Aging without Apolipoprotein D: Molecular and cellular modifications in the hippocampus and cortex

Area of Science:

• Neuroscience
• Aging Research
• Molecular Biology

Background:

• Understanding brain aging mechanisms is crucial for addressing functional decline and neurodegenerative diseases.
• Apolipoprotein D (ApoD) is upregulated in the aged brain, suggesting a protective role.
• The specific effects of ApoD in normal brain aging remain understudied.

Purpose of the Study:

• To investigate the role of Apolipoprotein D (ApoD) in the normal aging process of the brain.
• To analyze the impact of ApoD deficiency on factors maintaining aged brain function.
• To elucidate the cellular and molecular consequences of ApoD loss in the aging cortex and hippocampus.

Main Methods:

• Utilized an ApoD-knockout mouse model.
• Focused analyses on the cortex and hippocampus at an early senescence stage.
• Employed transcriptome analysis, alongside cellular and molecular assessments.

Main Results:

• ApoD-knockout mice exhibit a prematurely aged brain phenotype without altered lifespan.
• Age-dependent hyperkinesia and memory deficits were observed in ApoD-deficient mice.
• Transcriptome analysis revealed distinct molecular aging patterns in the cortex and hippocampus upon ApoD loss, with altered glial reactivity, proteostasis, and oxidative/inflammatory damage markers.
• Significant reduction in neuronal calcium-dependent functionality markers and early signs of neuronal loss in the cortex were noted in ApoD-knockout brains.

Conclusions:

• Physiological upregulation of ApoD in the brain functions as a homeostatic anti-aging mechanism.
• ApoD deficiency accelerates brain aging, impacting neuronal function and potentially increasing vulnerability to neurodegeneration.
• These findings highlight ApoD's critical role in maintaining brain health during aging.