Mild hyperhomocysteinemia alters spatial and recognition memories in male, but not female rats. Are inflammation, blood-brain barrier damage and Tau expression sex-specific predictors?

Abstract

Homocysteine (Hcy) is a non-proteic amino acid that participates in the remethylation cycle of methionine. Hcy levels in plasma around 16-30 µmol/L are characteristics of mild hyperhomocysteinemia (HHcy), which is a know risk factor for neurodegeneration. Given this, Hcy may serve as an early biomarker of cognitive decline. In the present study, we evaluated behavior in different tasks in adult male and female rats submitted to mild HHcy and analyzed markers of blood-brain barrier (BBB) integrity (aquaporin, occludin, and β-catenin), the expression of p- TAU217, inflammatory mediators (IL-6 and IL-10), and key cellular markers (GFAP, AIF1, and RbFOX3) in the hippocampus and cortex of these animals. Results revealed that mild HHcy induced short-term and spatial memory impairment in adult male rats, accompanied by region-specific alterations in the cortex and hippocampus. In males, we also observed that HHcy reduced occludin content, IL-10 and RbFOX3; in the hippocampus, HHcy increased the expression of IL-10 and AIF1. The female rats did not exhibit memory deficits, o the other hand, the expression of p- TAU217, and GFAP were increased in the cortex of these animals. Together our finding drive that mild HHcy may represent a valuable translational model for studying early-stage cognitive decline and tauopathy, particularly in the context of sex-specific vulnerability.