ERK/MAPK mediates beta-amyloid negative modulation of memory in an invertebrate model

FELD M; GALLI C; PICCINI A; ROMANO A

San Diego, California, estados Unidos

Congreso; Neuroscience 2007; 2007

Society for Neuroscience

The role of MAPK (mitogen-activated protein kinase) has been assessed in different models of synaptic plasticity and memory in vertebrates as well as in invertebrates, including Context-Signal Memory (CSM) of the crab Chasmagnathus. In this paradigm, we have recently demonstrated that long-term memory consolidation requires extra-nuclear ERK/MAPK phosphorylation 1 h after training. Amyloid β peptides (Aβ) are considered crucial agents of Alzheimer?s disease pathogenesis. Recently, it has been proposed that memory deficits are caused by different stages of Aβ aggregation, particularly by oligomers. Beyond its pathological role, it has been proposed that Aβ plays a physiological role as a synaptic transmission depressor in response to neuronal activity, as part of a negative-feedback mechanism. In addition, although memory impairment was found after Aβ administration in rodents and chicks, it is currently unknown whether these memory deficits can be induced in invertebrates.The present work was aimed at investigating the physiological role in memory of Aβ in invertebrates. We evaluated the effect of naturally secreted Aβ fibrils (nfAβ) and different synthetic Aβ peptides acute administration in a well characterized invertebrate memory model, the CSM. We also assessed the participation of different intracellular signalling pathways in the effect of nfAβ. We found a clear amnesic effect at very low doses of nfAβ only when administered immediately pre-and post-training, but not 24 h or 18 h before, or 6 h after training. nfAβ also induced nuclear and extra-nuclear ERK/MAPK activation 1 h after administration, but neither JNK/SAPK nor NF-κB transcription factor were activated. Furthermore, synthetic Aβ1-42 and Aβ3-42 administration induced amnesia when used after a protocol for fibrillation but not after a protocol for oligomerization. On the contrary, no amnestic effect was found when fibrillated Aβ1-40 and Aβ11-42 peptides were used.Thus, Aβ1-42 and Aβ3-42 peptides impaired memory and the effects were only found when fibrillated peptides were administered. The temporally- and signaling-specific effects of such low doses of fibrils suggest that Aβ impairs memory by inducing transient physiological, rather than permanent neuropathological, alterations of the brain. This effect seems to be achieved, at least in part, through generalized ERK activation, which otherwise would modulate memory consolidation.