Martin_2012_J.Neurochem_120_440

Intracellular deposition of fibrillar aggregates of alpha-synuclein (alphaSyn) characterizes neurodegenerative diseases such as Parkinson's disease (PD) and dementia with Lewy bodies. However, recent evidence indicates that small alphaSyn oligomeric aggregates that precede fibril formation may be the most neurotoxic species and can be found extracellularly. This new evidence has changed the view of pathological alphaSyn aggregation from a self-contained cellular phenomenon to an extracellular event and prompted investigation of the putative effects of extracellular alphaSyn oligomers. In this study, we report that extracellular application of alphaSyn oligomers detrimentally impacts neuronal welfare and memory function. We found that oligomeric alphaSyn increased intracellular Ca(2+) levels, induced calcineurin (CaN) activity, decreased cAMP response element-binding protein (CREB) transcriptional activity and resulted in calcineurin-dependent death of human neuroblastoma cells. Similarly, CaN induction and CREB inhibition were observed when alphaSyn oligomers were applied to organotypic brain slices, which opposed hippocampal long-term potentiation. Furthermore, alphaSyn oligomers induced CaN, inhibited CREB and evoked memory impairments in mice that received acute intracerebroventricular injections. Notably, all these events were reversed by pharmacological inhibition of CaN. Moreover, we found decreased active CaN and reduced levels of phosphorylated CREB in autopsy brain tissue from patients affected by dementia with Lewy bodies, which is characterized by deposition of alphaSyn aggregates and progressive cognitive decline. These results indicate that exogenously applied alphaSyn oligomers impact neuronal function and produce memory deficits through mechanisms that involve CaN activation.