Duke-UNC ADRC SLAM-DUNC 2022

Organophosphate toxin exposure, a military-related vulnerability that increases dementia risk, elicits synaptopathy, astrocytic activation, and altered structural dynamics

Farizatto KLG, McEwan SA, Almeida MF, Byrd A, Makriyannis A, and Bahr BA.

Biotechnology Research and Training Center, University of North Carolina – Pembroke, Pembroke, North Carolina

Center for Drug Discovery, Northeastern University, Boston, Massachusetts

Abstract
Age-related dementias are escalating to a crisis of the 21st century. Organophosphates account for the deadliest nerve agents, inhibiting acetylcholinesterase and causing survivors of the toxic exposure to experience excitotoxicity, seizure pathology, and increased risk for behavioral deficits. We used organotypic brain explants to show that such neuronal hyperexcitability leads to synaptopathy, altered cytoskeletal and adhesion dynamics, and astrocytic responses (Karanian et al. 2005–J Neuroscience 25:7813; Farizatto et al. 2019–Scientific Reports 9:6532). The organophosphate paraoxon induces similar toxicity as nerve agents and is a metabolite of insecticides that trigger a pathogenic cascade initiated by seizure, a cascade found reduced by selective neuroprotectants in vivo and in vitro (Farizatto et al. 2017-J Mol Neuroscience 63:115).

Our studies exposed tissue to paraoxon to understand the presynaptic vulnerability and progressive loss of synapse integrity. Synaptic decline occurred in the absence of overt neurodegeneration. Presynaptic markers were reduced in the dentate gyrus and CA1 after paraoxon exposure, particularly in the molecular layer (50-75% reductions) and stratum radiatum (37-51%). The punctate synaptic staining was reduced in correspondence with enhanced neuropilar staining of astrocytes. Interestingly, the decline in synapsin isoforms paralleled spectrin breakdown as well as increased labeling of the β1 integrin adhesion receptor. The distinct adhesion dynamics triggered by paraoxon exposure entailed a two-fold increase in β1 integrin, but no change in NCAM-180 or neurexin. This research strongly suggests that non-lethal, and perhaps asymptomatic, organophosphate exposures can enhance vulnerability to developing dementia later in life, involving an interplay between synaptotoxic and synaptoprotective pathways.