%0 Journal Article
%T 3,4-Dihydroxyphenylethanol Assuages Cognitive Impulsivity in Alzheimer¡¯s Disease by Attuning HPA-Axis via Differential Crosstalk of ¦Á7 nAChR with MicroRNA-124 and HDAC6
%J -
%D 2018
%R https://doi.org/10.1021/acschemneuro.7b00532
%X Cognitive impulsivity, a form of suboptimal cost-benefit decision making, is an illustrious attribute of an array of neurodegenerative diseases including Alzheimer¡¯s disease (AD). In this study, a delay discounting paradigm was used to assess the effect of 3,4-dihydroxyphenylethanol (DOPET) on cognitive impulsivity, in an oA42i (oligomeric amyloid ¦Â1¨C42 plus ibotenic acid) induced AD mouse model, using a nonspatial T-maze task. The results depicted that oA42i administration elevated cognitive impulsivity, whereas DOPET treatment attenuated the impulsive behavior and matched the choice of the sham-operated controls. In addition, DOPET treatment has ameliorated the anxiety-like behavior in the oA42i-challenged mice. Probing the molecular signaling cascades underpinning these functional ramifications in the oA42i-challenged mice revealed reduced cholinergic (¦Á7 nAChR; alpha 7 nicotinic acetylcholine receptor) function, dysregulated hypothalamic¨Cpituitary¨Cadrenal (HPA) axis (manifested by amplified glucocorticoid receptor expression and plasma corticosterone levels), and also aberrations in the neuroepigenetic (microRNA-124, HDAC6 (histone deacetylase 6), and HSP90 (heat-shock protein 90) expressions) as well as nucleocytoplasmic (importin-¦Á1 expression and nuclear ultra-architecture) continuum. Nonetheless, DOPET administration ameliorated these perturbations and the observations were in line with that of the sham-operated mice. Further validation of the results with organotypic hippocampal slice cultures (OHSCs) confirmed the in vivo findings. We opine that HPA-axis attunement by DOPET might be orchestrated through the ¦Á7 nAChR-mediated pathway. Based on these outcomes, we posit that 3,4-dihydroxyphenylethanol might be a potential multimodal agent for the management of cognitive impulsivity and neuromolecular quagmire in AD
%U https://pubs.acs.org/doi/10.1021/acschemneuro.7b00532