Abstract
Amyloid beta (Aβ) peptides represent one of the most studied etiological factors of Alzheimer’s disease. Nevertheless, the effects elicited by different molecular forms of amyloid beta peptides widely vary between the studies, mostly depending on experimental conditions. Despite the enormous amount of accumulated evidences concerning the pathological effects of amyloid beta peptides, the exact identity of the amyloid beta species is still controversial, and even less is clear as regards to the downstream effectors that mediate the devastating impact of these peptides on synapses in the central nervous system. Recent publications indicate that some of the neurotoxic effects of amyloid beta peptides may be mediated via the activation of proteins belonging to the Abelson non-receptor tyrosine kinase (Abl) family, that are known to regulate actin cytoskeleton structure as well as phosphorylate microtubule-associated tau protein, a hallmark of Alzheimer’s disease. By performing series of miniature excitatory postsynaptic currents (mEPSC) recordings in cultured hippocampal cells, we demonstrate that activation of Abl kinases by acute application of 42 amino acid-length monomeric amyloid beta (Aβ1-42) peptides reduces spontaneous synaptic release, while this effect can be rescued by pharmacologic inhibition of Abl kinase activity, or by reduction of Abl expression with small interfering RNAs. Our electrophysiological data are further reinforced by a subsequent biochemical analysis, showing enhanced phosphorylation of Abl kinase substrate CT10 Regulator of Kinase-homolog-Like (Crkl) upon treatment of hippocampal neurons with Aβ peptides. Thus, we conclude that Abl kinase activation may be involved in Aβ-induced weakening of synaptic transmission.
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Abbreviations
- Abl:
-
Abelson non-receptor tyrosine kinase
- Aβ:
-
Amyloid beta peptide
- CrkL:
-
CT10 Regulator of Kinase-homolog-Like protein
- DIV:
-
Days in vitro
- DMSO:
-
Dimethyl sulfoxide
- DPH:
-
5-(1,3-Diaryl-1H-pyrazol-4-yl) hydantoin
- ECS:
-
Extracellular recording solution
- IEIs:
-
Inter-event intervals
- mEPSC:
-
Miniature excitatory postsynaptic currents
- siRNA:
-
Small interfering RNAs
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MR designed and performed electrophysiological and biochemical experiments, analyzed data, prepared figures, participated in manuscript writing, AS performed electrophysiological experiments, analyzed data, NB performed biochemical experiments, analyzed Western blot data, TB performed HPLC experiments and analyzed HPLC data, IM designed experiments, integrated data, supervised, wrote the manuscript.
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Reichenstein, M., Borovok, N., Sheinin, A. et al. Abelson Kinases Mediate the Depression of Spontaneous Synaptic Activity Induced by Amyloid Beta 1–42 Peptides. Cell Mol Neurobiol 41, 431–448 (2021). https://doi.org/10.1007/s10571-020-00858-7
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DOI: https://doi.org/10.1007/s10571-020-00858-7