Increase in BACE1 Phosphorylation in the Rat Hippocampus and Phytosphingosine in Plasma After Chronic Administration of Scopolamine.

Alzheimer's disease (AD) is characterized by progressive cognitive decline associated with the accumulation of amyloid-β (Aβ) peptides and dysregulation of β-site amyloid precursor protein-cleaving enzyme (BACE1) and its phosphorylation at T252 (P-BACE1-T252) as well to the kinase's expression and activity. In this study, the effects of chronic scopolamine administration on Aβ1-42 levels, BACE1 expression and activity, P-BACE1-T252, PKA expression and BACE1, and PKA activity were evaluated, along with the identification of some metabolites in plasma. Twenty-seven male Wistar rats were divided into control and scopolamine-treated groups (2 mg/kg/day, i.p.) for six weeks. Scopolamine increased hippocampal Aβ1-42 2.1-fold (p < 0.0001) by ELISA, which correlates with the increase in BACE1 expression (85%) by Western blot and its activity (p < 0.05) relative to that in the control group. In addition, despite the fact that an increase in P-BACE1-T252 expression by Western blot was observed in hippocampus and prefrontal cortex, it was more in the hippocampus; notably, this result correlates with the PKA expression and activity which was reduced in the hippocampus (p < 0.05) but not in the prefrontal cortex. Identification of some metabolites that has been reported during the administration of Aβ and could be present in the scopolamine model were carried out by UHPLC-MS/MS, finding elevated plasma phytosphingosine and decreased acetylcarnitine, suggesting disrupted lipid metabolism associated with scopolamine-induced cognitive impairment.