Abstract
Recent studies indicate that soluble β-amyloid (sAβ) oligomers, rather than their fibrillar aggregates, contribute to the pathogenesis of Alzheimer's disease (AD), though the mechanisms of their neurotoxicity are still elusive. Here, we demonstrate that sAβ derived from 7PA2 cells exert a much stronger effect on the regulation of a set of functionally validated microRNAs (miRNAs) in primary cultured neurons than the synthetic insoluble Aβ fibrils (fAβ). Synthetic sAβ peptides at a higher concentration present comparable effect on these miRNAs in our neuronal model. Further, the sAβ-induced miR-134, miR-145 and miR-210 expressions are fully reversed by two selective N-methyl-d-aspartate (NMDA) receptor inhibitors, but are neither reversed by insulin nor by forskolin, suggesting an NMDA receptor-dependent, rather than PI3K/AKT or PKA/CREB signaling dependent regulatory mechanism. In addition, the repression of miR-107 expression by the sAβ containing 7PA2 CM is likely involved multiple mechanisms and multiple players including NMDA receptor, N-terminally truncated Aβ and reactive oxygen species (ROS).
Highlights
Alzheimer’s disease (AD) is pathologically characterized by extracellular amyloid plaques and cytoplasmic tau tangles, which are believed to contribute to neurodegeneration and cognitive impairment [1]
To address the possibility of these N terminal APP fragments in the regulation of these miRNAs, we examined the effect of 7PA2 CM after immunodepleted with 1G6 that recognizes the APP epitopes N-terminally proximal to the beta-secretase 1 (BACE1) cleavage site, or with 22C11 that recognizes amino acid 66–81 of the N terminus on APP
We observed that the deregulations of certain miRNAs that have been previously identified in human AD brains could be reproduced in our primary neuronal model of rodent brains through treatment with soluble Ab (sAb) from both natural and synthetic sources
Summary
Alzheimer’s disease (AD) is pathologically characterized by extracellular amyloid plaques and cytoplasmic tau tangles, which are believed to contribute to neurodegeneration (synapse loss and cell death) and cognitive impairment [1]. Overwhelming new evidence supports soluble Ab (sAb) oligomers as an early trigger of synaptic damage and cognitive impairment in AD. These include the weak correlation between the fAb and synaptic loss, neuronal death, or cognitive impairment [3,4,5], the strong correlation between sAb levels and the severity of neuropathological changes in AD, as well as the potent ability of sAb to cause synaptic failure and cognitive function disruption [6,7]. Exposure of hippocampal neurons to synthetic Ab [8] or to cell-derived sAb [9] induce progressive synaptic loss. The exact mechanisms underlying how sAb lead to neuronal dysfunction remain only partially understood
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