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Basic Science and Pathogenesis.

Matheus Scarpatto Rodrigues1,2, Natália Baltazar Nascimento3, Gabriela Joras Baumart4,5

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High cholesterol levels impair memory by affecting microglia in the brain. Minocycline treatment improved memory and brain function in mice with high cholesterol, suggesting a potential therapeutic target for cognitive decline.

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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.