Evidence that synaptically released β-amyloid accumulates as extracellular deposits in the hippocampus of transgenic mice

Orly Lazarov, Michael Lee, Daniel A. Peterson, Sangram S. Sisodia

Research output: Contribution to journalArticlepeer-review

241 Scopus citations

Abstract

A neuropathological hallmark of Alzheimer's disease is the deposition of amyloid-β (Abeta;) 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.

Original languageEnglish (US)
Pages (from-to)9785-9793
Number of pages9
JournalJournal of Neuroscience
Volume22
Issue number22
DOIs
StatePublished - Nov 15 2002

Keywords

  • Alzheimer's disease
  • Amyloid deposition
  • Amyloid precursor protein
  • Hippocampus
  • Perforant pathway
  • Synapse

Fingerprint Dive into the research topics of 'Evidence that synaptically released β-amyloid accumulates as extracellular deposits in the hippocampus of transgenic mice'. Together they form a unique fingerprint.

Cite this