Reconstruction of the human blood–brain barrier in vitro reveals a pathogenic mechanism of APOE4 in pericytes

• Published in: Nature medicine Vol. 26; no. 6; pp. 952 - 963
• Main Authors: Blanchard, Joel W., Bula, Michael, Davila-Velderrain, Jose, Akay, Leyla Anne, Zhu, Lena, Frank, Alexander, Victor, Matheus B., Bonner, Julia Maeve, Mathys, Hansruedi, Lin, Yuan-Ta, Ko, Tak, Bennett, David A., Cam, Hugh P., Kellis, Manolis, Tsai, Li-Huei
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.06.2020; Nature Publishing Group
• Subjects: 631/378/1341; 692/617/375/364; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Amyloidosis; Apolipoprotein E; Apolipoprotein E3 - genetics; Apolipoprotein E3 - metabolism; Apolipoprotein E4; Apolipoprotein E4 - genetics; Apolipoprotein E4 - metabolism; Apolipoproteins; Biomedical and Life Sciences; Biomedicine; Blood-brain barrier; Blood-Brain Barrier - cytology; Blood-Brain Barrier - metabolism; Calcineurin; Calcineurin - metabolism; Cancer Research; Cerebral amyloid angiopathy; Cerebral Amyloid Angiopathy - genetics; Cognitive ability; Combinatorial analysis; Degeneration; Development and progression; Extracellular matrix; Fibroblasts; Gene expression; Genetic aspects; Growth factors; Health aspects; Health risk assessment; Humans; In Vitro Techniques; In vivo methods and tests; Induced Pluripotent Stem Cells; Infectious Diseases; Lymphocytes; Metabolic Diseases; Molecular Medicine; Neurodegeneration; Neurodegenerative diseases; Neurosciences; NF-AT protein; NFATC Transcription Factors - genetics; NFATC Transcription Factors - metabolism; Pathology; Pericytes; Pericytes - metabolism; Permeability; Physiological aspects; Physiology; Pluripotency; Risk analysis; Risk factors; RNA-Seq; Signaling; Stem cells; Therapeutic applications; Three dimensional models; Transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; United States
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/s41591-020-0886-4

In Alzheimer’s disease, amyloid deposits along the brain vasculature lead to a condition known as cerebral amyloid angiopathy (CAA), which impairs blood–brain barrier (BBB) function and accelerates cognitive degeneration. Apolipoprotein ( APO E4 ) is the strongest risk factor for CAA, yet the mechanisms underlying this genetic susceptibility are unknown. Here we developed an induced pluripotent stem cell-based three-dimensional model that recapitulates anatomical and physiological properties of the human BBB in vitro. Similarly to CAA, our in vitro BBB displayed significantly more amyloid accumulation in APOE4 compared to APOE3. Combinatorial experiments revealed that dysregulation of calcineurin–nuclear factor of activated T cells (NFAT) signaling and APOE in pericyte-like mural cells induces APOE4-associated CAA pathology. In the human brain, APOE and NFAT are selectively dysregulated in pericytes of APOE4 carriers, and inhibition of calcineurin–NFAT signaling reduces APOE4-associated CAA pathology in vitro and in vivo. Our study reveals the role of pericytes in APOE4-mediated CAA and highlights calcineurin–NFAT signaling as a therapeutic target in CAA and Alzheimer’s disease. An iPSC-based three-dimensional model of the human blood–brain barrier reveals that NFAT and APOE dysregulation in pericyte-like mural cells contributes to cerebral amyloid angiopathy and can potentially be targeted to treat Alzheimer’s disease.