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      Evidence That Synaptically Released β-Amyloid Accumulates as Extracellular Deposits in the Hippocampus of Transgenic Mice

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          Abstract

          A neuropathological hallmark of Alzheimer's disease is the deposition of amyloid-β (Aβ) peptides in senile plaques in the hippocampus and cerebral cortex. Aβ 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 Aβ peptides at these sites was indeterminate. To test the hypothesis that APP-CTFs, generated from axonally transported APP, are further metabolized to Aβ 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 Aβ 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 Aβ deposits are dynamic structures and that the perforant path lesion alters the equilibrium between Aβ production–deposition toward clearance as a consequence of blocked axonal transport of APP from the entorhinal cortex to terminal fields in the hippocampus.

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          Author and article information

          Journal
          J Neurosci
          J. Neurosci
          jneuro
          jneurosci
          J. Neurosci
          The Journal of Neuroscience
          Society for Neuroscience
          0270-6474
          1529-2401
          15 November 2002
          : 22
          : 22
          : 9785-9793
          Affiliations
          [ 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
          Article
          PMC6757836 PMC6757836 6757836 7029
          10.1523/JNEUROSCI.22-22-09785.2002
          6757836
          12427834
          400c1c4b-032f-44f1-8416-376cef20042a
          Copyright © 2002 Society for Neuroscience
          History
          : 22 May 2002
          : 16 August 2002
          : 16 August 2002
          Categories
          ARTICLE
          Cellular/Molecular
          Custom metadata
          5.00

          perforant pathway,synapse,hippocampus,amyloid deposition,amyloid precursor protein,Alzheimer's disease

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