APP transgenic mice Tg2576 accumulate Aβ peptides that are distinct from the chemically modified and insoluble peptides deposited in Alzheimer's disease senile plaques

Walter Kalback, M. Desiree Watson, Tyler A. Kokjohn, Yu-Min Kuo, Nicole Weiss, Dean C. Luehrs, John Lopez, Daniel Brune, Sangram S. Sisodia, Matthias Staufenbiel, Mark Emmerling, Alex E. Roher

Research output: Contribution to journalArticle

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Abstract

The amyloid (Aβ) peptides generated in Hsiao's APP Tg2576 transgenic (Tg) mice are physically and chemically distinct from those characteristic of Alzheimer's disease (AD). Transgenic mouse Aβ peptides were purified using sequential size-exclusion and reverse-phase chromatographic systems and subjected to amino acid sequencing and mass spectrometry analyses. The mouse Aβ peptides lacked the extensive N-terminal degradations, posttranslational modifications, and cross-linkages abundant in the stable Aβ peptide deposits observed in AD. Truncated Aβ molecules appear to be generated in vivo by hydrolysis at multiple sites rather than by post-mortem C-terminal degradation. In contrast to AD amyloid cores, the Tg mice peptides were soluble in Tris-SDS-EDTA solutions, revealing both monomeric and SDS-stable oligomeric species of Aβ. In contrast to our report on Novartis Pharma APP23 Tg mice [Kuo et al. (2001) J. Biol. Chem. 276, 12991], which maintain high levels of soluble Aβ early on with later development of extensive vascular amyloid, Tg2576 mice exhibited an age-related elevation of soluble Aβ with relatively limited vascular amyloid deposition. The transgenic mouse levels of carboxy-terminal (CT) APP fragments were nearly 10-fold greater than those of human brains, and this condition may contribute to the unique pathology observed in these animals. Immunization of transgenic mice may act to prevent the pathological effects of βAPP overproduction by binding CT molecules or halting their processing to toxic forms, in addition to having any effects on Aβ itself. Thus, differences in disease evolution and biochemistry must be considered when using transgenic animals to evaluate drugs or therapeutic interventions intended to reduce the Aβ burden in Alzheimer's disease.

Original languageEnglish
Pages (from-to)922-928
Number of pages7
JournalBiochemistry
Volume41
Issue number3
DOIs
Publication statusPublished - 2002 Jan 22

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Amyloid Plaques
Transgenic Mice
Alzheimer Disease
Amyloid
Peptides
Animals
Blood Vessels
Immunization
Degradation
Biochemistry
Molecules
Poisons
Pathology
Genetically Modified Animals
Edetic Acid
Protein Sequence Analysis
Mass spectrometry
Post Translational Protein Processing
Hydrolysis
Brain

All Science Journal Classification (ASJC) codes

  • Biochemistry

Cite this

Kalback, Walter ; Watson, M. Desiree ; Kokjohn, Tyler A. ; Kuo, Yu-Min ; Weiss, Nicole ; Luehrs, Dean C. ; Lopez, John ; Brune, Daniel ; Sisodia, Sangram S. ; Staufenbiel, Matthias ; Emmerling, Mark ; Roher, Alex E. / APP transgenic mice Tg2576 accumulate Aβ peptides that are distinct from the chemically modified and insoluble peptides deposited in Alzheimer's disease senile plaques. In: Biochemistry. 2002 ; Vol. 41, No. 3. pp. 922-928.
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title = "APP transgenic mice Tg2576 accumulate Aβ peptides that are distinct from the chemically modified and insoluble peptides deposited in Alzheimer's disease senile plaques",
abstract = "The amyloid (Aβ) peptides generated in Hsiao's APP Tg2576 transgenic (Tg) mice are physically and chemically distinct from those characteristic of Alzheimer's disease (AD). Transgenic mouse Aβ peptides were purified using sequential size-exclusion and reverse-phase chromatographic systems and subjected to amino acid sequencing and mass spectrometry analyses. The mouse Aβ peptides lacked the extensive N-terminal degradations, posttranslational modifications, and cross-linkages abundant in the stable Aβ peptide deposits observed in AD. Truncated Aβ molecules appear to be generated in vivo by hydrolysis at multiple sites rather than by post-mortem C-terminal degradation. In contrast to AD amyloid cores, the Tg mice peptides were soluble in Tris-SDS-EDTA solutions, revealing both monomeric and SDS-stable oligomeric species of Aβ. In contrast to our report on Novartis Pharma APP23 Tg mice [Kuo et al. (2001) J. Biol. Chem. 276, 12991], which maintain high levels of soluble Aβ early on with later development of extensive vascular amyloid, Tg2576 mice exhibited an age-related elevation of soluble Aβ with relatively limited vascular amyloid deposition. The transgenic mouse levels of carboxy-terminal (CT) APP fragments were nearly 10-fold greater than those of human brains, and this condition may contribute to the unique pathology observed in these animals. Immunization of transgenic mice may act to prevent the pathological effects of βAPP overproduction by binding CT molecules or halting their processing to toxic forms, in addition to having any effects on Aβ itself. Thus, differences in disease evolution and biochemistry must be considered when using transgenic animals to evaluate drugs or therapeutic interventions intended to reduce the Aβ burden in Alzheimer's disease.",
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Kalback, W, Watson, MD, Kokjohn, TA, Kuo, Y-M, Weiss, N, Luehrs, DC, Lopez, J, Brune, D, Sisodia, SS, Staufenbiel, M, Emmerling, M & Roher, AE 2002, 'APP transgenic mice Tg2576 accumulate Aβ peptides that are distinct from the chemically modified and insoluble peptides deposited in Alzheimer's disease senile plaques', Biochemistry, vol. 41, no. 3, pp. 922-928. https://doi.org/10.1021/bi015685+

APP transgenic mice Tg2576 accumulate Aβ peptides that are distinct from the chemically modified and insoluble peptides deposited in Alzheimer's disease senile plaques. / Kalback, Walter; Watson, M. Desiree; Kokjohn, Tyler A.; Kuo, Yu-Min; Weiss, Nicole; Luehrs, Dean C.; Lopez, John; Brune, Daniel; Sisodia, Sangram S.; Staufenbiel, Matthias; Emmerling, Mark; Roher, Alex E.

In: Biochemistry, Vol. 41, No. 3, 22.01.2002, p. 922-928.

Research output: Contribution to journalArticle

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T1 - APP transgenic mice Tg2576 accumulate Aβ peptides that are distinct from the chemically modified and insoluble peptides deposited in Alzheimer's disease senile plaques

AU - Kalback, Walter

AU - Watson, M. Desiree

AU - Kokjohn, Tyler A.

AU - Kuo, Yu-Min

AU - Weiss, Nicole

AU - Luehrs, Dean C.

AU - Lopez, John

AU - Brune, Daniel

AU - Sisodia, Sangram S.

AU - Staufenbiel, Matthias

AU - Emmerling, Mark

AU - Roher, Alex E.

PY - 2002/1/22

Y1 - 2002/1/22

N2 - The amyloid (Aβ) peptides generated in Hsiao's APP Tg2576 transgenic (Tg) mice are physically and chemically distinct from those characteristic of Alzheimer's disease (AD). Transgenic mouse Aβ peptides were purified using sequential size-exclusion and reverse-phase chromatographic systems and subjected to amino acid sequencing and mass spectrometry analyses. The mouse Aβ peptides lacked the extensive N-terminal degradations, posttranslational modifications, and cross-linkages abundant in the stable Aβ peptide deposits observed in AD. Truncated Aβ molecules appear to be generated in vivo by hydrolysis at multiple sites rather than by post-mortem C-terminal degradation. In contrast to AD amyloid cores, the Tg mice peptides were soluble in Tris-SDS-EDTA solutions, revealing both monomeric and SDS-stable oligomeric species of Aβ. In contrast to our report on Novartis Pharma APP23 Tg mice [Kuo et al. (2001) J. Biol. Chem. 276, 12991], which maintain high levels of soluble Aβ early on with later development of extensive vascular amyloid, Tg2576 mice exhibited an age-related elevation of soluble Aβ with relatively limited vascular amyloid deposition. The transgenic mouse levels of carboxy-terminal (CT) APP fragments were nearly 10-fold greater than those of human brains, and this condition may contribute to the unique pathology observed in these animals. Immunization of transgenic mice may act to prevent the pathological effects of βAPP overproduction by binding CT molecules or halting their processing to toxic forms, in addition to having any effects on Aβ itself. Thus, differences in disease evolution and biochemistry must be considered when using transgenic animals to evaluate drugs or therapeutic interventions intended to reduce the Aβ burden in Alzheimer's disease.

AB - The amyloid (Aβ) peptides generated in Hsiao's APP Tg2576 transgenic (Tg) mice are physically and chemically distinct from those characteristic of Alzheimer's disease (AD). Transgenic mouse Aβ peptides were purified using sequential size-exclusion and reverse-phase chromatographic systems and subjected to amino acid sequencing and mass spectrometry analyses. The mouse Aβ peptides lacked the extensive N-terminal degradations, posttranslational modifications, and cross-linkages abundant in the stable Aβ peptide deposits observed in AD. Truncated Aβ molecules appear to be generated in vivo by hydrolysis at multiple sites rather than by post-mortem C-terminal degradation. In contrast to AD amyloid cores, the Tg mice peptides were soluble in Tris-SDS-EDTA solutions, revealing both monomeric and SDS-stable oligomeric species of Aβ. In contrast to our report on Novartis Pharma APP23 Tg mice [Kuo et al. (2001) J. Biol. Chem. 276, 12991], which maintain high levels of soluble Aβ early on with later development of extensive vascular amyloid, Tg2576 mice exhibited an age-related elevation of soluble Aβ with relatively limited vascular amyloid deposition. The transgenic mouse levels of carboxy-terminal (CT) APP fragments were nearly 10-fold greater than those of human brains, and this condition may contribute to the unique pathology observed in these animals. Immunization of transgenic mice may act to prevent the pathological effects of βAPP overproduction by binding CT molecules or halting their processing to toxic forms, in addition to having any effects on Aβ itself. Thus, differences in disease evolution and biochemistry must be considered when using transgenic animals to evaluate drugs or therapeutic interventions intended to reduce the Aβ burden in Alzheimer's disease.

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