APP Transgenic Mice Tg2576 Accumulate A Peptides That Are Distinct from the Chemically Modified and Insoluble Peptide
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- 作者：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 ; and Alex E. Roher
- 刊名：Biochemistry
- 出版年：2002
- 出版时间：January 22, 2002
- 年：2002
- 卷：41
- 期：3
- 页码：922 - 928
- 全文大小：89K
- 年卷期：v.41,no.3(January 22, 2002)
- ISSN：1520-4995
文摘
The amyloid (A
) peptides generated in Hsiao's APP Tg2576 transgenic (Tg) mice arephysically and chemically distinct from those characteristic of Alzheimer's disease (AD). Transgenicmouse A peptides were purified using sequential size-exclusion and reverse-phase chromatographicsystems and subjected to amino acid sequencing and mass spectrometry analyses. The mouse A peptideslacked the extensive N-terminal degradations, posttranslational modifications, and cross-linkages abundantin the stable A peptide deposits observed in AD. Truncated A molecules appear to be generated invivo by hydrolysis at multiple sites rather than by post-mortem C-terminal degradation. In contrast to ADamyloid cores, the Tg mice peptides were soluble in Tris-SDS-EDTA solutions, revealing both monomericand SDS-stable oligomeric species of A. 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 A early on withlater development of extensive vascular amyloid, Tg2576 mice exhibited an age-related elevation of solubleA 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 maycontribute to the unique pathology observed in these animals. Immunization of transgenic mice may actto prevent the pathological effects of APP overproduction by binding CT molecules or halting theirprocessing to toxic forms, in addition to having any effects on A itself. Thus, differences in diseaseevolution and biochemistry must be considered when using transgenic animals to evaluate drugs ortherapeutic interventions intended to reduce the A burden in Alzheimer's disease.
) peptides generated in Hsiao's APP Tg2576 transgenic (Tg) mice arephysically and chemically distinct from those characteristic of Alzheimer's disease (AD). Transgenicmouse A peptides were purified using sequential size-exclusion and reverse-phase chromatographicsystems and subjected to amino acid sequencing and mass spectrometry analyses. The mouse A peptideslacked the extensive N-terminal degradations, posttranslational modifications, and cross-linkages abundantin the stable A peptide deposits observed in AD. Truncated A molecules appear to be generated invivo by hydrolysis at multiple sites rather than by post-mortem C-terminal degradation. In contrast to ADamyloid cores, the Tg mice peptides were soluble in Tris-SDS-EDTA solutions, revealing both monomericand SDS-stable oligomeric species of A. 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 A early on withlater development of extensive vascular amyloid, Tg2576 mice exhibited an age-related elevation of solubleA 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 maycontribute to the unique pathology observed in these animals. Immunization of transgenic mice may actto prevent the pathological effects of APP overproduction by binding CT molecules or halting theirprocessing to toxic forms, in addition to having any effects on A itself. Thus, differences in diseaseevolution and biochemistry must be considered when using transgenic animals to evaluate drugs ortherapeutic interventions intended to reduce the A burden in Alzheimer's disease.