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The Journal of Neuroscience, November 15, 2002, 22(22):9785-9793
Evidence That Synaptically Released  -Amyloid Accumulates as
Extracellular Deposits in the Hippocampus of Transgenic Mice
Orly
Lazarov1,
Michael
Lee2,
Daniel A.
Peterson3, and
Sangram S.
Sisodia1
1 Department of Neurobiology, Pharmacology, and
Physiology, The University of Chicago, Chicago, Illinois 60637, 2 Department of Pathology, The Johns Hopkins University
School of Medicine, Baltimore, Maryland 21205, and
3 Department of Neuroscience, The Chicago Medical School,
The Finch University, North Chicago, Illinois 60064
A neuropathological hallmark of Alzheimer's disease is the
deposition of amyloid- (A) peptides in senile plaques in the hippocampus and cerebral cortex. A is derived from larger integral membrane proteins termed amyloid precursor proteins (APP). We demonstrated previously that APP, synthesized by neurons in the entorhinal cortex, is transported via the perforant pathway to presynaptic terminals in the dentate gyrus. We reported that, although
full-length APP and membrane-tethered, C-terminal APP derivatives
(APP-CTFs) accumulate at terminal fields, the production of A
peptides at these sites was indeterminate. To test the hypothesis that
APP-CTFs, generated from axonally transported APP, are further metabolized to A peptides that are subsequently released and deposited proximal to nerve terminals, we created unilateral knife lesions of the perforant pathway of transgenic mice that exhibit hippocampal amyloid deposits. We observed pronounced reductions in
amyloid burden in the ipsilateral dentate gyrus, findings that lead us
to conclude that axonally transported APP gives rise to A peptides
that are released from presynaptic sites in the dentate gyrus and
deposited in extracellular plaques. Moreover, our findings are
consistent with the view that A deposits are dynamic structures and
that the perforant path lesion alters the equilibrium between A
production-deposition toward clearance as a consequence of blocked
axonal transport of APP from the entorhinal cortex to terminal fields
in the hippocampus.
Key words:
Alzheimer's disease; amyloid precursor protein; amyloid
deposition; perforant pathway; hippocampus; synapse
Copyright © 2002 Society for Neuroscience 0270-6474/02/22229785-09$05.00/0
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