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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Impaired amyloid-\u03b2 (A\u03b2) clearance across the blood\u2013brain barrier (BBB) is a major contributor to A\u03b2 accumulation in Alzheimer\u2019s disease (AD). P-glycoprotein (P-gp) has been identified as a key BBB efflux transporter involved in A\u03b2 clearance, whereas emerging evidence suggests that organic anion transporting polypeptide 1A2 (OATP1A2) and its rodent counterparts, such as Oatp1a4, may participate in the influx component of A\u03b2 transport. Nuclear factor erythroid 2\u2013related factor 2 (Nrf2) and pregnane X receptor (PXR) are important transcriptional regulators of oxidative stress responses, xenobiotic metabolism, and transporter expression and may therefore modulate OATP1A2 and P-gp expression at the BBB. However, the mechanisms by which Nrf2\u2013PXR crosstalk may regulate OATP1A2\/P-gp expression in BBB endothelial cells under AD-relevant pathological conditions, as well as the consequences of this regulation for A\u03b2 transport homeostasis, remain incompletely understood. This review summarizes current evidence linking P-gp, OATP1A2\/Oatp1a4, Nrf2, and PXR to BBB transporter homeostasis in AD. A \u201cnet-effect\u201d model is further proposed, in which Nrf2\u2013PXR crosstalk may shift the BBB transporter balance toward enhanced P-gp-mediated efflux and reduced OATP1A2-associated influx. Because several key components of this model, particularly OATP1A2-mediated A\u03b2 influx and BBB-specific Nrf2\u2013PXR regulation, remain insufficiently validated, this model should be regarded as a mechanistic framework for future experimental investigation rather than as an established pathogenic pathway. Clarifying this regulatory axis may provide new insights into BBB dysfunction and impaired A\u03b2 clearance in AD and may help identify potential molecular targets for therapeutic intervention.<\/jats:p>","DOI":"10.3390\/ijms27167264","type":"journal-article","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T10:39:01Z","timestamp":1786703941000},"page":"7264","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Putative Modulation of OATP1A2 and P-gp Expression at the Blood\u2013Brain Barrier by Nrf2\u2013PXR: An Associative Hypothesis for Amyloid-\u03b2 Transport in Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"27","author":[{"given":"Lin","family":"Li","sequence":"first","affiliation":[{"name":"School of Pharmacy, Nanchang University, Nanchang 330006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Nanchang University, Nanchang 330006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sihong","family":"Li","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Nanchang University, Nanchang 330006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Menghua","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of GCP, The First Affiliated Hospital of Nanchang University, Nanchang 330006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiqiang","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, The First Affiliated Hospital of Nanchang University, Nanchang 330006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuwei","family":"Xiao","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Nanchang University, Nanchang 330006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinhua","family":"Wen","sequence":"additional","affiliation":[{"name":"Department of GCP, The First Affiliated Hospital of Nanchang University, Nanchang 330006, China"},{"name":"Key Laboratory of New Drug Transformation and Evaluation of Jiangxi Province, Nanchang 330031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1016\/S0140-6736(20)32205-4","article-title":"Alzheimer\u2019s Disease","volume":"397","author":"Scheltens","year":"2021","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Breijyeh, Z., and Karaman, R. 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