Physiological role for amyloid precursor protein in adult experience-dependent plasticity

Abstract

Changes in neural circuits after experience-dependent plasticity are brought about by the formation of new circuits via axonal growth and pruning. Here, using a combination of electrophysiology, adeno-associated virus-delivered fluorescent proteins, analysis of mutant mice, and two-photon microscopy, we follow long-range horizontally projecting axons in primary somatosensory cortex before and after selective whisker plucking. Whisker plucking induces axonal growth and pruning of horizontal projecting axons from neurons located in the surrounding intact whisker representations. We report that amyloid precursor protein is crucial for axonal pruning and contributes in a cell autonomous way.axon pruning | long-range axons | amyloid precursor protein | somatosensory cortex | experience-dependent plasticity A lterations in sensory experience lead to substantial modifications in cortical circuits. This plasticity is mediated, in part, through changes in the strength of synaptic transmission, but can also involve massive anatomical changes that include the sprouting of new axon collaterals, pruning of existing collaterals (1-3), and turnover of synapses along stable axons. After sensory loss, the cortical topography of the sensory map is permanently altered within the lesion projection zone (LPZ), the area of the cortex that receives input from the deafferented part of the periphery (4). Initially, the LPZ is silenced, but it subsequently recovers sensory input by the sprouting of afferents originating from nondeprived regions of the sensory periphery. This culminates in the reorganization of the cortical topographic map (4, 5). We have previously demonstrated that this reorganization of the cortical map is mediated through anatomical changes in horizontally projecting axons of layer II/III neurons within and around the LPZ (1-3). Electrophysiological changes occur along the same temporal scale (4, 5).Axonal changes associated with adult cortical plasticity are seen for both excitatory neurons, which send enriched projections into the LPZ, and inhibitory neurons located within the LPZ, which send reciprocal connections outside the LPZ (1-3). Previously, we demonstrated that axonal pruning after sensory deprivation (e.g., selective whisker plucking) requires death receptor 6 (DR6) (6). DR6 interacts with the E2 domain of amyloid precursor protein (APP) (7,8), and together, these proteins initiate an apoptotic cascade that mediates axon pruning in the absence of cell body death during development (8-10). It remains to be determined whether DR6-mediated pruning of axons after sensory deprivation in the adult may also involve APP.APP is best known for its role in Alzheimer's disease, where proteolytic cleavage of APP by beta-and gamma-secretases liberates Aβ (11), which impairs synaptic plasticity (12) and is thought to induce neuronal cell death. However, the physiological roles for APP are slowly coming into focus. Under normal conditions, APP is present on both sides of the synapse (13-18). APP −/− mice show performance ...

Systematic elucidation of neuron-astrocyte interaction in models of amyotrophic lateral sclerosis using multi-modal integrated bioinformatics workflow

“…In light of our results, we propose that APP-DR6 contribute to neurodegeneration via a β-secretase-dependent non-cell autonomous scenario, which is in contrast with the β-secretase-independent cell autonomous scenario put forward in the axonal homeostatic situations 32 , 34 , 53 , 54 . Given the role of DR6 in axonal pruning during development, surprisingly but importantly, DR6 silencing in our in vivo model of ALS protected against the loss of MN cell bodies but was less effective in mitigating motor axon damage (Fig.…”

“…As mentioned above, of the three significant ligand–receptor pairs identified by SEARCHIN, we began our experimental validation by studying the role of APP and DR6 in our ALS models, as APP–DR6 interaction has been previously validated 32 – 34 and proposed in a few neurobiology-relevant phenotypes. For instance, APP-DR6 emerged as instrumental to axonal pruning during development 32 , 34 and both DR6 and APP are critical for axonal plasticity in adult mice 53 , 54 . In addition, it was reported that APP-DR6 has a role in the pathophysiology of Alzheimer’s disease 32 , a view that could not be confirmed 33 .…”

A Role for Drosophila Amyloid Precursor Protein in Retrograde Trafficking of L1-Type Cell Adhesion Molecule Neuroglian

“…While previously described APPL d null mutant phenotypes suggest a role for APPL in axon growth and synaptogenesis (Torroja et al, 1999b; Mora et al, 2013; Soldano et al, 2013), interaction of vertebrate APP with the Death Receptor 6 has been suggested to cell-autonomously also regulate axonal pruning (Nikolaev et al, 2009; Kallop et al, 2014; Olsen et al, 2014; Marik et al, 2016). Our finding that APPL is retrogradely transported, implies a role for APPL at the GF terminals.…”

“…APPL processing and trafficking of the full-length protein and fragments is distinctive in different types of neurons (Torroja et al, 1996; Ramaker et al, 2016) and with respect to its functional roles in neurite growth (Singh and Mlodzik, 2012; Mora et al, 2013; Soldano et al, 2013; Singh et al, 2017), synapse formation (Torroja et al, 1999b), and in pruning of GF as well (Figure 4A). Death Receptor 6 has been suggested to regulate axonal pruning via its interaction with vertebrate APP (Nikolaev et al, 2009; Kallop et al, 2014; Olsen et al, 2014; Marik et al, 2016). Therefore, altered signaling at the plasma membrane or defective sorting of a tumor necrosis factor receptor may cause the observed degenerative phenotypes in some but not all cell types of APPL-SD expressing animals.…”

Amyloid Precursor Protein (APP) and GABAergic Neurotransmission

“…Aβ is well known for causing pathological dysregulation of postsynaptic trafficking of both the AMPA [39] and N -Methyl- d -aspartate (NMDA) [40]-type glutamate receptors. Notably, APP also has physiological roles in the function and trafficking of these glutamate receptors [41,42,43] and may thus be important for synaptic plasticity and learning/memory [44,45,46,47,48]. The actions of APP at the synapse are also known to be mediated by the secreted (s)APPs, mainly sAPPα generated by α-secretase cleavage [49,50,51,52,53].…”