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The Journal of Neuroscience, January 15, 2001, 21(2):372-381
Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's
Disease
Takeshi
Kawarabayashi1, 2,
Linda H.
Younkin1,
Takaomi
C.
Saido3,
Mikio
Shoji2,
Karen Hsiao
Ashe4, and
Steven G.
Younkin1
1 Mayo Clinic Jacksonville, Jacksonville, Florida
32224, 2 Department of Neurology, Gunma University, Gunma,
Japan 371-8511, 3 Proteolytic Neuroscience Laboratory,
RIKEN Brain Science Institute, Saitama, Japan 351-0198, and
4 Departments of Neurology and Neuroscience, Center for
Clinical and Molecular Neurobiology, University of Minnesota,
Minneapolis, Minnesota 55455
The accumulation of amyloid  protein (A) in the Tg2576 mouse
model of Alzheimer's disease (AD) was evaluated by ELISA,
immunoblotting, and immunocytochemistry. Changes in A begin at 6-7
months as SDS-insoluble forms of A42 and A40 that require formic
acid for solubilization appear. From 6 to 10 months, these
insoluble forms increase exponentially. As insoluble A appears,
SDS-soluble A decreases slightly, suggesting that it may be
converting to an insoluble form. Our data indicate that it is
full-length unmodified A that accumulates initially in Tg2576 brain.
SDS-resistant A oligomers and most A 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 A42 and A40
are easily detected in every animal, histopathology is minimal because
only isolated A 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 A42 and
A40 increase to levels like those observed in AD brains. Coincident with the marked deposition of A in brain, there is a decrease in CSF
A and a substantial, highly significant decrease in plasma A. If
a similar decline occurs in human plasma, it is possible that
measurement of plasma A may be useful as a premorbid biomarker for AD.
Key words:
Alzheimer's disease; neurodegeneration; Tg2576
transgenic animal model; amyloid protein; cerebrospinal
fluid; plasma
Copyright © 2001 Society for Neuroscience 0270-6474/01/212372-10$05.00/0
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