Amyloid b-Protein Fragments and Related Peptides
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Amyloid b-Protein Fragments and Related Peptides
Definition
Alzheimer's disease (AD) is one of the most common forms of senile dementia, whose pathogenetic basis is related to the presence of amyloid ß-peptide (Aß), a ß-sheet peptide formed by 39-43-amino acid residues that aggregates in the brain to form the major component of characteristic deposits known as senile plaques.
Discovery
Histopathological studies of affected brain regions in AD patients typically show neurofibrillary tangles (NFTs) in both dying and already degenerated neurons and senile plaques. The senile plaques are often surrounded by dystrophic neurites, activated microglia and reactive astrocytes. The major protein component of the core of the senile plaques is Aß, a 39±43 amino acid-long peptide derived from the larger amyloid b-protein precursor (APP), a ubiquitously expressed transmembrane glycoprotein, as shown by Glenner and Wong, 1984 1.
Structural Characteristics
Aß is formed after sequential cleavage of the amyloid precursor protein, a transmembrane glycoprotein of undetermined function. The ? secretase, which produces the C-terminal end of the Aß peptide, cleaves within the transmembrane region of APP and can generate a number of isoforms of 39-43 amino acid residues in length. The 40-amino acid form of Aß (Aß40) accounts for %u02DC90% of all Aß normally released from cells, it appears to contribute only to later phases of the pathology. In contrast, the longer more amyloidogenic 42-residue form (Aß42), accounting for only %u02DC10% of secreted Aß, is deposited in the earliest phase of AD and remains the major constituent of most amyloid plaques throughout the disease. Moreover, its levels have been shown to be increased in all known forms of early-onset familial AD. Aß fragment 25-35 and Aß fragment 31-35, dose-dependently potentiate long term depression 2.
Mode of Action
Aß (31-35) and Aß (25-35) fragments of amyloid beta-protein induce cellular death through apoptotic signals: Exposure of isolated rat brain mitochondria to Aß(31-35) and Aß(25-35) peptides determine release of cytochrome c; mitochondrial swelling and a significant reduction in mitochondrial oxygen consumption. In contrast, the amplitude of these events, the isolated brain mitochondria exposed to the Aß(31-35)Met35, the methionine-35 was oxidized to methionine sulfoxide3. Taken together our result indicate that Aß(31-35) and Aß(25-35) peptides in non-aggregated form, i.e., predominantly monomeric, are strongly neurotoxic, having the ability to enter within the cells, determining mitochondrial damage with an evident trigger of apoptotic signals.
Functions
Oxidative Stress and Neurotoxicity for Alzheimer's Aß(1-42) and Aß(25-35): The mechanism by which the predominant form of Aß found in AD brains, Aß(1-42), causes oxidative stress and neurotoxicity remains unknown. Numerous laboratories have used the smaller 11-amino acid fragment of the full-length peptide, Aß(25-35), as a convenient alternative in AD investigations since the smaller peptide mimics several of the toxicological and oxidative stress properties of the native full-length peptide.The studies reveal that two different mechanisms may be operative in the two peptides; however, the single methionine residue in the peptides appears to play a crucial role in both mechanisms. That methionine is C-terminal in Aß(25-35) seems to be the cause for its exaggerated effects. When the next amino acid in the sequence of Aß(1-42) (valine) is appended to Aß(25-35), the resultant peptide, Aß(25-36), in which methionine is no longer C-terminal, is neither toxic to cultured neuron nor does it cause oxidative damage4. Additionally, oxidizing the sulfur of methionine to a sulfoxide abrogates the damaging effects of both Aß(25-35) and Aß(1-42).
ß-amyloid peptide fragment 31-35 induces apoptosis in cultured cortical neurons: In a study, a synthetic fragment 31-35 of ß-amyloid peptide was used in cultured cortical neurons to examine whether this smaller sequence could trigger apoptotic degeneration in vitro by using morphological, biochemical and flow-cytometric examinations. The results showed that: neurons treated with fragment 31-35 of ß-amyloid peptide exhibited membrane blebbing, compaction of nuclear chromatin, nuclear shrinkage and nuclear fragmentation; a typical DNA ladder was revealed by agarose gel electrophoresis following fragment 31-35 of ß-amyloid peptide exposure. Furthermore, the internucleosome DNA fragmentation was also detected by flow-cytometric examination following fragment 31-35 of ß-amyloid peptide exposure; and the DNA fragmentation induced by fragment 31-35 of ß-amyloid peptide could be blocked by co-treatment with aurintricarboxylic acid or actinomycin D. It is suggested that fragment 31-35 of the ß-amyloid peptide may be a shorter sequence of ß-amyloid peptide responsible for triggering an apoptotic process in cultured neurons5.
References
1. Glenner GG, Wong CW (1984). Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem. Biophys. Res. Commun., 120:885-890.
2. Cheng L, Yin WJ, Zhang JF, Qi JS (2009). Amyloid ß -protein fragments 25-35 and 31-35 potentiate long-term depression in hippocampal CA1 region of rats in vivo. Synapse., 63:206-214.
3. Clementi ME, Marini S, Coletta M, Orsini F, Giardina B, Misiti F (2005). Aß(31-35) and Aß(25-35) fragments of amyloid beta-protein induce cellular death through apoptotic signals: Role of the redox state of methionine-35. FEBS Letters., 579(13):2913-2918.
4. Varadarajan S, Kanski J, Aksenova M, Lauderback C, Butterfield DA (2001). Different Mechanisms of Oxidative Stress and Neurotoxicity for Alzheimer's Aß(1-42) and Aß(25-35). J. Am. Chem. Soc., 123(24):5625-5631.
5. Yan XZ, Qiao JT, Dou Y, Qiao ZD (1999). ß-amyloid peptide fragment 31-35 induces apoptosis in cultured cortical neurons. Neuroscience., 92(1):177-184.
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Alzheimer's disease (AD) is one of the most common forms of senile dementia, whose pathogenetic basis is related to the presence of amyloid ß-peptide (Aß), a ß-sheet peptide formed by 39-43-amino acid residues that aggregates in the brain to form the major component of characteristic deposits known as senile plaques.
Discovery
Histopathological studies of affected brain regions in AD patients typically show neurofibrillary tangles (NFTs) in both dying and already degenerated neurons and senile plaques. The senile plaques are often surrounded by dystrophic neurites, activated microglia and reactive astrocytes. The major protein component of the core of the senile plaques is Aß, a 39±43 amino acid-long peptide derived from the larger amyloid b-protein precursor (APP), a ubiquitously expressed transmembrane glycoprotein, as shown by Glenner and Wong, 1984 1.
Structural Characteristics
Aß is formed after sequential cleavage of the amyloid precursor protein, a transmembrane glycoprotein of undetermined function. The ? secretase, which produces the C-terminal end of the Aß peptide, cleaves within the transmembrane region of APP and can generate a number of isoforms of 39-43 amino acid residues in length. The 40-amino acid form of Aß (Aß40) accounts for %u02DC90% of all Aß normally released from cells, it appears to contribute only to later phases of the pathology. In contrast, the longer more amyloidogenic 42-residue form (Aß42), accounting for only %u02DC10% of secreted Aß, is deposited in the earliest phase of AD and remains the major constituent of most amyloid plaques throughout the disease. Moreover, its levels have been shown to be increased in all known forms of early-onset familial AD. Aß fragment 25-35 and Aß fragment 31-35, dose-dependently potentiate long term depression 2.
Mode of Action
Aß (31-35) and Aß (25-35) fragments of amyloid beta-protein induce cellular death through apoptotic signals: Exposure of isolated rat brain mitochondria to Aß(31-35) and Aß(25-35) peptides determine release of cytochrome c; mitochondrial swelling and a significant reduction in mitochondrial oxygen consumption. In contrast, the amplitude of these events, the isolated brain mitochondria exposed to the Aß(31-35)Met35, the methionine-35 was oxidized to methionine sulfoxide3. Taken together our result indicate that Aß(31-35) and Aß(25-35) peptides in non-aggregated form, i.e., predominantly monomeric, are strongly neurotoxic, having the ability to enter within the cells, determining mitochondrial damage with an evident trigger of apoptotic signals.
Functions
Oxidative Stress and Neurotoxicity for Alzheimer's Aß(1-42) and Aß(25-35): The mechanism by which the predominant form of Aß found in AD brains, Aß(1-42), causes oxidative stress and neurotoxicity remains unknown. Numerous laboratories have used the smaller 11-amino acid fragment of the full-length peptide, Aß(25-35), as a convenient alternative in AD investigations since the smaller peptide mimics several of the toxicological and oxidative stress properties of the native full-length peptide.The studies reveal that two different mechanisms may be operative in the two peptides; however, the single methionine residue in the peptides appears to play a crucial role in both mechanisms. That methionine is C-terminal in Aß(25-35) seems to be the cause for its exaggerated effects. When the next amino acid in the sequence of Aß(1-42) (valine) is appended to Aß(25-35), the resultant peptide, Aß(25-36), in which methionine is no longer C-terminal, is neither toxic to cultured neuron nor does it cause oxidative damage4. Additionally, oxidizing the sulfur of methionine to a sulfoxide abrogates the damaging effects of both Aß(25-35) and Aß(1-42).
ß-amyloid peptide fragment 31-35 induces apoptosis in cultured cortical neurons: In a study, a synthetic fragment 31-35 of ß-amyloid peptide was used in cultured cortical neurons to examine whether this smaller sequence could trigger apoptotic degeneration in vitro by using morphological, biochemical and flow-cytometric examinations. The results showed that: neurons treated with fragment 31-35 of ß-amyloid peptide exhibited membrane blebbing, compaction of nuclear chromatin, nuclear shrinkage and nuclear fragmentation; a typical DNA ladder was revealed by agarose gel electrophoresis following fragment 31-35 of ß-amyloid peptide exposure. Furthermore, the internucleosome DNA fragmentation was also detected by flow-cytometric examination following fragment 31-35 of ß-amyloid peptide exposure; and the DNA fragmentation induced by fragment 31-35 of ß-amyloid peptide could be blocked by co-treatment with aurintricarboxylic acid or actinomycin D. It is suggested that fragment 31-35 of the ß-amyloid peptide may be a shorter sequence of ß-amyloid peptide responsible for triggering an apoptotic process in cultured neurons5.
References
1. Glenner GG, Wong CW (1984). Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem. Biophys. Res. Commun., 120:885-890.
2. Cheng L, Yin WJ, Zhang JF, Qi JS (2009). Amyloid ß -protein fragments 25-35 and 31-35 potentiate long-term depression in hippocampal CA1 region of rats in vivo. Synapse., 63:206-214.
3. Clementi ME, Marini S, Coletta M, Orsini F, Giardina B, Misiti F (2005). Aß(31-35) and Aß(25-35) fragments of amyloid beta-protein induce cellular death through apoptotic signals: Role of the redox state of methionine-35. FEBS Letters., 579(13):2913-2918.
4. Varadarajan S, Kanski J, Aksenova M, Lauderback C, Butterfield DA (2001). Different Mechanisms of Oxidative Stress and Neurotoxicity for Alzheimer's Aß(1-42) and Aß(25-35). J. Am. Chem. Soc., 123(24):5625-5631.
5. Yan XZ, Qiao JT, Dou Y, Qiao ZD (1999). ß-amyloid peptide fragment 31-35 induces apoptosis in cultured cortical neurons. Neuroscience., 92(1):177-184.
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"The use of state-of-the art technology has allowed Bio-Synthesis, Inc. to rapidly gain recognition for its manufacturing quality & dependability of delivery."
Founded in 1984, Bio-Synthesis, Inc. was first known as OCS Laboratories. It was the first producer of commercially available synthetic DNA and, in 1985, became a producer of synthetic peptides. In 1989, OCS incorporated as Bio-Synthesis, Inc. and moved its laboratories to Lewisville, Texas. Today, BSI occupies 10,000 square feet of modern laboratory space (completed in 1995) located 20 miles from downtown Dallas and 10 miles from D/FW airport. Among the surrounding academic institutions are: University of Texas Southwestern Medical School (12 miles), University of North Texas (10 miles), and University of North Texas Health Science Center (25 miles). These universities provide excellent library resources. Since its inception, BSI has steadily expanded its product lines and services to meet the growing needs of the molecular biology community. It has maintained its position as an aggressive, innovative company in a highly competitive marketplace without sacrificing quality. In the beginning, our primary emphasis was on synthesizing high quality DNA primers and linkers, which were the initial uses of oligos. Today, newer technologies, such as gene construction, PCR, mutagenesis, combinatorial libraries, dye/adduct labeling, DNA microarrays, peptide-nucleic acid chimeras, etc. have challenged the molecular biology field. In response, BSI has branched into several related areas including DNA paternity testing, DNA HLA typing, PNA synthesis, genomic sequencing, fluorescence-based genotyping, custom organic synthesis and other molecular biology based applications.
The Research and Development Division comprises a number of Ph.D. and M.D. professionals with backgrounds in molecular biology, immunology, nucleic acids, peptide synthesis, general organic chemistry, and automated amino acid sequencing. The Molecular Biology Division is set up to handle most modern experimental procedures; the Immunology Division specializes in immunodiagnostic-based reagents.
Not only has BSI continued to provide quality DNA products and services for the research community, but it has also become a world leader in providing custom peptide products and services. Using state-of-the-art solid phase peptide chemistries, BSI provides high quality custom peptides, performs carrier conjugations, antipeptide antibody production, antigenic peptide design, synthesis of long and/or modified peptides, MALDI TOF analysis, contract research, consultation services and more.
Biomedical researchers worldwide in universities, biotech companies, private clinics, and government agencies use products from Bio-Synthesis, Inc. in studies ranging from PCR diagnostics to cancer research and the Human Genome Project. Contact us to discover how BSI can customize products/services to suit your research requirements.
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Address: 612 E. Main street
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Phone Number: 972-420-8505
Founded in 1984, Bio-Synthesis, Inc. was first known as OCS Laboratories. It was the first producer of commercially available synthetic DNA and, in 1985, became a producer of synthetic peptides. In 1989, OCS incorporated as Bio-Synthesis, Inc. and moved its laboratories to Lewisville, Texas. Today, BSI occupies 10,000 square feet of modern laboratory space (completed in 1995) located 20 miles from downtown Dallas and 10 miles from D/FW airport. Among the surrounding academic institutions are: University of Texas Southwestern Medical School (12 miles), University of North Texas (10 miles), and University of North Texas Health Science Center (25 miles). These universities provide excellent library resources. Since its inception, BSI has steadily expanded its product lines and services to meet the growing needs of the molecular biology community. It has maintained its position as an aggressive, innovative company in a highly competitive marketplace without sacrificing quality. In the beginning, our primary emphasis was on synthesizing high quality DNA primers and linkers, which were the initial uses of oligos. Today, newer technologies, such as gene construction, PCR, mutagenesis, combinatorial libraries, dye/adduct labeling, DNA microarrays, peptide-nucleic acid chimeras, etc. have challenged the molecular biology field. In response, BSI has branched into several related areas including DNA paternity testing, DNA HLA typing, PNA synthesis, genomic sequencing, fluorescence-based genotyping, custom organic synthesis and other molecular biology based applications.
The Research and Development Division comprises a number of Ph.D. and M.D. professionals with backgrounds in molecular biology, immunology, nucleic acids, peptide synthesis, general organic chemistry, and automated amino acid sequencing. The Molecular Biology Division is set up to handle most modern experimental procedures; the Immunology Division specializes in immunodiagnostic-based reagents.
Not only has BSI continued to provide quality DNA products and services for the research community, but it has also become a world leader in providing custom peptide products and services. Using state-of-the-art solid phase peptide chemistries, BSI provides high quality custom peptides, performs carrier conjugations, antipeptide antibody production, antigenic peptide design, synthesis of long and/or modified peptides, MALDI TOF analysis, contract research, consultation services and more.
Biomedical researchers worldwide in universities, biotech companies, private clinics, and government agencies use products from Bio-Synthesis, Inc. in studies ranging from PCR diagnostics to cancer research and the Human Genome Project. Contact us to discover how BSI can customize products/services to suit your research requirements.
For more detail please visit About Us
Please Contact Us :
Address: 612 E. Main street
City: Lewisville
State: Texas
Country: USA
Postal Code: 75057
Phone Number: 972-420-8505
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