C-Abl Deficiency Provides Synaptic Resiliency Against Aβ-Oligomers.

Daniela A Gutierrez,Lina M Vargas,Catalina De La Fuente,Alejandra R Alvarez,América Chandia-Cristi,Nancy Leal

doi:10.3389/fncel.2019.00526

Daniela A Gutierrez, Lina M Vargas + Show 4 more

Open Access

https://doi.org/10.3389/fncel.2019.00526

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Abstract

Spine pathology has been implicated in the early onset of Alzheimer’s disease (AD), where Aβ-Oligomers (AβOs) cause synaptic dysfunction and loss. Previously, we described that pharmacological inhibition of c-Abl prevents AβOs-induced synaptic alterations. Hence, this kinase seems to be a key element in AD progression. Here, we studied the role of c-Abl on dendritic spine morphological changes induced by AβOs using c-Abl null neurons (c-Abl-KO). First, we characterized the effect of c-Abl deficiency on dendritic spine density and found that its absence increases dendritic spine density. While AβOs-treatment reduces the spine number in both wild-type (WT) and c-Abl-KO neurons, AβOs-driven spine density loss was not affected by c-Abl. We then characterized AβOs-induced morphological changes in dendritic spines of c-Abl-KO neurons. AβOs induced a decrease in the number of mushroom spines in c-Abl-KO neurons while preserving the populations of immature stubby, thin, and filopodia spines. Furthermore, synaptic contacts evaluated by PSD95/Piccolo clustering and cell viability were preserved in AβOs-exposed c-Abl-KO neurons. In conclusion, our results indicate that in the presence of AβOs c-Abl participates in synaptic contact removal, increasing susceptibility to AβOs damage. Its deficiency increases the immature spine population reducing AβOs-induced synapse elimination. Therefore, c-Abl signaling could be a relevant actor in the early stages of AD.

Highlights

In the adult central nervous system, synaptic connections are highly dynamic, allowing the brain to reorganize and integrate new information
Since we found only a 3% difference in dendritic spine density between c-Abl-KO and WT neurons treated with AβOs, suggesting that AβOs-driven spine loss seems to be independent of c-Abl
Dendritic spines are specialized structures that protrude from dendrites and are the morphological correlate of excitatory synapses (Rochefort and Konnerth, 2012; Maiti et al, 2015)

Summary

Introduction

In the adult central nervous system, synaptic connections are highly dynamic, allowing the brain to reorganize and integrate new information. Excitatory synaptic contacts have actin-enriched structures known as dendritic spines, which are constantly modified. Dendritic spines arise from the dendritic shaft and have immature forms known as filopodia and thin spines. The mature forms known as mushroom spines have post-synaptic densities enriched in scaffolding proteins and glutamate receptors (Harris, 1999; Hayashi and Majwska, 2005). The formation, maturation, shape-changing and pruning of c-Abl Mediates AβOs-Induced Synapsis Loss dendritic spines have been associated with learning and memory (Riccomagno and Kolodkin, 2015; Piochon et al, 2016). Processes that alter the size, shape and density of dendritic spines such as the remodeling of synaptic complexes, and changes in actin cytoskeleton, have been implicated in synaptic plasticity, synaptic dysfunction and neuronal death (Kommaddi et al, 2018). Synaptic dysfunction has been associated with the genesis and progression of different neurodegenerative diseases (Hardy and Selkoe, 2002; Clare et al, 2010; Henstridge et al, 2018)

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