The study investigates the role of apolipoprotein E (APOE) in maintaining cerebrovascular integrity and its impact on neurovascular dysfunction. Human APOE has three isoforms: APOE2, APOE3, and APOE4, with APOE4 being a major genetic risk factor for Alzheimer's disease and associated with Down's syndrome dementia and poor neurological outcomes after traumatic brain injury. The research uses various APOE transgenic mice models to explore how APOE genotype affects brain microcirculation. Key findings include: 1. **BBB Breakdown**: APOE4 and lack of murine Apoe lead to blood-brain barrier (BBB) breakdown by activating a proinflammatory cyclophilin A (CypA)-nuclear factor-κB-matrix-metalloproteinase-9 (MMP9) pathway in pericytes, leading to neuronal uptake of neurotoxic proteins and reduced microvascular and cerebral blood flow. 2. **CypA as a Therapeutic Target**: CypA is identified as a key target for treating APOE4-mediated neurovascular injury and resulting neuronal dysfunction and degeneration. Inhibition of CypA with cyclosporine A can correct BBB disruption and improve neuronal function. 3. **APOE3's Protective Role**: Astrocyte-secreted APOE3 suppresses the CypA-NF-κB-MMP9 pathway in pericytes through a lipoprotein receptor, providing a mechanism for APOE3's protective effect on the BBB. 4. **Molecular Mechanisms**: The study elucidates the molecular mechanisms underlying CypA-mediated BBB breakdown, including the activation of MMP9 and its substrates, which are crucial for maintaining BBB integrity. 5. **Preclinical Implications**: The vascular defects in Apoe-deficient and APOE4-expressing mice precede neuronal dysfunction and can initiate neurodegenerative changes, suggesting that early intervention targeting the CypA-NF-κB-MMP9 pathway may be beneficial. Overall, the study highlights the importance of APOE isoforms in maintaining cerebrovascular health and provides a potential therapeutic target for conditions associated with APOE4.The study investigates the role of apolipoprotein E (APOE) in maintaining cerebrovascular integrity and its impact on neurovascular dysfunction. Human APOE has three isoforms: APOE2, APOE3, and APOE4, with APOE4 being a major genetic risk factor for Alzheimer's disease and associated with Down's syndrome dementia and poor neurological outcomes after traumatic brain injury. The research uses various APOE transgenic mice models to explore how APOE genotype affects brain microcirculation. Key findings include: 1. **BBB Breakdown**: APOE4 and lack of murine Apoe lead to blood-brain barrier (BBB) breakdown by activating a proinflammatory cyclophilin A (CypA)-nuclear factor-κB-matrix-metalloproteinase-9 (MMP9) pathway in pericytes, leading to neuronal uptake of neurotoxic proteins and reduced microvascular and cerebral blood flow. 2. **CypA as a Therapeutic Target**: CypA is identified as a key target for treating APOE4-mediated neurovascular injury and resulting neuronal dysfunction and degeneration. Inhibition of CypA with cyclosporine A can correct BBB disruption and improve neuronal function. 3. **APOE3's Protective Role**: Astrocyte-secreted APOE3 suppresses the CypA-NF-κB-MMP9 pathway in pericytes through a lipoprotein receptor, providing a mechanism for APOE3's protective effect on the BBB. 4. **Molecular Mechanisms**: The study elucidates the molecular mechanisms underlying CypA-mediated BBB breakdown, including the activation of MMP9 and its substrates, which are crucial for maintaining BBB integrity. 5. **Preclinical Implications**: The vascular defects in Apoe-deficient and APOE4-expressing mice precede neuronal dysfunction and can initiate neurodegenerative changes, suggesting that early intervention targeting the CypA-NF-κB-MMP9 pathway may be beneficial. Overall, the study highlights the importance of APOE isoforms in maintaining cerebrovascular health and provides a potential therapeutic target for conditions associated with APOE4.