Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions ca... more Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal postures, repetitive movements, or both. Research in dystonia has been challenged by several factors. First, dystonia is uncommon. Dystonia is not a single disorder but a family of heterogenous disorders with varied clinical manifestations and different causes. The different subtypes may be seen by providers in different clinical specialties including neurology, ophthalmology, otolaryngology, and others. These issues have made it difficult for any single center to recruit large numbers of subjects with specific types of dystonia for research studies in a timely manner. The Dystonia Coalition is a consortium of investigators that was established to address these challenges. Since 2009, the Dystonia Coalition has encouraged collaboration by engaging 56 sites across North America, Europe, Asia, and Australia. Its emphasis on collaboration has facilitated establishment of inte...
ABSTRACT Alzheimer's disease is characterized by accumulation in the brain of a family of... more ABSTRACT Alzheimer's disease is characterized by accumulation in the brain of a family of insoluble amyloid peptides (Abeta peptides), which are produced as a result of the normal processing of beta-amyloid precursor protein (beta-APP). Russo et al. claim that a truncated Abeta peptide that lacks the first ten amino acids accumulates in the brains of patients carrying a mutant form of pre-senilin 1 (PS1), a protein that is involved in cleavage of beta-APP. However, we have found that this same species is also overrepresented in Alzheimer's patients with mutations in beta-APP itself. Our findings do not support the conclusion of Russo et al. that pathogenic PS1 mutations may control cleavage of beta-APP by beta-secretase.
A putative catalytic aspartyl residue, Asp-165, in the active site of clostridial glutamate dehyd... more A putative catalytic aspartyl residue, Asp-165, in the active site of clostridial glutamate dehydrogenase has been replaced with serine by site-directed mutagenesis. The mutant enzyme is efficiently overexpressed in Escherichia coli as a soluble protein and can be successfully purified by the dye-ligand chromatographic procedure normally employed for the wild-type enzyme. By several criteria, including circular dichroism spectrum, sulphydryl reactivity with Ellman's reagent, crystallization and mobility in non-denaturing electrophoresis, the enzyme appears to be correctly folded. NAD+ protects the D165S mutant against modification by Ellman's reagent, suggesting unimpaired binding of coenzyme. In standard assays the specific activity is decreased 10(3)-fold in the reductive amination reaction and 10(5)-fold for oxidative deamination. Kinetic studies show that apparent Km values for NADH and 2-oxoglutarate are almost unchanged. The large reduction in the reaction rate coincid...
The Task Force for Nomenclature of Genetic Movement Disorders recently proposed a new system of n... more The Task Force for Nomenclature of Genetic Movement Disorders recently proposed a new system of naming genetically determined movement disorders. 1 These recommendations apply to a wide spectrum of movement disorders, including parkinsonisms, dystonias, choreas, paroxysmal movement disorders, cerebellar ataxias, and spastic paraplegias. We agree that current genetic classifications are cumbersome and "unsuitable" for accurate and comprehensive categorization of genetic movement disorders. We appreciate that the task force addressed the discordance between phenotype and list designation by assigning more appropriate phenotype-prefix relationships. They propose 29 DYT symbols for inherited dystonias that occur in isolation or combined with other movement disorders, designated by an additional symbol: PARK, CHOR, or NBIA. The task Relevant conflicts of interest/financial disclosures: Nothing to report.
Comparative Biochemistry and Physiology Part B: Comparative Biochemistry, 1983
Differential effects of Triton X-100 on Tenebrio molitor glutamate dehydrogenase measured in mito... more Differential effects of Triton X-100 on Tenebrio molitor glutamate dehydrogenase measured in mitochondrial preparations were dependent on osmotic properties of the assay medium. 2. Maximal velocities were reached at lower concentrations of 2-oxoglutarate for glutamate dehydrogenase in detergent-treated mitochondria as opposed to untreated preparations. There was an increase in affinity constants for compartmentalized enzyme. Hill coefficient remained unchanged for enzyme studied in the damaged mitochondria, but was lower for enzyme in intact mitochondria. 3. The results suggest that the tested concentrations of Triton X-100 had no effect on the catalytic properties of glutamate dehydrogenase. The changes observed were caused by increased accessibility of substrates to the enzyme after solubilization of mitochondrial membranes.
Comparative Biochemistry and Physiology Part B: Comparative Biochemistry, 1985
Insulin immunoreactivity and proteolytic activity in phosphate buffer and acid-ethanol extracts f... more Insulin immunoreactivity and proteolytic activity in phosphate buffer and acid-ethanol extracts from larval heads and midguts of the mealworm were measured. 2. These two types of extraction gave very different values of IRI in the same tissue. 3. By the use of direct and indirect methods strong degradation of ~25I-insulin by proteolytic enzymes active in neutral extracts was shown. 4. Differences in IRI were due to interferences in radioimmunoassay caused by co-extracted proteolytic enzymes. 5. It is not possible to determine IRI precisely in neutral extracts of insect tissues.
Comparative Biochemistry and Physiology Part B: Comparative Biochemistry, 1988
Glutamate dehydrogenase (GDH) purified from the mealworm fat body was investigated in the glutama... more Glutamate dehydrogenase (GDH) purified from the mealworm fat body was investigated in the glutamate synthesizing direction. 2. Kinetic constants for the NADH and NADPH linked reactions were determined in the presence and absence of the activator, ADP. 3. ADP has influenced maximal velocities, substrate constants and cooperativity coefficients. 4. Strong substrate inhibition was observed at high concentrations of all substrates. 5. GDH was also activated by leucine and EDTA, and inhibited by zinc ions. 6. The enzyme displays allosteric properties being precisely controlled by substrates and effector concentrations. 7. The kinetic properties of Tenebrio molitor GDH suggest the regulatory role of the enzyme in nitrogen and carbohydrate metabolism of the fat body.
Purpose of review-The dystonias are a family of related disorders with many different clinical ma... more Purpose of review-The dystonias are a family of related disorders with many different clinical manifestations and causes. This review summarizes recent developments regarding these disorders, focusing mainly on advances with direct clinical relevance from the past two years. Recent findings-The dystonias are generally defined by their clinical characteristics, rather than by their underlying genetic or neuropathological defects. The many varied clinical manifestations and causes contribute to the fact that they are one of the most poorly recognized of all movement disorders. A series of recent publications has addressed these issues offering a revised definition and more logical means for classifying the many subtypes. Our understanding of the genetic and neurobiological mechanisms responsible for different types of dystonias also has grown rapidly, creating new opportunities and challenges for diagnosis and identifying increasing numbers of rare subtypes for which specific treatments are available. Summary-Recent advances in describing the clinical phenotypes and determining associated genotypes have pointed to the need for new strategies for diagnosis, classification and treatment of the dystonias.
The gene encoding the NAD +-dependent glutamate dehydrogenase (GDH) of Clostridium symbiosum was ... more The gene encoding the NAD +-dependent glutamate dehydrogenase (GDH) of Clostridium symbiosum was cloned using the polymerase chain reaction (PCR) because it could not be recovered by standard techniques. The nucleotide sequence of the gdh gene was determined and it was overexpressed from the controllable tac promoter in Escherichia coli so that active clostridial GDH represented 20% of total cell protein. The recombinant plasmid complemented the nutritional lesion of an E. coli glutamate auxotroph. There was a marked difference between the nucleotide compositions of the coding region (G + C = 52%) and the flanking sequences (G + C = 30% and 37%). The structural gene encoded a polypeptide of 450 amino acid residues and relative molecular mass (M,) 49 295 which corresponds to a single subunit of the hexameric enzyme. The DNA-derived amino acid sequence was consistent with a partial sequence from tryptic and cyanogen bromide peptides of the clostridial enzyme. The N-terminal amino acid sequence matched that of the purified protein, indicating that the initiating methionine is removed post-translationally, as in the natural host. The amino acid sequence is similar to those of other bacterial GDHs although it has a Gly-Xaa-Gly-Xaa-Xaa-Ala motif in the NADf-binding domain, which is more typical of the NADPf-dependent enzymes. The sequence data now permit a detailed interpretation of the X-ray crystallographic structure of the enzyme and the cloning and expression of the clostridial gene will facilitate sitedirected mutagenesis. The NAD +-dependent glutamate dehydrogenase (GDH) of Clostridium symbiosum catalyses the first step in the hydroxyglutarate pathway of glutamate fermentation 11, 21. This anaerobe is an abundant source of GDH, which amounts to approximately 1 5 % of the total cell protein during growth with glutamate. The enzyme has been purified and extensively characterized (3-51 and peptides representing about 75% of the primary structure have been sequenced 161. In addition, C. symbiosum GDH has been crystallized in a form suitable for high-resolution X-ray analysis and the structure has been solved to 0.196 nm [7-lo]. The cloning of the gdh gene and the determination of its nucleotide sequence are important for deducing the complete amino acid sequence of the enzyme, for permitting a full interpretation of the molecular structure and for designing site-directed mutagenesis experiments. Conventional approaches for cloning the gdh gene of C. symbiosum
Comparative Biochemistry and Physiology Part A: Physiology, 1983
... 71A. ~o. 3. ph. 763 to -16~. 19s 3 "rtnt,cl )n Great lBritain. upon-96-9 st u'tu63-... more ... 71A. ~o. 3. ph. 763 to -16~. 19s 3 "rtnt,cl )n Great lBritain. upon-96-9 st u'tu63-u;s03.0n o I`1 Pereamon Pre Ltd THE PRESENCE OF INSULIN-LIKE HORMONE IN HEADS AND MIDGUTS OF TENEBRIO iWOLITOR L. (COLEOPTERA) LARVAE JK Tet.LI-RG ROSIN~SKi. L. Pit.(. ...
With advances in the understanding of the pathophysiology of dystonia, novel therapeutics are bei... more With advances in the understanding of the pathophysiology of dystonia, novel therapeutics are being developed. Such therapies will require clinical investigation ranging from exploratory studies to examine safety, tolerability, dosage selection, and preliminary efficacy to confirmatory studies to evaluate efficacy definitively. As dystonia is a rare and complex disorder with clinical and etiological heterogeneity, clinical trials will require careful consideration of the trial design, including enrollment criteria, concomitant medication use, and outcome measures. Given the complexities of designing and implementing efficient clinical trials, it is important for clinicians and statisticians to collaborate closely throughout the clinical development process and that each has a basic understanding of both the clinical and statistical issues that must be addressed. To facilitate designing appropriate clinical trials in this field, we review important general clinical trial and regulatory principles, and discuss the critical components of trials with an emphasis on considerations specific to dystonia. Additionally, we discuss designs used in early exploratory, late exploratory, and confirmatory phases, including adaptive designs.
Proceedings of the National Academy of Sciences, 1998
We have characterized the interaction between apolipoprotein E (apoE) and amyloid β peptide (Aβ) ... more We have characterized the interaction between apolipoprotein E (apoE) and amyloid β peptide (Aβ) 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 Aβ peptides ending at residues 40 and 42. The apoE–Aβ 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 Aβ bound to apoE is more sensitive to protease digestion than is the unbound Aβ. Taken together, our results indicate that in normal brains apoE efficiently binds and sequesters Aβ, preventing its aggregation. In AD, the impaired apoE–Aβ binding leads to the critical accumulation of Aβ, facilitating plaque format...
The major amyloid beta (Aβ) peptides found in the brain of familial and late onset Alzheimer's di... more The major amyloid beta (Aβ) peptides found in the brain of familial and late onset Alzheimer's disease include the full-length Aβ1-42 and N-terminally truncated, pyroglutamylated peptides Aβp3-42 and Aβp11-42. The biophysical properties of Aβ1-42 have been extensively studied, yet little is known about the other modified peptides. We investigated the aggregation kinetics of brainspecific Aβ peptides to better understand their potential roles in plaque formation. Synthetic peptides were analyzed individually and in mixtures representing various ratios found in the brain. Spectrofluorometric analyses using Thioflavin-T showed that the aggregation of Aβ1-42 was faster compared to Aβp3-42; however, Aβp11-42 displayed similar kinetics. Surprisingly, mixtures of fulllength Aβ1-42 and Aβp3-42 showed an initial delay in beta-sheet formation from both equimolar and non-equimolar samples. Electron microscopy of peptides individually and in mixtures further supported fluorescence data. These results indicate that Aβ-Aβ peptide interactions involving different forms may play a critical role in senile plaque formation and maintenance of the soluble Aβ pool in the brain.
Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions ca... more Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal postures, repetitive movements, or both. Research in dystonia has been challenged by several factors. First, dystonia is uncommon. Dystonia is not a single disorder but a family of heterogenous disorders with varied clinical manifestations and different causes. The different subtypes may be seen by providers in different clinical specialties including neurology, ophthalmology, otolaryngology, and others. These issues have made it difficult for any single center to recruit large numbers of subjects with specific types of dystonia for research studies in a timely manner. The Dystonia Coalition is a consortium of investigators that was established to address these challenges. Since 2009, the Dystonia Coalition has encouraged collaboration by engaging 56 sites across North America, Europe, Asia, and Australia. Its emphasis on collaboration has facilitated establishment of inte...
ABSTRACT Alzheimer's disease is characterized by accumulation in the brain of a family of... more ABSTRACT Alzheimer's disease is characterized by accumulation in the brain of a family of insoluble amyloid peptides (Abeta peptides), which are produced as a result of the normal processing of beta-amyloid precursor protein (beta-APP). Russo et al. claim that a truncated Abeta peptide that lacks the first ten amino acids accumulates in the brains of patients carrying a mutant form of pre-senilin 1 (PS1), a protein that is involved in cleavage of beta-APP. However, we have found that this same species is also overrepresented in Alzheimer's patients with mutations in beta-APP itself. Our findings do not support the conclusion of Russo et al. that pathogenic PS1 mutations may control cleavage of beta-APP by beta-secretase.
A putative catalytic aspartyl residue, Asp-165, in the active site of clostridial glutamate dehyd... more A putative catalytic aspartyl residue, Asp-165, in the active site of clostridial glutamate dehydrogenase has been replaced with serine by site-directed mutagenesis. The mutant enzyme is efficiently overexpressed in Escherichia coli as a soluble protein and can be successfully purified by the dye-ligand chromatographic procedure normally employed for the wild-type enzyme. By several criteria, including circular dichroism spectrum, sulphydryl reactivity with Ellman's reagent, crystallization and mobility in non-denaturing electrophoresis, the enzyme appears to be correctly folded. NAD+ protects the D165S mutant against modification by Ellman's reagent, suggesting unimpaired binding of coenzyme. In standard assays the specific activity is decreased 10(3)-fold in the reductive amination reaction and 10(5)-fold for oxidative deamination. Kinetic studies show that apparent Km values for NADH and 2-oxoglutarate are almost unchanged. The large reduction in the reaction rate coincid...
The Task Force for Nomenclature of Genetic Movement Disorders recently proposed a new system of n... more The Task Force for Nomenclature of Genetic Movement Disorders recently proposed a new system of naming genetically determined movement disorders. 1 These recommendations apply to a wide spectrum of movement disorders, including parkinsonisms, dystonias, choreas, paroxysmal movement disorders, cerebellar ataxias, and spastic paraplegias. We agree that current genetic classifications are cumbersome and "unsuitable" for accurate and comprehensive categorization of genetic movement disorders. We appreciate that the task force addressed the discordance between phenotype and list designation by assigning more appropriate phenotype-prefix relationships. They propose 29 DYT symbols for inherited dystonias that occur in isolation or combined with other movement disorders, designated by an additional symbol: PARK, CHOR, or NBIA. The task Relevant conflicts of interest/financial disclosures: Nothing to report.
Comparative Biochemistry and Physiology Part B: Comparative Biochemistry, 1983
Differential effects of Triton X-100 on Tenebrio molitor glutamate dehydrogenase measured in mito... more Differential effects of Triton X-100 on Tenebrio molitor glutamate dehydrogenase measured in mitochondrial preparations were dependent on osmotic properties of the assay medium. 2. Maximal velocities were reached at lower concentrations of 2-oxoglutarate for glutamate dehydrogenase in detergent-treated mitochondria as opposed to untreated preparations. There was an increase in affinity constants for compartmentalized enzyme. Hill coefficient remained unchanged for enzyme studied in the damaged mitochondria, but was lower for enzyme in intact mitochondria. 3. The results suggest that the tested concentrations of Triton X-100 had no effect on the catalytic properties of glutamate dehydrogenase. The changes observed were caused by increased accessibility of substrates to the enzyme after solubilization of mitochondrial membranes.
Comparative Biochemistry and Physiology Part B: Comparative Biochemistry, 1985
Insulin immunoreactivity and proteolytic activity in phosphate buffer and acid-ethanol extracts f... more Insulin immunoreactivity and proteolytic activity in phosphate buffer and acid-ethanol extracts from larval heads and midguts of the mealworm were measured. 2. These two types of extraction gave very different values of IRI in the same tissue. 3. By the use of direct and indirect methods strong degradation of ~25I-insulin by proteolytic enzymes active in neutral extracts was shown. 4. Differences in IRI were due to interferences in radioimmunoassay caused by co-extracted proteolytic enzymes. 5. It is not possible to determine IRI precisely in neutral extracts of insect tissues.
Comparative Biochemistry and Physiology Part B: Comparative Biochemistry, 1988
Glutamate dehydrogenase (GDH) purified from the mealworm fat body was investigated in the glutama... more Glutamate dehydrogenase (GDH) purified from the mealworm fat body was investigated in the glutamate synthesizing direction. 2. Kinetic constants for the NADH and NADPH linked reactions were determined in the presence and absence of the activator, ADP. 3. ADP has influenced maximal velocities, substrate constants and cooperativity coefficients. 4. Strong substrate inhibition was observed at high concentrations of all substrates. 5. GDH was also activated by leucine and EDTA, and inhibited by zinc ions. 6. The enzyme displays allosteric properties being precisely controlled by substrates and effector concentrations. 7. The kinetic properties of Tenebrio molitor GDH suggest the regulatory role of the enzyme in nitrogen and carbohydrate metabolism of the fat body.
Purpose of review-The dystonias are a family of related disorders with many different clinical ma... more Purpose of review-The dystonias are a family of related disorders with many different clinical manifestations and causes. This review summarizes recent developments regarding these disorders, focusing mainly on advances with direct clinical relevance from the past two years. Recent findings-The dystonias are generally defined by their clinical characteristics, rather than by their underlying genetic or neuropathological defects. The many varied clinical manifestations and causes contribute to the fact that they are one of the most poorly recognized of all movement disorders. A series of recent publications has addressed these issues offering a revised definition and more logical means for classifying the many subtypes. Our understanding of the genetic and neurobiological mechanisms responsible for different types of dystonias also has grown rapidly, creating new opportunities and challenges for diagnosis and identifying increasing numbers of rare subtypes for which specific treatments are available. Summary-Recent advances in describing the clinical phenotypes and determining associated genotypes have pointed to the need for new strategies for diagnosis, classification and treatment of the dystonias.
The gene encoding the NAD +-dependent glutamate dehydrogenase (GDH) of Clostridium symbiosum was ... more The gene encoding the NAD +-dependent glutamate dehydrogenase (GDH) of Clostridium symbiosum was cloned using the polymerase chain reaction (PCR) because it could not be recovered by standard techniques. The nucleotide sequence of the gdh gene was determined and it was overexpressed from the controllable tac promoter in Escherichia coli so that active clostridial GDH represented 20% of total cell protein. The recombinant plasmid complemented the nutritional lesion of an E. coli glutamate auxotroph. There was a marked difference between the nucleotide compositions of the coding region (G + C = 52%) and the flanking sequences (G + C = 30% and 37%). The structural gene encoded a polypeptide of 450 amino acid residues and relative molecular mass (M,) 49 295 which corresponds to a single subunit of the hexameric enzyme. The DNA-derived amino acid sequence was consistent with a partial sequence from tryptic and cyanogen bromide peptides of the clostridial enzyme. The N-terminal amino acid sequence matched that of the purified protein, indicating that the initiating methionine is removed post-translationally, as in the natural host. The amino acid sequence is similar to those of other bacterial GDHs although it has a Gly-Xaa-Gly-Xaa-Xaa-Ala motif in the NADf-binding domain, which is more typical of the NADPf-dependent enzymes. The sequence data now permit a detailed interpretation of the X-ray crystallographic structure of the enzyme and the cloning and expression of the clostridial gene will facilitate sitedirected mutagenesis. The NAD +-dependent glutamate dehydrogenase (GDH) of Clostridium symbiosum catalyses the first step in the hydroxyglutarate pathway of glutamate fermentation 11, 21. This anaerobe is an abundant source of GDH, which amounts to approximately 1 5 % of the total cell protein during growth with glutamate. The enzyme has been purified and extensively characterized (3-51 and peptides representing about 75% of the primary structure have been sequenced 161. In addition, C. symbiosum GDH has been crystallized in a form suitable for high-resolution X-ray analysis and the structure has been solved to 0.196 nm [7-lo]. The cloning of the gdh gene and the determination of its nucleotide sequence are important for deducing the complete amino acid sequence of the enzyme, for permitting a full interpretation of the molecular structure and for designing site-directed mutagenesis experiments. Conventional approaches for cloning the gdh gene of C. symbiosum
Comparative Biochemistry and Physiology Part A: Physiology, 1983
... 71A. ~o. 3. ph. 763 to -16~. 19s 3 "rtnt,cl )n Great lBritain. upon-96-9 st u'tu63-... more ... 71A. ~o. 3. ph. 763 to -16~. 19s 3 "rtnt,cl )n Great lBritain. upon-96-9 st u'tu63-u;s03.0n o I`1 Pereamon Pre Ltd THE PRESENCE OF INSULIN-LIKE HORMONE IN HEADS AND MIDGUTS OF TENEBRIO iWOLITOR L. (COLEOPTERA) LARVAE JK Tet.LI-RG ROSIN~SKi. L. Pit.(. ...
With advances in the understanding of the pathophysiology of dystonia, novel therapeutics are bei... more With advances in the understanding of the pathophysiology of dystonia, novel therapeutics are being developed. Such therapies will require clinical investigation ranging from exploratory studies to examine safety, tolerability, dosage selection, and preliminary efficacy to confirmatory studies to evaluate efficacy definitively. As dystonia is a rare and complex disorder with clinical and etiological heterogeneity, clinical trials will require careful consideration of the trial design, including enrollment criteria, concomitant medication use, and outcome measures. Given the complexities of designing and implementing efficient clinical trials, it is important for clinicians and statisticians to collaborate closely throughout the clinical development process and that each has a basic understanding of both the clinical and statistical issues that must be addressed. To facilitate designing appropriate clinical trials in this field, we review important general clinical trial and regulatory principles, and discuss the critical components of trials with an emphasis on considerations specific to dystonia. Additionally, we discuss designs used in early exploratory, late exploratory, and confirmatory phases, including adaptive designs.
Proceedings of the National Academy of Sciences, 1998
We have characterized the interaction between apolipoprotein E (apoE) and amyloid β peptide (Aβ) ... more We have characterized the interaction between apolipoprotein E (apoE) and amyloid β peptide (Aβ) 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 Aβ peptides ending at residues 40 and 42. The apoE–Aβ 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 Aβ bound to apoE is more sensitive to protease digestion than is the unbound Aβ. Taken together, our results indicate that in normal brains apoE efficiently binds and sequesters Aβ, preventing its aggregation. In AD, the impaired apoE–Aβ binding leads to the critical accumulation of Aβ, facilitating plaque format...
The major amyloid beta (Aβ) peptides found in the brain of familial and late onset Alzheimer's di... more The major amyloid beta (Aβ) peptides found in the brain of familial and late onset Alzheimer's disease include the full-length Aβ1-42 and N-terminally truncated, pyroglutamylated peptides Aβp3-42 and Aβp11-42. The biophysical properties of Aβ1-42 have been extensively studied, yet little is known about the other modified peptides. We investigated the aggregation kinetics of brainspecific Aβ peptides to better understand their potential roles in plaque formation. Synthetic peptides were analyzed individually and in mixtures representing various ratios found in the brain. Spectrofluorometric analyses using Thioflavin-T showed that the aggregation of Aβ1-42 was faster compared to Aβp3-42; however, Aβp11-42 displayed similar kinetics. Surprisingly, mixtures of fulllength Aβ1-42 and Aβp3-42 showed an initial delay in beta-sheet formation from both equimolar and non-equimolar samples. Electron microscopy of peptides individually and in mixtures further supported fluorescence data. These results indicate that Aβ-Aβ peptide interactions involving different forms may play a critical role in senile plaque formation and maintenance of the soluble Aβ pool in the brain.
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