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Integrin adhesion dynamics may govern the dementia risk factor arising from cholinergic crises

Integrin adhesion dynamics may govern the dementia risk factor arising from cholinergic crises

  1. J. TUTON, M. F. ALMEIDA, B. A. BAHR, *K. L. G. FARIZATTO

Acute exposure to an acetylcholinesterase inhibitor of the Organophosphate (OP) class leads to a cholinergic crisis, resulting in an increased risk in developing long-term neurological disorders. OPs are used worldwide as agricultural pesticides and as warfare agents. Understanding the synaptotoxic profile of OPs is vital for long-term treatment strategies. Distinct OP-mediated synaptopathology has been described (Farizatto et al. 2019 Sci Rep.9:6532), with the latter study identifying an involvement of cell adhesion responses. Integrins, a neuronal-enriched cell adhesion molecules, are linked to synaptogenesis, synaptic plasticity, and axon regeneration. Here, hippocampal explants were exposed to the OP toxin paraoxon (Pxn) to decipher if integrins influence synaptic vulnerability, and synaptic changes were assessed by protein evaluation methods. Pxn exposure mediated loss of pre- and postsynaptic staining among neuropilar dendrites, occurring in correspondence with abnormal induction of β1 integrin across the hippocampal dendritic fields. Interestingly, in the Pxn model, the distinctive adhesion response was mediated solely by the β1-type integrin family when assessed in parallel with neurexin and NCAM.

To further examine the integrin’s role during OP-mediated synaptopathology, we co-treated the Pxn-exposed tissue with a neuroprotectant and observed that the abnormal integrin-type response was offset resulting in synaptic protection. Similar results were found with a pxn wash-out procedure. Additionally, the synaptic compromise observed in Pxn-exposed explants was not exhibited after the application of the β1-integrin inhibitor BIO 5192, suggesting that blocking β1 integrin signaling attenuates the unique Pxn-mediated synaptotoxicity. These findings postulate that integrins can respond to cholinergic crises and strongly influences synaptic integrity and maintenance.