Minocycline Ameliorates Cognitive Impairments Without Modulating Microglial Reactivity in Sporadic Hypercholesterolemia: A Sex-Specific Analysis in Mice

Abstract

High blood cholesterol levels have been progressively recognized as an important risk factor for dementia, yet the underlying mechanisms remain poorly understood. Emerging evidence indicates that blood–brain barrier (BBB) dysfunction and microglia-mediated neuroinflammation are key mechanisms contributing to the cognitive decline associated with hypercholesterolemia. In this study, we investigated sex-dependent differences in cognitive impairments, synaptic protein levels, microglial reactivity, and neurovascular changes associated with sporadic hypercholesterolemia, as well as the potential modulatory effects of minocycline. Adult male and female CF-1 mice (3-month-old) were fed either a normal or high-fat high-cholesterol diet for 8 weeks, with daily oral minocycline administered during the final 4 weeks. Mice fed a cholesterol-rich diet exhibited a significant increase in plasma cholesterol levels, which remained unaffected by minocycline treatment. Hypercholesterolemia was associated with memory deficits in the object recognition task, accompanied by decreased claudin-5 expression, reduced numbers of lectin-positive cells, and diminished microglial presence in the hippocampal perivascular area. While minocycline treatment ameliorated cognitive deficits and increased claudin-5 levels and lectin-positive cell numbers in the hippocampus, no significant effects of either diet or treatment were observed on classical microglial reactivity parameters. In addition, diet seemed to impact the content of synaptophysin in the prefrontal cortex and hippocampus. Notably, female mice exhibited greater susceptibility to hypercholesterolemia-induced metabolic and cognitive alterations and showed a more pronounced response to minocycline treatment compared to males. Overall, our findings highlight sex-dependent differences in susceptibility to hypercholesterolemia-induced cognitive dysfunction and in the therapeutic response to minocycline. These results underscore the relevance of BBB alterations and perivascular microglial changes, independent of classical microglial activation, in the pathophysiology of hypercholesterolemia-associated cognitive impairment.