Microglia contribute to cognitive decline in hypercholesterolemic LDLr^-/- mice

Area of Science:

• Neuroscience
• Genetics
• Pharmacology

Background:

• Familial hypercholesterolemia (FH) is a genetic disorder causing high LDL cholesterol.
• FH is associated with neurological issues like memory impairment, but mechanisms are unclear.
• Microgliosis, or brain immune cell activation, is implicated in FH-related brain changes.

Purpose of the Study:

• To investigate the role of microgliosis in neurochemical and behavioral changes in FH.
• To examine the effects of minocycline, a microglial inhibitor, on FH mouse models.

Main Methods:

• Utilized LDL receptor knockout (LDLr-/-) mice as an FH model.
• Administered minocycline or vehicle to adult LDLr-/- mice.
• Assessed microgliosis, synaptic protein markers, blood-brain barrier integrity (claudin-5), and memory function.

Main Results:

• LDLr-/- mice showed increased hippocampal microgliosis, altered microglial morphology, and reduced claudin-5 in the prefrontal cortex.
• Minocycline treatment ameliorated memory impairment in LDLr-/- mice.
• Minocycline reduced perivascular microglia in the brain but did not affect microglial phagocytic activity.

Conclusions:

• Hippocampal microgliosis, morphological changes, and perivascular microglial presence are linked to cognitive deficits in FH.
• Microglial phagocytic activity is not the primary driver of cognitive impairment in this FH model.
• Targeting microglial reactivity may offer therapeutic potential for FH-related neurological complications.