Age-Dependent Changes in Brain, CSF, and Plasma Amyloid β Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease

Journal of Neuroscience - Tập 21 Số 2 - Trang 372-381 - 2001
Takeshi Kawarabayashi1,2, Linda H. Younkin2, Takaomi C. Saido3, Mikio Shoji4, Karen H. Ashe5, Steven G. Younkin6
1Gunma University
2Mayo Clinic, Jacksonville, FL
3RIKEN
4Gunma University#TAB#
5Departments of Neurology and Neuroscience, Center for Clinical and Molecular Neurobiology, University of Minnesota, Minneapolis, Minnesota 55455,
6Mayo Clinic Jacksonville, Jacksonville, Florida 32224

Tóm tắt

The accumulation of amyloid β protein (Aβ) in the Tg2576 mouse model of Alzheimer's disease (AD) was evaluated by ELISA, immunoblotting, and immunocytochemistry. Changes in Aβ begin at 6–7 months as SDS-insoluble forms of Aβ42 and Aβ40 that require formic acid for solubilization appear. From 6 to 10 months, these insoluble forms increase exponentially. As insoluble Aβ appears, SDS-soluble Aβ decreases slightly, suggesting that it may be converting to an insoluble form. Our data indicate that it is full-length unmodified Aβ that accumulates initially in Tg2576 brain. SDS-resistant Aβ oligomers and most Aβ species that are N-terminally truncated or modified develop only in older Tg2576 mice, in which they are present at levels far lower than in human AD brain. Between 6 and 10 months, when SDS-insoluble Aβ42 and Aβ40 are easily detected in every animal, histopathology is minimal because only isolated Aβ cores can be identified. By 12 months, diffuse plaques are evident. From 12 to 23 months, diffuse plaques, neuritic plaques with amyloid cores, and biochemically extracted Aβ42 and Aβ40 increase to levels like those observed in AD brains. Coincident with the marked deposition of Aβ in brain, there is a decrease in CSF Aβ and a substantial, highly significant decrease in plasma Aβ. If a similar decline occurs in human plasma, it is possible that measurement of plasma Aβ may be useful as a premorbid biomarker for AD.

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Tài liệu tham khảo

10.1001/archneur.56.6.673

10.1016/S0896-6273(00)80230-5

10.1126/science.8424174

Carp, 1971, A method for obtaining cerebrospinal fluid from mice., Res Vet Sci, 12, 499, 10.1016/S0034-5288(18)34150-X

10.1038/6374

10.1038/353844a0

10.1073/pnas.91.25.11993

10.1038/nm0197-67

10.1038/383710a0

10.1016/S0002-9440(10)65273-X

Funato, 1998, Quantitation of amyloid β-protein (Aβ) in the cortex during aging and in Alzheimer's disease., Am J Pathol, 152, 1633

10.1046/j.1471-4159.1996.67020880.x

10.1016/S0006-291X(84)80190-4

10.1038/349704a0

10.1074/jbc.270.13.7013

10.1097/00005072-199811000-00012

10.1126/science.274.5284.99

10.1097/00005072-199709000-00002

10.1016/S0197-4580(98)00015-3

10.1016/0896-6273(94)90458-8

10.1021/bi00069a001

10.1002/ana.410440108

10.1038/325733a0

10.1016/0197-4580(95)02061-6

Kuo, 1998, Irreversible dimerization/tetramerization and post-translational modifications inhibit proteolytic degradation of Aβ peptides of Alzheimer's disease., Biochim Biophys Acta, 1406, 291, 10.1016/S0925-4439(98)00014-3

10.1126/science.7638621

10.1073/pnas.82.12.4245

10.1002/1531-8249(199904)45:4<537::AID-ANA20>3.0.CO;2-2

10.1002/ana.410380413

10.1038/ng0892-345

10.1126/science.1925564

10.1002/ana.410370414

Roher, 1993, Structural alterations in the peptide backbone of β-amyloid core protein may account for its deposition and stability in Alzheimer's disease., J Biol Chem, 268, 3072, 10.1016/S0021-9258(18)53661-9

10.1016/0896-6273(95)90301-1

10.1016/0304-3940(96)12970-0

10.1038/nm0896-864

10.1038/375754a0

10.1126/science.8191290

Westerman, 2000, Age-dependent behavioral deficit in a transgenic mouse model of Alzheimer's disease., Soc Neurosci Abstr, 26, 1318

Younkin, 1998, Genetic elevation of plasma amyloid β protein in typical late onset Alzheimer's disease., Soc Neurosci Abstr, 24, 263

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Journal of Neuroscience

Tập 21 Số 2

372-381

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