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The Journal of Neuroscience, May 15, 2000, 20(10):3606-3611
Evidence for Seeding of  -Amyloid by Intracerebral Infusion of
Alzheimer Brain Extracts in -Amyloid Precursor Protein-Transgenic
Mice
Michael D.
Kane1,
William J.
Lipinski1,
Michael J.
Callahan1,
Feng
Bian1,
Robert A.
Durham1,
Roy D.
Schwarz1,
Alex E.
Roher2, and
Lary C.
Walker1
1 Neuroscience Therapeutics, Parke-Davis Research,
Division of Warner-Lambert, Ann Arbor, Michigan 48105, and
2 Haldeman Laboratory for Alzheimer's Disease Research,
Sun Health Research Institute, Sun City, Arizona 85372
Many neurodegenerative diseases are associated with the abnormal
sequestration of disease-specific proteins in the brain, but the events
that initiate this process remain unclear. To determine whether the
deposition of the  -amyloid peptide (A), a key pathological feature of Alzheimer's disease (AD), can be induced in
vivo, we infused dilute supernatants of autopsy-derived
neocortical homogenates from Alzheimer's patients unilaterally into
the hippocampus and neocortex of 3-month-old -amyloid precursor
protein (APP)-transgenic mice. Up to 4 weeks after the infusion
there was no A-deposition in the brain; however, after 5 months, the
AD-tissue-injected hemisphere of the transgenic mice had developed
profuse A-immunoreactive senile plaques and vascular deposits, some
of which were birefringent with Congo Red. There was limited deposition
of diffuse A also in the brains of APP-transgenic mice infused
with tissue from an age-matched, non-AD brain with mild
-amyloidosis, but none in mice receiving extract from a young
control case. A deposits also were not found in either
vehicle-injected or uninjected transgenic mice or in any nontransgenic
mice. The results show that cerebral -amyloid can be seeded
in vivo by a single inoculation of dilute AD brain
extract, demonstrating a key pathogenic commonality between -amyloidosis and other neurodegenerative diseases involving abnormal protein polymerization. The paradigm can be used to clarify the conditions that initiate in vivo -amyloidogenesis in
the brain and may yield a more authentic animal model of Alzheimer's
disease and other neurodegenerative disorders.
Key words:
Alzheimer's disease; amyloid; angiopathy; A; transgenic; prion; seeding; neurodegeneration; neuroinflammation; animal model; conformational disease
Copyright © 2000 Society for Neuroscience 0270-6474/00/20103606-06$05.00/0
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