Abstract
Secreted amyloid precursor protein-α (sAPPα) is a neuroprotective and memory-enhancing molecule, however, the mechanisms through which sAPPα promotes these effects are not well understood. Recently, we have shown that sAPPα enhances cell-surface expression of glutamate receptors. Activity-related cytoskeletal-associated protein Arc (Arg3.1) is an immediate early gene capable of modulating long-term potentiation, long-term depression and homeostatic plasticity through regulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor localization. Accordingly, we hypothesized that sAPPα may enhance synaptic plasticity, in part, by the de novo synthesis of Arc. Using primary cortical and hippocampal neuronal cultures we found that sAPPα (1 nM, 2 h) enhances levels of Arc mRNA and protein. Arc protein levels were increased in both the neuronal somata and dendrites in a Ca2+/calmodulin-dependent protein kinase II-dependent manner. Additionally, dendritic Arc expression was dependent upon activation of mitogen-activated protein kinase and protein kinase G. The enhancement of dendritic Arc protein was significantly reduced by antagonism of N-methyl-D-aspartate (NMDA) and nicotinic acetylcholine (α7nACh) receptors, and fully eliminated by dual application of these antagonists. This effect was further corroborated in area CA1 of acute hippocampal slices. These data suggest sAPPα-regulated plasticity within hippocampal neurons is mediated by cooperation of NMDA and α7nACh receptors to engage a cascade of signal transduction molecules to enhance the transcription and translation of Arc.
Highlights
Secreted amyloid precursor protein-alpha is a neuroprotective and neurotrophic protein, derived from the same parent protein as neurotoxic amyloid-ß
Numerous studies have identified the importance of the immediate early gene (IEG) activity-regulated cytoskeletalassociated protein Arc in mediating synaptic changes associated with long-term potentiation (LTP), long-term depression (LTD) and homeostatic plasticity, which together permit the formation and maintenance of long term memories (Lyford et al, 1995; Guzowski et al, 2000; Plath et al, 2006; Messaoudi et al, 2007; Nakayama et al, 2016)
We found that exogenously delivered recombinant Secreted amyloid precursor protein-α (sAPPα) (1 nM, 2 h) enhanced both Arc mRNA and protein through activation of both NMDA and α7nACh receptors, and that this effect is dependent on the activity of CaMKII, mitogen activated protein kinase (MAPK) and protein kinase G (PKG)
Summary
Secreted amyloid precursor protein-alpha (sAPPα) is a neuroprotective and neurotrophic protein, derived from the same parent protein as neurotoxic amyloid-ß. Arc has been shown to associate with CaMKIIβ, the so-called ‘inverse tag’ of inactive synapses, promoting AMPA receptor internalization (Okuno et al, 2012), as well as CaMKIIα (Husi et al, 2000) and stimulate neurite extension (Donai et al, 2003). While these data suggest a role for Arc in depotentiation or metaplasticity, new data indicate that Arc is released from neurons in virus-like caspids and may play a role in cell-to-cell communication (Pastuzyn et al, 2018)
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