosine, phenylalanine, methionine, or histidine representing the varied residue X, cleavages at F-X, X-R, and RK were seen, whereas with tryptophan equal cleavage occurred at the F-W and W-R bonds. Variable P-2' residues produce less of a change in both K-m and k(cat) and have little influence on the cleavage site. Exceptions are phenylalanine, tyrosine, leucine, and isoleucine, which in addition to producing cleavage at the RK bond, produce significant cleavage at the GR bond. Alanine and tyrosine were unique in producing cleavage at the F-L bond. Taken together, these data suggest that Insulysin specificity is directed toward the amino side of hydrophobic and basic residues and that the enzyme has an extended substrate binding site.Univ Kentucky, Albert B Chandler Med Ctr, Coll Med, Dept Biochem, Lexington, KY 40536 USAUniv Kentucky, Mass Spectrometry Facil, Lexington, KY 40506 USAEscola Paulista Med, Dept Biophys, BR-04034 São Paulo, BrazilEscola Paulista Med, Dept Biophys, BR-04034 São Paulo, BrazilWeb of Scienc
Dwain L Thiele - One of the best experts on this subject based on the ideXlab platform.
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amyloid β peptide levels in brain are inversely correlated with Insulysin activity levels in vivo
Proceedings of the National Academy of Sciences of the United States of America, 2003Co-Authors: Bonnie C Miller, Louis B Hersh, Elizabeth A Eckman, Kumar Sambamurti, Nicole Dobbs, Martin K Chow, Christopher B Eckman, Dwain L ThieleAbstract:Abstract Factors that elevate amyloid-β (Aβ) peptide levels are associated with an increased risk for Alzheimer's disease. Insulysin has been identified as one of several proteases potentially involved in Aβ degradation based on its hydrolysis of Aβ peptides in vitro. In this study, in vivo levels of brain Aβ40 and Aβ42 peptides were found to be increased significantly (1.6- and 1.4-fold, respectively) in an Insulysin-deficient gene-trap mouse model. A 6-fold increase in the level of the γ-secretase-generated C-terminal fragment of the Aβ precursor protein in the Insulysin-deficient mouse also was found. In mice heterozygous for the Insulysin gene trap, in which Insulysin activity levels were decreased ≈50%, brain Aβ peptides were increased to levels intermediate between those in wild-type mice and homozygous Insulysin gene-trap mice that had no detectable Insulysin activity. These findings indicate that there is an inverse correlation between in vivo Insulysin activity levels and brain Aβ peptide levels and suggest that modulation of Insulysin activity may alter the risk for Alzheimer's disease.