{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T22:46:21Z","timestamp":1788821181783,"version":"build-2803163510"},"reference-count":93,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2020,12,29]],"date-time":"2020-12-29T00:00:00Z","timestamp":1609200000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Ageing","award":["2R01AG039621"],"award-info":[{"award-number":["2R01AG039621"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Defective clearance mechanisms lead to the accumulation of amyloid-beta (A\u03b2) peptides in the Alzheimer\u2019s brain. Though predominantly generated in neurons, little is known about how these hydrophobic, aggregation-prone, and tightly membrane-associated peptides exit into the extracellular space where they deposit and propagate neurotoxicity. The ability for P-glycoprotein (P-gp), an ATP-binding cassette (ABC) transporter, to export A\u03b2 across the blood-brain barrier (BBB) has previously been reported. However, controversies surrounding the P-gp\u2013A\u03b2 interaction persist. Here, molecular data affirm that both A\u03b240 and A\u03b242 peptide isoforms directly interact with and are substrates of P-gp. This was reinforced ex vivo by the inhibition of A\u03b242 transport in brain capillaries from P-gp-knockout mice. Moreover, we explored whether P-gp could exert the same role in neurons. Comparison between non-neuronal CHO-APP and human neuroblastoma SK-N-SH cells revealed that P-gp is expressed and active in both cell types. Inhibiting P-gp activity using verapamil and nicardipine impaired A\u03b240 and A\u03b242 secretion from both cell types, as determined by ELISA. Collectively, these findings implicate P-gp in A\u03b2 export from neurons, as well as across the BBB endothelium, and suggest that restoring or enhancing P-gp function could be a viable therapeutic approach for removing excess A\u03b2 out of the brain in Alzheimer\u2019s disease.<\/jats:p>","DOI":"10.3390\/ijms22010246","type":"journal-article","created":{"date-parts":[[2020,12,29]],"date-time":"2020-12-29T10:04:46Z","timestamp":1609236286000},"page":"246","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":45,"title":["New Evidence for P-gp-Mediated Export of Amyloid-\u03b2 Peptides in Molecular, Blood-Brain Barrier and Neuronal Models"],"prefix":"10.3390","volume":"22","author":[{"given":"Amanda B.","family":"Chai","sequence":"first","affiliation":[{"name":"School of Pharmacy, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anika M. S.","family":"Hartz","sequence":"additional","affiliation":[{"name":"Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40504, USA"},{"name":"Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40504, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7984-6919","authenticated-orcid":false,"given":"Xuexin","family":"Gao","sequence":"additional","affiliation":[{"name":"Research School of Biology and Medical School, Australian National University, Canberra, ACT 2601, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alryel","family":"Yang","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Callaghan","sequence":"additional","affiliation":[{"name":"Research School of Biology and Medical School, Australian National University, Canberra, ACT 2601, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid C.","family":"Gelissen","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,12,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"292","DOI":"10.15698\/cst2018.11.162","article-title":"Making the final cut: Pathogenic amyloid-\u03b2 peptide generation by \u03b3-secretase","volume":"2","author":"Steiner","year":"2018","journal-title":"Cell Stress"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"311","DOI":"10.3233\/JAD-2010-1221","article-title":"Alzheimer\u2019s disease and the amyloid-beta peptide","volume":"19","author":"Murphy","year":"2010","journal-title":"J. Alzheimers Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1186\/1742-2094-8-150","article-title":"The contribution of activated astrocytes to A\u03b2 production: Implications for Alzheimer\u2019s disease pathogenesis","volume":"8","author":"Zhao","year":"2011","journal-title":"J. Neuroinflamm."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2092","DOI":"10.1073\/pnas.90.5.2092","article-title":"Generation of beta-amyloid in the secretory pathway in neuronal and nonneuronal cells","volume":"90","author":"Busciglio","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1038\/nm1438","article-title":"Human amyloid-\u03b2 synthesis and clearance rates as measured in cerebrospinal fluid in vivo","volume":"12","author":"Bateman","year":"2006","journal-title":"Nat. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1774","DOI":"10.1126\/science.1197623","article-title":"Decreased clearance of CNS beta-amyloid in Alzheimer\u2019s disease","volume":"330","author":"Mawuenyega","year":"2010","journal-title":"Science"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1007\/s00401-015-1386-3","article-title":"Amyloid \u03b2 oligomers in Alzheimer\u2019s disease pathogenesis, treatment, and diagnosis","volume":"129","author":"Viola","year":"2015","journal-title":"Acta Neuropathol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"S67","DOI":"10.3233\/JAD-2012-129001","article-title":"Molecular mechanisms of amyloid oligomers toxicity","volume":"33","author":"Kayed","year":"2013","journal-title":"J. Alzheimers Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"S567","DOI":"10.3233\/JAD-179941","article-title":"The Amyloid-\u03b2 Oligomer Hypothesis: Beginning of the Third Decade","volume":"64","author":"Cline","year":"2018","journal-title":"J. Alzheimers Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"184","DOI":"10.2353\/ajpath.2006.050593","article-title":"A dynamic relationship between intracellular and extracellular pools of Abeta","volume":"168","author":"Oddo","year":"2006","journal-title":"Am. J. Pathol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1111\/j.1750-3639.2005.tb00101.x","article-title":"Intracellular and Extracellular A\u03b2, a Tale of Two Neuropathologies","volume":"15","author":"Cuello","year":"2005","journal-title":"Brain Pathol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Bayer, T., and Wirths, O. (2010). Intracellular accumulation of amyloid-beta\u2014A predictor for synaptic dysfunction and neuron loss in Alzheimer\u2019s disease. Front. Aging Neurosci., 2.","DOI":"10.3389\/fnagi.2010.00008"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Mucke, L., and Selkoe, D.J. (2012). Neurotoxicity of amyloid \u03b2-protein: Synaptic and network dysfunction. Cold Spring Harb. Perspect. Med., 2.","DOI":"10.1101\/cshperspect.a006338"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Callaghan, R., Gelissen, I.C., George, A.M., and Hartz, A.M.S. (2020). Mamma Mia, P-glycoprotein binds again. FEBS Lett.","DOI":"10.1002\/1873-3468.13951"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"7468","DOI":"10.1038\/sj.onc.1206948","article-title":"P-glycoprotein: From genomics to mechanism","volume":"22","author":"Ambudkar","year":"2003","journal-title":"Oncogene"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1111\/febs.15148","article-title":"P-glycoprotein: A role in the export of amyloid-\u03b2 in Alzheimer\u2019s disease?","volume":"287","author":"Chai","year":"2020","journal-title":"FEBS J."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1007\/s12192-014-0566-8","article-title":"Evidence against a role of P-glycoprotein in the clearance of the Alzheimer\u2019s disease A\u03b21-42 peptides","volume":"20","author":"Bello","year":"2015","journal-title":"Cell Stress Chaperones"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1124\/mol.109.061754","article-title":"Restoring blood-brain barrier P-glycoprotein reduces brain amyloid-beta in a mouse model of Alzheimer\u2019s disease","volume":"77","author":"Hartz","year":"2010","journal-title":"Mol. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.bcp.2016.10.002","article-title":"Location of contact residues in pharmacologically distinct drug binding sites on P-glycoprotein","volume":"123","author":"Mittra","year":"2017","journal-title":"Biochem. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3974","DOI":"10.1111\/j.1742-4658.2010.07789.x","article-title":"Transmembrane helix 12 plays a pivotal role in coupling energy provision and drug binding in ABCB1","volume":"277","author":"Crowley","year":"2010","journal-title":"FEBS J."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1609","DOI":"10.1038\/sj.bjp.0704400","article-title":"Detailed characterization of cysteine-less P-glycoprotein reveals subtle pharmacological differences in function from wild-type protein","volume":"134","author":"Taylor","year":"2001","journal-title":"Br. J. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/j.tips.2004.02.012","article-title":"Principles: Receptor theory in pharmacology","volume":"25","author":"Kenakin","year":"2004","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"14927","DOI":"10.1021\/bi0018786","article-title":"Intrinsic fluorescence of the P-glycoprotein multidrug transporter: Sensitivity of tryptophan residues to binding of drugs and nucleotides","volume":"39","author":"Liu","year":"2000","journal-title":"Biochemistry"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"15208","DOI":"10.1021\/bi9718696","article-title":"Binding of steroid modulators to recombinant cytosolic domain from mouse P-glycoprotein in close proximity to the ATP site","volume":"36","author":"Dayan","year":"1997","journal-title":"Biochemistry"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1021\/bi0267745","article-title":"Transition state P-glycoprotein binds drugs and modulators with unchanged affinity, suggesting a concerted transport mechanism","volume":"42","author":"Qu","year":"2003","journal-title":"Biochemistry"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1046\/j.1471-4159.2001.00113.x","article-title":"\u03b2-Amyloid efflux mediated by p-glycoprotein","volume":"76","author":"Lam","year":"2001","journal-title":"J. Neurochem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"13603","DOI":"10.1074\/jbc.C300073200","article-title":"Substrate-induced conformational changes in the transmembrane segments of human P-glycoprotein. Direct evidence for the substrate-induced fit mechanism for drug binding","volume":"278","author":"Loo","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"20986","DOI":"10.1074\/jbc.272.34.20986","article-title":"Drug-stimulated ATPase activity of human P-glycoprotein requires movement between transmembrane segments 6 and 12","volume":"272","author":"Loo","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1877","DOI":"10.1074\/jbc.271.4.1877","article-title":"Altered drug-stimulated ATPase activity in mutants of the human multidrug resistance protein","volume":"271","author":"Bakos","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1016\/S0006-2952(99)00139-2","article-title":"Interaction of the P-glycoprotein multidrug transporter (MDR1) with high affinity peptide chemosensitizers in isolated membranes, reconstituted systems, and intact cells","volume":"58","author":"Sharom","year":"1999","journal-title":"Biochem. Pharmacol."},{"key":"ref_31","first-page":"3109","article-title":"Multiple recognition of various amphiphilic molecules by the multidrug resistance P-glycoprotein: Molecular mechanisms and pharmacological consequences coming from functional interactions between various drugs","volume":"19","author":"Orlowski","year":"1999","journal-title":"Anticancer Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1038\/sj.bjp.0702807","article-title":"The molecular interaction of the high affinity reversal agent XR9576 with P-glycoprotein","volume":"128","author":"Martin","year":"1999","journal-title":"Br. J. Pharmacol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/S0169-409X(98)00085-4","article-title":"P-Glycoprotein, a gatekeeper in the blood\u2013brain barrier","volume":"36","author":"Schinkel","year":"1999","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.bbi.2018.07.017","article-title":"The concerted amyloid-beta clearance of LRP1 and ABCB1\/P-gp across the blood-brain barrier is linked by PICALM","volume":"73","author":"Storck","year":"2018","journal-title":"Brain Behav. Immun."},{"key":"ref_35","first-page":"4337","article-title":"Expression of a drug resistance gene in human neuroblastoma cell lines: Modulation by retinoic acid-induced differentiation","volume":"9","author":"Bates","year":"1989","journal-title":"Mol. Cell Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1186\/s12935-020-01291-y","article-title":"SNHG16 promotes tumorigenesis and cisplatin resistance by regulating miR-338-3p\/PLK4 pathway in neuroblastoma cells","volume":"20","author":"Xu","year":"2020","journal-title":"Cancer Cell Int."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1002\/cpt.1847","article-title":"P-Glycoprotein Inhibition Exacerbates Paclitaxel Neurotoxicity in Neurons and Patients with Cancer","volume":"108","author":"Stage","year":"2020","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.mad.2014.08.003","article-title":"Vascular and extravascular distribution of the ATP-binding cassette transporters ABCB1 and ABCC1 in aged human brain and pituitary","volume":"141\u2013142","author":"Bernstein","year":"2014","journal-title":"Mech. Ageing Dev."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"17477","DOI":"10.1038\/s41598-017-17475-y","article-title":"The Human Blood-Nerve Barrier Transcriptome","volume":"7","author":"Palladino","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1111\/j.1085-9489.2005.10308.x","article-title":"Patterns of P-glycoprotein activity in the nervous system during vincristine-induced neuropathy in rats","volume":"10","author":"Balayssac","year":"2005","journal-title":"J. Peripher. Nerv. Syst."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1124\/jpet.117.245613","article-title":"Drug Distribution into Peripheral Nerve","volume":"365","author":"Liu","year":"2018","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1038","DOI":"10.1093\/jnen\/63.10.1038","article-title":"Altered P-Glycoprotein Expression in AIDS Patients with HIV Encephalitis","volume":"63","author":"Langford","year":"2004","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/j.seizure.2007.03.011","article-title":"Expression and cellular distribution of multidrug resistance-related proteins in patients with focal cortical dysplasia","volume":"16","author":"Ak","year":"2007","journal-title":"Seizure"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Lautz, T.B., Jie, C., Clark, S., Naiditch, J.A., Jafari, N., Qiu, Y.-Y., Zheng, X., Chu, F., and Madonna, M.B. (2012). The Effect of Vorinostat on the Development of Resistance to Doxorubicin in Neuroblastoma. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0040816"},{"key":"ref_45","first-page":"518637","article-title":"Midkine Mediates Intercellular Crosstalk between Drug-Resistant and Drug-Sensitive Neuroblastoma Cells In Vitro and In Vivo","volume":"2013","author":"Chu","year":"2013","journal-title":"ISRN Oncol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/S0002-9440(10)63656-5","article-title":"MYCN enhances P-gp\/MDR1 gene expression in the human metastatic neuroblastoma IGR-N-91 model","volume":"163","author":"Blanc","year":"2003","journal-title":"Am. J. Pathol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"7905486","DOI":"10.1155\/2017\/7905486","article-title":"P-glycoprotein (ABCB1) and Oxidative Stress: Focus on Alzheimer\u2019s Disease","volume":"2017","author":"Sita","year":"2017","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1016\/0005-2736(94)90190-2","article-title":"Calcein accumulation as a fluorometric functional assay of the multidrug transporter","volume":"1191","author":"Homolya","year":"1994","journal-title":"Biochim. Biophys. Acta Biomembr."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2495","DOI":"10.1016\/j.jacc.2013.02.058","article-title":"The P-Glycoprotein Transport System and Cardiovascular Drugs","volume":"61","author":"Wessler","year":"2013","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/S0928-0987(02)00082-9","article-title":"Effects of 12 Ca2+ antagonists on multidrug resistance, MDR1-mediated transport and MDR1 mRNA expression","volume":"16","author":"Takara","year":"2002","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1002\/jnr.22172","article-title":"Memantine lowers amyloid-beta peptide levels in neuronal cultures and in APP\/PS1 transgenic mice","volume":"88","author":"Alley","year":"2010","journal-title":"J. Neurosci. Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/S0165-0270(01)00388-0","article-title":"High throughput screens for the identification of compounds that alter the accumulation of the Alzheimer\u2019s amyloid \u03b2 peptide (A\u03b2)","volume":"108","author":"Haugabook","year":"2001","journal-title":"J. Neurosci. Methods"},{"key":"ref_53","first-page":"530","article-title":"Verapamil stimulates glutathione transport by the 190-kDa multidrug resistance protein 1 (MRP1)","volume":"293","author":"Loe","year":"2000","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1089\/adt.2007.107","article-title":"High-throughput flow cytometry to detect selective inhibitors of ABCB1, ABCC1, and ABCG2 transporters","volume":"6","author":"Larson","year":"2008","journal-title":"ASSAY Drug Dev. Technol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"155","DOI":"10.3233\/JAD-2012-112189","article-title":"ABCG2- and ABCG4-mediated efflux of amyloid-beta peptide 1-40 at the mouse blood-brain barrier","volume":"30","author":"Do","year":"2012","journal-title":"J. Alzheimers Dis."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2628","DOI":"10.1161\/01.STR.0000143452.85382.d1","article-title":"RAGE (yin) versus LRP (yang) balance regulates alzheimer amyloid beta-peptide clearance through transport across the blood-brain barrier","volume":"35","author":"Deane","year":"2004","journal-title":"Stroke"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"54","DOI":"10.3389\/fpsyt.2012.00054","article-title":"ABC Transporters and the Alzheimer\u2019s Disease Enigma","volume":"3","author":"Wolf","year":"2012","journal-title":"Front. Psychiatry"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"3924","DOI":"10.1172\/JCI57867","article-title":"Cerebral amyloid-\u03b2 proteostasis is regulated by the membrane transport protein ABCC1 in mice","volume":"121","author":"Krohn","year":"2011","journal-title":"J. Clin. Investig."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2023","DOI":"10.1007\/s11095-005-8384-4","article-title":"BCRP transports dipyridamole and is inhibited by calcium channel blockers","volume":"22","author":"Zhang","year":"2005","journal-title":"Pharm. Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1097\/FPC.0b013e328323f680","article-title":"Characterization and analyses of multidrug resistance-associated protein 1 (MRP1\/ABCC1) polymorphisms in Chinese population","volume":"19","author":"Yin","year":"2009","journal-title":"Pharm. Genom."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1124\/mol.111.075143","article-title":"Characterization of the role of ABCG2 as a bile acid transporter in liver and placenta","volume":"81","author":"Blazquez","year":"2012","journal-title":"Mol. Pharmacol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1016\/j.jdermsci.2013.02.005","article-title":"CD147 promotes MTX resistance by immune cells through up-regulating ABCG2 expression and function","volume":"70","author":"Zhao","year":"2013","journal-title":"J. Dermatol. Sci."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1111\/j.1750-3639.2007.00075.x","article-title":"MDR1-P-Glycoprotein (ABCB1) Mediates Transport of Alzheimer\u2019s amyloid-beta peptides--implications for the mechanisms of Abeta clearance at the blood-brain barrier","volume":"17","author":"Kuhnke","year":"2007","journal-title":"Brain Pathol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1111\/j.2042-7158.2011.01309.x","article-title":"Up-regulation of P-glycoprotein reduces intracellular accumulation of beta amyloid: Investigation of P-glycoprotein as a novel therapeutic target for Alzheimer\u2019s disease","volume":"63","author":"Abuznait","year":"2011","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"149","DOI":"10.2119\/molmed.2010.00180","article-title":"Selective antihypertensive dihydropyridines lower A\u03b2 accumulation by targeting both the production and the clearance of A\u03b2 across the blood-brain barrier","volume":"17","author":"Paris","year":"2011","journal-title":"Mol. Med."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"11914","DOI":"10.1074\/jbc.274.17.11914","article-title":"\u03b3-Secretase, Evidence for Multiple Proteolytic Activities and Influence of Membrane Positioning of Substrate on Generation of Amyloid \u03b2 Peptides of Varying Length","volume":"274","author":"Murphy","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.nbd.2007.12.005","article-title":"LRP promotes endocytosis and degradation, but not transcytosis, of the amyloid-beta peptide in a blood-brain barrier in vitro model","volume":"30","author":"Nazer","year":"2008","journal-title":"Neurobiol. Dis."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"11172","DOI":"10.1073\/pnas.0603838103","article-title":"Alzheimer\u2019s disease \u03b2-amyloid peptides are released in association with exosomes","volume":"103","author":"Rajendran","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Yuyama, K., and Igarashi, Y. (2017). Exosomes as Carriers of Alzheimer\u2019s Amyloid-\u00df. Front. Neurosci., 11.","DOI":"10.3389\/fnins.2017.00229"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"118","DOI":"10.3389\/fnagi.2018.00118","article-title":"The Physiological Roles of Amyloid-\u03b2 Peptide Hint at New Ways to Treat Alzheimer\u2019s Disease","volume":"10","author":"Brothers","year":"2018","journal-title":"Front. Aging Neurosci."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"2046","DOI":"10.1016\/j.febslet.2013.05.010","article-title":"The amyloid precursor protein: A biochemical enigma in brain development, function and disease","volume":"587","author":"Nalivaeva","year":"2013","journal-title":"FEBS Lett."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Hartz, A.M.S., Zhong, Y., Shen, A.N., Abner, E.L., and Bauer, B. (2018). Preventing P-gp Ubiquitination Lowers A\u03b2 Brain Levels in an Alzheimer\u2019s Disease Mouse Model. Front. Aging Neurosci., 10.","DOI":"10.3389\/fnagi.2018.00186"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1111\/bpa.12069","article-title":"John\u2019s Wort reduces beta-amyloid accumulation in a double transgenic Alzheimer\u2019s disease mouse model-role of P-glycoprotein","volume":"24","author":"Brenn","year":"2014","journal-title":"Brain Pathol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/s00401-019-02087-9","article-title":"From the prion-like propagation hypothesis to therapeutic strategies of anti-tau immunotherapy","volume":"139","author":"Colin","year":"2020","journal-title":"Acta Neuropathol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1007\/s00401-015-1413-4","article-title":"Templated misfolding of Tau by prion-like seeding along neuronal connections impairs neuronal network function and associated behavioral outcomes in Tau transgenic mice","volume":"129","author":"Stancu","year":"2015","journal-title":"Acta Neuropathol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1007\/s00401-019-02040-w","article-title":"Evidence for bidirectional and trans-synaptic parasympathetic and sympathetic propagation of alpha-synuclein in rats","volume":"138","author":"Ferreira","year":"2019","journal-title":"Acta Neuropathol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1186\/s40478-019-0865-5","article-title":"Organotypic slice culture model demonstrates inter-neuronal spreading of alpha-synuclein aggregates","volume":"7","author":"Elfarrash","year":"2019","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Walker, L.C., Schelle, J., and Jucker, M. (2016). The Prion-Like Properties of Amyloid-\u03b2 Assemblies: Implications for Alzheimer\u2019s Disease. Cold Spring Harb. Perspect. Med., 6.","DOI":"10.1101\/cshperspect.a024398"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1016\/j.neuron.2014.01.045","article-title":"ApoE and Abeta in Alzheimer\u2019s disease: Accidental encounters or partners?","volume":"81","author":"Kanekiyo","year":"2014","journal-title":"Neuron"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1038\/s41582-019-0228-7","article-title":"Apolipoprotein E and Alzheimer disease: Pathobiology and targeting strategies","volume":"15","author":"Yamazaki","year":"2019","journal-title":"Nat. Rev. Neurol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1038","DOI":"10.3389\/fnins.2018.01038","article-title":"Functional and Structural Changes of the Blood-Nerve-Barrier in Diabetic Neuropathy","volume":"12","author":"Richner","year":"2018","journal-title":"Front. Neurosci."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"2475","DOI":"10.1016\/j.neurobiolaging.2015.05.020","article-title":"P-glycoprotein expression and amyloid accumulation in human aging and Alzheimer\u2019s disease: Preliminary observations","volume":"36","author":"Chiu","year":"2015","journal-title":"Neurobiol. Aging"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1818","DOI":"10.1016\/j.neurobiolaging.2008.02.002","article-title":"Blood-brain barrier P-glycoprotein function decreases in specific brain regions with aging: A possible role in progressive neurodegeneration","volume":"30","author":"Bartels","year":"2009","journal-title":"Neurobiol. Aging"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.brainres.2011.08.044","article-title":"Beta amyloid effects on expression of multidrug efflux transporters in brain endothelial cells","volume":"1418","author":"Kania","year":"2011","journal-title":"Brain Res."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"e1299","DOI":"10.1038\/cddis.2014.258","article-title":"Abeta1-42 reduces P-glycoprotein in the blood-brain barrier through RAGE-NF-kappaB signaling","volume":"5","author":"Park","year":"2014","journal-title":"Cell Death Dis."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1930","DOI":"10.1523\/JNEUROSCI.0350-15.2016","article-title":"A\u03b240 Reduces P-Glycoprotein at the Blood\u2013Brain Barrier through the Ubiquitin\u2013Proteasome Pathway","volume":"36","author":"Hartz","year":"2016","journal-title":"J. Neurosci."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1038\/s41588-018-0311-9","article-title":"Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer\u2019s disease risk","volume":"51","author":"Jansen","year":"2019","journal-title":"Nat. Genet."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1186\/2191-219X-2-57","article-title":"Blood-brain barrier P-glycoprotein function in healthy subjects and Alzheimer\u2019s disease patients: Effect of polymorphisms in the ABCB1 gene","volume":"2","author":"Lubberink","year":"2012","journal-title":"EJNMMI Res."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/S0076-6879(06)13002-5","article-title":"Preparation of Amyloid \u03b2-Protein for Structural and Functional Studies","volume":"413","author":"Teplow","year":"2006","journal-title":"Methods Enzymol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0003-2697(88)90002-4","article-title":"A method for the determination of inorganic phosphate in the presence of labile organic phosphate and high concentrations of protein: Application to lens ATPases","volume":"168","author":"Chifflet","year":"1988","journal-title":"Anal. Biochem."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1016\/j.bbalip.2010.05.012","article-title":"Modulation of amyloid precursor protein processing by synthetic ceramide analogues","volume":"1801","author":"Li","year":"2010","journal-title":"Biochim. Biophys. Acta Mol. Cell Biol. Lipids"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.neulet.2009.11.016","article-title":"Memantine treatment decreases levels of secreted Alzheimer\u2019s amyloid precursor protein (APP) and amyloid beta (A beta) peptide in the human neuroblastoma cells","volume":"470","author":"Ray","year":"2010","journal-title":"Neurosci. Lett."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"160","DOI":"10.4077\/CJP.2009.AMH062","article-title":"Inhibitory effect of piperlonguminine\/dihydropiperlonguminine on the production of amyloid beta and APP in SK-N-SH cells","volume":"52","author":"Qi","year":"2009","journal-title":"Chin. J. Physiol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/1\/246\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:47:15Z","timestamp":1760179635000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/1\/246"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,29]]},"references-count":93,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,1]]}},"alternative-id":["ijms22010246"],"URL":"https:\/\/doi.org\/10.3390\/ijms22010246","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,29]]}}}