Basic Science and Pathogenesis.

Area of Science:

• Neuroscience
• Cholesterol Metabolism
• Neuroinflammation

Background:

• High blood cholesterol is a risk factor for dementia, including Alzheimer's disease (AD).
• Mechanisms linking cholesterol to cognitive decline involve blood-brain barrier dysfunction and neuroinflammation.
• Elevated cholesterol activates microglia, impacting central nervous system reactivity.

Purpose of the Study:

• Investigate the role of microglial reactivity in cognitive impairments associated with sporadic hypercholesterolemia.
• Determine the effects of minocycline, a microglia modulator, on cognitive function and brain markers in a hypercholesterolemia model.

Main Methods:

• Induced sporadic hypercholesterolemia in mice using a high-cholesterol diet for eight weeks.
• Treated mice with minocycline during the final four weeks of the diet.
• Assessed cognitive performance using hippocampal-dependent memory tasks and analyzed brain tissue for microglial markers and Claudin-5.

Main Results:

• Hypercholesterolemic mice exhibited increased plasma cholesterol and impaired memory performance.
• Minocycline treatment improved memory deficits in hypercholesterolemic mice.
• Memory deficits were associated with reduced microglial presence in the hippocampal perivascular area, unaffected by minocycline or sex.
• Minocycline increased Claudin-5 immunocontent in the prefrontal cortex and hippocampus without altering microglial density or morphology.

Conclusions:

• Sporadic hypercholesterolemia in mice leads to memory deficits and altered microglial distribution in the hippocampus.
• Minocycline treatment ameliorated memory impairments and enhanced Claudin-5 levels in hypercholesterolemic mice.
• These findings suggest minocycline's potential in mitigating cognitive decline associated with high cholesterol, independent of microglial density changes.