Intracellular accumulation of amyloid-β (Aβ) protein plays a major role in Aβ-induced alterations of glutamatergic synaptic transmission and plasticity

Cristian Ripoli, Sara Cocco, Domenica D. Li Puma, Roberto Piacentini, Alessia Mastrodonato, Federico Scala, Daniela Puzzo, Marcello D’Ascenzo, Claudio Grassi

Research output: Contribution to journalArticle

Abstract

Intracellular accumulation of amyloid-β (Aβ) protein has been proposed as an early event in AD pathogenesis. In patients with mild cognitive impairment, intraneuronal Aβ immunoreactivity was found especially in brain regions critically involved in the cognitive deficits of AD. Although a large body of evidence demonstrates that Aβ42 accumulates intraneuronally (inAβ), the action and the role of Aβ42 buildup on synaptic function have been poorly investigated. Here, we demonstrate that basal synaptic transmission and LTP were markedly depressed following Aβ42 injection into the neuron through the patch pipette. Control experiments performed with the reverse peptide (Aβ42-1) allowed us to exclude that the effects of inAβ depended on changes in oncotic pressure. To further investigate inAβsynaptotoxicity we used an Aβ variant harboring oxidized methionine in position 35 that does not cross the neuronal plasma membrane and is not uploaded from the extracellular space. This Aβ42 variant had no effects on synaptic transmission and plasticity when applied extracellularly, but induced synaptic depression and LTP inhibition after patch-pipette dialysis. Finally, the injection of an antibody raised against human Aβ42 (6E10) in CA1 pyramidal neurons of mouse hippocampal brain slices and autaptic microcultures did not, per se, significantly affect LTP and basal synaptic transmission, but it protected against the toxic effects of extracellular Aβ42. Collectively, these findings suggest that Aβ42-induced impairment of glutamatergic synaptic function depends on its internalization and intracellular accumulation thus paving the way to a systemic proteomic analysis of intracellular targets/partners of Aβ42.

Original languageEnglish
Pages (from-to)12893-12903
Number of pages11
JournalJournal of Neuroscience
Volume34
Issue number38
DOIs
Publication statusPublished - Sep 17 2014

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Keywords

  • 6E10
  • Amyloid-β protein
  • Autaptic hippocampal neurons
  • Intraneuronal accumulation
  • Synaptic transmission
  • Whole-cell LTP

ASJC Scopus subject areas

  • Neuroscience(all)
  • Medicine(all)

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