1. Reconstruction of the human blood–brain barrier in vitro reveals a pathogenic mechanism of APOE4 in pericytes
- Author
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Yuan-Ta Lin, Alexander Frank, Li-Huei Tsai, Joel W. Blanchard, Michael Bula, Matheus B. Victor, Hansruedi Mathys, Jose Davila-Velderrain, Lena Zhu, Manolis Kellis, Julia Maeve Bonner, Tak Ko, Leyla Anne Akay, Hugh P. Cam, and David A. Bennett
- Subjects
0301 basic medicine ,Apolipoprotein E ,Amyloid ,Apolipoprotein E4 ,Induced Pluripotent Stem Cells ,Apolipoprotein E3 ,In Vitro Techniques ,Biology ,Permeability ,Article ,General Biochemistry, Genetics and Molecular Biology ,Mural cell ,03 medical and health sciences ,0302 clinical medicine ,In vivo ,mental disorders ,medicine ,Humans ,RNA-Seq ,cardiovascular diseases ,Induced pluripotent stem cell ,Amyloid beta-Peptides ,NFATC Transcription Factors ,Calcineurin ,nutritional and metabolic diseases ,NFAT ,General Medicine ,Human brain ,medicine.disease ,Cell biology ,Cerebral Amyloid Angiopathy ,030104 developmental biology ,medicine.anatomical_structure ,Blood-Brain Barrier ,030220 oncology & carcinogenesis ,cardiovascular system ,lipids (amino acids, peptides, and proteins) ,Cerebral amyloid angiopathy ,Pericytes ,Transcription Factors - Abstract
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 (APOE4) 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.
- Published
- 2020
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