In Vivo Sub-chronic Treatment with Dichlorvos in Young Rats Promotes Synaptic Plasticity and Learning by a Mechanism that Involves Acylpeptide Hydrolase Instead of Acetylcholinesterase Inhibition. Correlation with Endogenous β-Amyloid Levels

Abstract

Acylpeptide hydrolase (APEH) is a serine hydrolase that displays two catalytic activities, acting both as an exopeptidase toward short N-acylated peptides and as an endopeptidase toward oxidized peptides or proteins. It has been demonstrated that this enzyme can degrade monomers, dimers, and trimers of the Aβ1-40 peptide in the conditioned media of neuroblastoma cells. In a previous report, we showed that the specific inhibition of this enzyme by the organophosphate molecule dichlorvos (DDVP) triggers an enhancement of long-term potentiation in rat hippocampal slices. In this study, we demonstrate that the same effect can be accomplished in vivo by sub-chronic treatment of young rats with a low dose of DDVP (0.1 mg/kg). Besides exhibiting a significant enhancement of LTP, the treated animals also showed improvements in parameters of spatial learning and memory. Interestingly, higher doses of DDVP such as 2 mg/kg did not prove to be beneficial for synaptic plasticity or behavior. Due to the fact that at 2 mg/kg we observed inhibition of both APEH and acetylcholinesterase, we interpret that in order to achieve positive effects on the measured parameters only APEH inhibition should be obtained. The treatment with both DDVP doses produced an increase in the endogenous concentration of Aβ1-40, although this was statistically significant only at the dose of 0.1 mg/kg. We propose that APEH represents an interesting pharmacological target for cognitive enhancement, acting through the modulation of the endogenous concentration of Aβ1-40.

Glucocorticoid receptors signaling impairment potentiates amyloid‐β oligomers‐induced pathology in an acute model of Alzheimer’s disease

“…Finally, to confirm the induction of the amyloidogenic pathway, we assayed the endogenous levels of Aβ 1-42 in the PFC ( Figure S3). 60 For experimental protocol, see Figure 1A. This upregulation was totally reversed by the treatment with CORT113176 ( Figure S3B).…”

“…Even if the levels of Aβ 1-42 assayed in the PFC were relatively low, they are consistent with some previous studies in rats. 60,61 | 1157 CANET ET Al.…”

Intratracheal Transplantation of Amnion-Derived Mesenchymal Stem Cells Ameliorates Hyperoxia-Induced Neonatal Hyperoxic Lung Injury via Aminoacyl-Peptide Hydrolase

“…In mammalian cells, APEH has been found to pay an important role in the clearance of oxidatively damaged proteins, as well as in the degradation of β -amyloid peptides in Alzheimer’s disease ( 58 ). Zeng et al ( 59 ) also identified APEH as an integral part of the cellular response to DNA damage.…”

Reduced neurobehavioral functioning in agricultural workers and rural inhabitants exposed to pesticides in northern Chile and its association with blood biomarkers inhibition

“…In addition to cholinesterases, inhibition of APEH activity was also measured during field biomonitoring. This enzyme is a highly sensitive target for some OPs [ 17 ] and has physiological functions in central synapses [ 42 ].…”