Disruption of corticocortical connections ameliorates amyloid burden in terminal fields in a transgenic model of Aβ amyloidosis

Jin G. Sheng, Donald L. Price, Vassilis E. Koliatsos

Research output: Contribution to journalArticlepeer-review

Abstract

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 β peptide (Aβ) domain. The present study was designed to test the hypothesis that APP derived from ERC neurons is the source of the Aβ peptide deposited in the hippocampal dentate gyrus in Alzheimer's disease (AD) and in transgenic mice with Aβ amyloidosis. We used mice harboring two familial AD-linked genes (human APP Swedish and presenilin1-ΔE9), in which levels of Aβ (especially Aβ42) 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 Aβ burden were significantly reduced by ∼40 and 45%, respectively, in the dentate gyrus compared with the contralateral side. Reductions in APP and Aβ 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 Aβ 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 Aβ in the dentate gyrus, and they suggest an important role of corticocortical and corticolimbic forward connections in determining patterns of amyloid deposition in AD.

Original languageEnglish (US)
Pages (from-to)9794-9799
Number of pages6
JournalJournal of Neuroscience
Volume22
Issue number22
DOIs
StatePublished - Nov 15 2002

Keywords

  • APP
  • Alzheimer's disease
  • Axonal transport
  • Entorhinal cortex
  • Perforant pathway
  • Senile plaques

ASJC Scopus subject areas

  • Neuroscience(all)

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