Apolipoprotein E controls cerebrovascular integrity via cyclophilin A

Area of Science:

• Neuroscience
• Genetics
• Vascular Biology

Background:

• Human apolipoprotein E (APOE) has three isoforms: APOE2, APOE3, and APOE4.
• APOE4 is a significant genetic risk factor for Alzheimer's disease and other neurological conditions.
• Neurovascular dysfunction is observed in APOE4 carriers and related disorders, but the underlying mechanisms are unclear.

Purpose of the Study:

• To investigate how APOE genotype influences brain microcirculation and blood-brain barrier (BBB) integrity.
• To elucidate the molecular pathways involved in APOE4-associated neurovascular dysfunction.

Main Methods:

• Utilized APOE transgenic mice models, including those with genetic manipulation of cyclophilin A (CypA).
• Examined the effects of different APOE isoforms and Apoe deficiency on BBB integrity and neurovascular function.
• Investigated the role of the CypA-nuclear factor-κB-matrix-metalloproteinase-9 (NF-κB-MMP9) pathway in pericytes.

Main Results:

• Expression of APOE4 and lack of murine Apoe, but not APOE2 or APOE3, caused BBB breakdown.
• This breakdown was mediated by the activation of a proinflammatory CypA-NF-κB-MMP9 pathway in pericytes.
• Vascular defects, including reduced microvascular and cerebral blood flow, preceded neuronal dysfunction and initiated neurodegenerative changes.
• Astrocyte-secreted APOE3, unlike APOE4, suppressed this pathway via a lipoprotein receptor.

Conclusions:

• APOE4 and Apoe deficiency induce BBB breakdown through the CypA-NF-κB-MMP9 pathway in pericytes, leading to neurovascular damage.
• These vascular defects precede and can initiate neurodegenerative processes.
• Cyclophilin A (CypA) is identified as a key therapeutic target for mitigating APOE4-mediated neurovascular injury and subsequent neuronal dysfunction.