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The <jats:italic>APOE4<\/jats:italic> allele is the strongest known genetic risk factor for late-onset Alzheimer\u2019s Disease (AD), and its expression has been shown to correlate with increased central nervous system (CNS) amyloid deposition and accelerated neurodegeneration. Conversely, <jats:italic>APOE2<\/jats:italic> is associated with reduced AD risk and lower CNS amyloid burden. Recent clinical data have suggested that increased blood-brain barrier (BBB) leakage is commonly observed among AD patients and <jats:italic>APOE4<\/jats:italic> carriers. However, it remains unclear how different <jats:italic>APOE<\/jats:italic> isoforms may impact AD-related pathologies at the BBB.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>To explore potential impacts of <jats:italic>APOE<\/jats:italic> genotypes on BBB properties and BBB interactions with amyloid beta, we differentiated isogenic human induced pluripotent stem cell (iPSC) lines with different <jats:italic>APOE<\/jats:italic> genotypes into both brain microvascular endothelial cell-like cells (BMEC-like cells) and brain pericyte-like cells. We then compared the effect of different <jats:italic>APOE<\/jats:italic> isoforms on BBB-related and AD-related phenotypes. Statistical significance was determined via ANOVA with Tukey\u2019s post hoc testing as appropriate.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Isogenic BMEC-like cells with different <jats:italic>APOE<\/jats:italic> genotypes had similar trans-endothelial electrical resistance, tight junction integrity and efflux transporter gene expression. However, recombinant APOE4 protein significantly impeded the \u201cbrain-to-blood\u201d amyloid beta 1\u201340 (A\u03b240) transport capabilities of BMEC-like cells, suggesting a role in diminished amyloid clearance. Conversely, APOE2 increased amyloid beta 1\u201342 (A\u03b242) transport in the model. Furthermore, we demonstrated that APOE-mediated amyloid transport by BMEC-like cells is dependent on LRP1 and p-glycoprotein pathways, mirroring in vivo findings. Pericyte-like cells exhibited similar APOE secretion levels across genotypes, yet <jats:italic>APOE4<\/jats:italic> pericyte-like cells showed heightened extracellular amyloid deposition, while <jats:italic>APOE2<\/jats:italic> pericyte-like cells displayed the least amyloid deposition, an observation in line with vascular pathologies in AD patients.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>While <jats:italic>APOE<\/jats:italic> genotype did not directly impact general BMEC or pericyte properties, APOE4 exacerbated amyloid clearance and deposition at the model BBB. Conversely, APOE2 demonstrated a potentially protective role by increasing amyloid transport and decreasing deposition. Our findings highlight that iPSC-derived BBB models can potentially capture amyloid pathologies at the BBB, motivating further development of such in vitro models in AD modeling and drug development.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12987-024-00580-2","type":"journal-article","created":{"date-parts":[[2024,10,11]],"date-time":"2024-10-11T08:01:36Z","timestamp":1728633696000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["iPSC-derived blood-brain barrier modeling reveals APOE isoform-dependent interactions with amyloid beta"],"prefix":"10.1186","volume":"21","author":[{"given":"Yunfeng","family":"Ding","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean P.","family":"Palecek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric V.","family":"Shusta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,10,11]]},"reference":[{"key":"580_CR1","doi-asserted-by":"publisher","first-page":"405","DOI":"10.3389\/fncel.2019.00405","volume":"13","author":"A Villabona-Rueda","year":"2019","unstructured":"Villabona-Rueda A, Erice C, Pardo CA, Stins MF. 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