Basic Science and Pathogenesis.

Area of Science:

• Neuroscience
• Genetics
• Vascular Biology

Background:

• Apolipoprotein E (APOE) is crucial for lipid transport and cholesterol homeostasis.
• The APOE E4 variant is a major genetic risk factor for Alzheimer's disease (AD) and vascular conditions.
• Mechanisms of APOE's role in blood-brain barrier breakdown (BBB-B) are not fully understood.

Purpose of the Study:

• To investigate how APOE influences BBB-B and cerebrovascular function.
• To characterize the distinct molecular profiling associated with APOE variants in vivo.
• To understand the pathophysiology of vascular contributions to dementia.

Main Methods:

• Longitudinal analyses of humanized transgenic APOE knock-in (KI) mice.
• Utilized behavioral analyses, immunohistochemistry, proteomics, and MRI.
• Assessed APOE3 and APOE4 KI mice at multiple age-equivalent timepoints.

Main Results:

• Demonstrated genotype-dependent and age-related differences in cerebral blood flow and BBB permeability.
• Revealed dysregulation of pathways in mitochondrial function and cell proliferation in APOE-KI mice.
• Observed differential expression of key factors like VEGFR2.

Conclusions:

• APOE4 contributes to impaired cerebrovascular function via pericyte recruitment and vascular destabilization.
• Findings support APOE4's role in cognitive impairment and BBB breakdown.
• Provides insights into staging APOE-related BBB breakdown.