科研之友
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摘要
Synaptopathy underlying memory deficits in Alzheimer's disease (AD) is increasingly thought to be instigated by toxic oligomers of the amyloid beta peptide (A beta Os). Given the long latency and incomplete penetrance of AD dementia with respect to A beta pathology, we hypothesized that factors present in the CNS may physiologically protect neurons from the deleterious impact of A beta Os. Here we employed physically separated neuron-astrocyte cocultures to investigate potential non-cell autonomous neuroprotective factors influencing A beta O toxicity. Neurons cultivated in the absence of an astrocyte feeder layer showed abundant A beta O binding to dendritic processes and associated synapse deterioration. In contrast, neurons in the presence of astrocytes showed markedly reduced A beta O binding and synaptopathy. Results identified the protective factors released by astrocytes as insulin and insulinlike growth factor-1 (IGF1). The protective mechanism involved release of newly bound A beta Os into the extracellular medium dependent upon trafficking that was sensitive to exosome pathway inhibitors. Delaying insulin treatment led to A beta O binding that was no longer releasable. The neuroprotective potential of astrocytes was itself sensitive to chronic A beta O exposure, which reduced insulin/IGF1 expression. Our findings support the idea that physiological protection against synaptotoxic A beta Os can be mediated by astrocyte-derived insulin/IGF1, but that this protection itself is vulnerable to A beta O buildup.
