c-Abl Deficiency Provides Synaptic Resiliency Against Aβ-Oligomers

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.

SHANK2 mutations impair apoptosis, proliferation and neurite outgrowth during early neuronal differentiation in SH-SY5Y cells

“…10 and 11 ). PVDF membranes (Millipore) were probed with rabbit polyclonal β3-Tubulin 53 (1:20,000; Abcam, ab18207, knockout validated), sheep anti-SHANK2 31 (1:2,500; R&D Systems, AF7035), rabbit anti-GRIN2B 54 (1:1,000; Abcam, ab65783), mouse anti-PSD95 55 , 56 (1:500; NeuroMab, 75–028, knockout validated), rabbit anti-Synaptophysin 57 (1:7,500; Abcam, ab32127, knockout validated), mouse anti-GAPDH 58 (1:10,000; Novus Biologicals, NB300-328), mouse anti-Nestin 59 (1:2,500; Abcam, ab22035), rabbit anti-AKT 45 (1:1,000; Cell Signaling Technology, 9272), mouse anti p-AKT(Ser473) 45 , 60 (1:1,000; Cell Signaling Technology, 4051) and rabbit anti-APP 45 (1:500, Abcam, ab126732, knockout validated).…”

A human-based multi-gene signature enables quantitative drug repurposing for metabolic disease

“…Erlotinib (IR-DR score = +72), which also inhibits ABL1, reduces kidney inflammation and preserves pancreas function and insulin sensitivity in a mouse model of diabetes ( Li et al, 2018b ). Furthermore, Aβ activates neuronal ABL1 in vitro, intra-hippocampal injection of Aβ fibrils increases expression of ABL1 in vivo and imatinib (STI571), a 90 nM inhibitor of ABL1, inhibits ABL1-mediated Aβ neurodegenerative pathways ( Cancino et al, 2011 ; Cancino et al, 2008 ; Gutierrez et al, 2019 ). However, imatinib does not yield a significant IR-DR score (nor inhibit EGFR), indicating that targeting ABL1 alone might be insufficient to treat human IR.…”

The c-Abl/p73 pathway induces neurodegeneration in a Parkinson's disease model

“…This strain originated and was maintained on a mixed B6.129S4, C57BL/6 background and did not display any gross physical or behavioral abnormalities. Genotyping was performed using a PCR-based screening to evaluate c-Abl ablation ( Gutierrez et al, 2019 ). Male and female mice were housed on a 12/12-h light/ dark cycle at 24 °C with ad libitum access to food and water.…”