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The Journal of Neuroscience, November 15, 2002, 22(22):9794-9799
Disruption of Corticocortical Connections Ameliorates Amyloid
Burden in Terminal Fields in a Transgenic Model of A Amyloidosis
Jin G.
Sheng1,
Donald L.
Price1, 2, 3, and
Vassilis E.
Koliatsos1, 2, 3, 4
Departments of 1 Pathology (Division of
Neuropathology), 2 Neurology, 3 Neuroscience,
and 4 Psychiatry and Behavioral Sciences, The Johns Hopkins
University School of Medicine, Baltimore, Maryland 21205
We demonstrated previously that amyloid precursor protein (APP) is
anterogradely transported from the entorhinal cortex (ERC) to the
dentate gyrus via axons of the perforant pathway. In the terminal
fields of these inputs, APP undergoes proteolysis to generate
C-terminal fragments containing the entire amyloid  peptide (A)
domain. The present study was designed to test the hypothesis that APP
derived from ERC neurons is the source of the A peptide deposited in
the hippocampal dentate gyrus in Alzheimer's disease (AD) and in
transgenic mice with A amyloidosis. We used mice harboring
two familial AD-linked genes (human APP Swedish and
presenilin1- E9), in which levels of A (especially
A42) are elevated, leading to the formation of
amyloid plaques, and lesioned the ERC to interrupt the transport of APP
from ERC to hippocampus. Our results show that, on the side of ERC
lesion, numbers of APP-immunoreactive dystrophic neurites and A
burden were significantly reduced by ~40 and 45%, respectively, in
the dentate gyrus compared with the contralateral side. Reductions in
APP and A were more substantial in the molecular layer of the
dentate, i.e., a region that contains the ERC terminals, and were
associated with a parallel decrease in total APP and A measured by
Western blot and ProteinChip immunoassays. Silver and thioflavine staining confirmed the reduction of amyloid plaques on the side of
deafferentation. These results are consistent with the hypothesis that
ERC may be the primary source of amyloidogenic A in the dentate
gyrus, and they suggest an important role of corticocortical and
corticolimbic forward connections in determining patterns of amyloid
deposition in AD.
Key words:
Alzheimer's disease; A; APP; axonal transport; entorhinal cortex; perforant pathway; senile plaques
Copyright © 2002 Society for Neuroscience 0270-6474/02/22229794-06$05.00/0
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