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

Intracellular accumulation of amyloid-beta (A beta) protein has been proposed as an early event in AD pathogenesis. In patients with mild cognitive impairment, intraneuronal A beta immunoreactivity was found especially in brain regions critically involved in the cognitive deficits of AD. Although a large body of evidence demonstrates that A beta 42 accumulates intraneuronally ((in)A beta), the action and the role of A beta 42 buildup on synaptic function have been poorly investigated. Here, we demonstrate that basal synaptic transmission and LTP were markedly depressed following A beta 42 injection into the neuron through the patch pipette. Control experiments performed with the reverse peptide (A beta 42-1) allowed us to exclude that the effects of (in)A beta depended on changes in oncotic pressure. To further investigate (in)A beta synaptotoxicity we used an A beta variant harboring oxidized methionine in position 35 that does not cross the neuronal plasma membrane and is not uploaded from the extracellular space. This A beta 42 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 A beta 42 (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 A beta 42. Collectively, these findings suggest that A beta 42-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 A beta 42.