Abstract
The accumulation of neurotoxic amyloid-beta (Aβ) in the brain is one of the characteristic hallmarks of Alzheimer’s disease (AD). Aβ-peptide brain homeostasis is governed by its production and various clearance mechanisms. The blood-brain barrier provides a large surface area for influx and efflux mechanisms into and out of the brain. Different transporters and receptors have been implicated to play crucial roles in Aβ clearance from brain. Besides Aβ transport, the blood-brain barrier tightly regulates the brain’s microenvironment; however, vascular alterations have been shown in patients with AD. Here, we summarize how the blood-brain barrier changes during aging and in disease and focus on recent findings of how the ABC transporter P-glycoprotein (ABCB1/P-gp) and the receptor low-density lipoprotein receptor-related protein 1 (LRP1) play a role in Aβ clearance from brain.
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Abbott NJ, Pizzo ME, Preston JE, Janigro D, Thorne RG (2018) The role of brain barriers in fluid movement in the CNS: is there a ‘glymphatic’ system? Acta Neuropathol 135(3):387–407. https://doi.org/10.1007/s00401-018-1812-4
Alzheimer A (1906) Über einen eigenartigen schweren Erkrankungsprozeß der Hirnrind. Neurologisches Centralblatt 23:1129–1136
Alzheimer A (1907) Über eine eigenartige Erkrankung der Hirnrinde. Allgemeine Zeitschrift für Psychiatrie und Psychisch-Gerichtliche Medizin 64:146–148
Barakat S, Demeule M, Pilorget A, Regina A, Gingras D, Baggetto LG, Beliveau R (2007) Modulation of p-glycoprotein function by caveolin-1 phosphorylation. J Neurochem 101(1):1–8. https://doi.org/10.1111/j.1471-4159.2006.04410.x
Barthelemy NR, Li Y, Joseph-Mathurin N, Gordon BA, Hassenstab J, Benzinger TLS, Dominantly Inherited Alzheimer, N (2020) A soluble phosphorylated tau signature links tau, amyloid and the evolution of stages of dominantly inherited Alzheimer's disease. [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t]. Nat Med 26(3):398–407. https://doi.org/10.1038/s41591-020-0781-z
Bateman RJ, Munsell LY, Morris JC, Swarm R, Yarasheski KE, Holtzman DM (2006) Human amyloid-beta synthesis and clearance rates as measured in cerebrospinal fluid in vivo. [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t]. Nat Med 12(7):856–861. https://doi.org/10.1038/nm1438
Bell RD, Zlokovic BV (2009) Neurovascular mechanisms and blood-brain barrier disorder in Alzheimer's disease. [Research Support, N.I.H., Extramural Review]. Acta Neuropathol 118(1):103–113. https://doi.org/10.1007/s00401-009-0522-3
Bell RD, Sagare AP, Friedman AE, Bedi GS, Holtzman DM, Deane R, Zlokovic BV (2007) Transport pathways for clearance of human Alzheimer's amyloid beta-peptide and apolipoproteins E and J in the mouse central nervous system. [Research Support, N.I.H., Extramural]. J Cereb Blood Flow Metab 27(5):909–918. https://doi.org/10.1038/sj.jcbfm.9600419
Bell RD, Deane R, Chow N, Long X, Sagare A, Singh I, Zlokovic BV (2009) SRF and myocardin regulate LRP-mediated amyloid-beta clearance in brain vascular cells. [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t]. Nat Cell Biol 11(2):143–153. https://doi.org/10.1038/ncb1819
Bell RD, Winkler EA, Singh I, Sagare AP, Deane R, Wu Z, Zlokovic BV (2012) Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature 485(7399):512–516. https://doi.org/10.1038/nature11087
Ben-Zvi A, Lacoste B, Kur E, Andreone BJ, Mayshar Y, Yan H, Gu C (2014) Mfsd2a is critical for the formation and function of the blood-brain barrier. Nature 509(7501):507–511. https://doi.org/10.1038/nature13324
Berkenbosch F, Refolo LM, Friedrich VL Jr, Casper D, Blum M, Robakis NK (1990) The Alzheimer’s amyloid precursor protein is produced by type I astrocytes in primary cultures of rat neuroglia. [Research Support, Non-U.S. Gov't Research Support, U.S. Gov’t, P.H.S.]. J Neurosci Res 25(3):431–440. https://doi.org/10.1002/jnr.490250321
Biron KE, Dickstein DL, Gopaul R, Jefferies WA (2011) Amyloid triggers extensive cerebral angiogenesis causing blood brain barrier permeability and hypervascularity in Alzheimer’s disease. [Research Support, Non-U.S. Gov’t]. PLoS One 6(8):e23789. https://doi.org/10.1371/journal.pone.0023789
Blanchard JW, Bula M, Davila-Velderrain J, Akay LA, Zhu L, Frank A, Tsai LH (2020) Reconstruction of the human blood-brain barrier in vitro reveals a pathogenic mechanism of APOE4 in pericytes. Nat Med 26(6):952–963. https://doi.org/10.1038/s41591-020-0886-4
Bloom GS (2014) Amyloid-beta and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurol 71(4):505–508. https://doi.org/10.1001/jamaneurol.2013.5847
Bu XL, Xiang Y, Jin WS, Wang J, Shen LL, Huang ZL, Wang YJ (2017) Blood-derived amyloid-beta protein induces Alzheimer’s disease pathologies. Mol Psychiatry. https://doi.org/10.1038/mp.2017.204
Burstein AH, Sabbagh M, Andrews R, Valcarce C, Dunn I, Altstiel L (2018) Development of Azeliragon, an Oral small molecule antagonist of the receptor for advanced glycation Endproducts, for the potential slowing of loss of cognition in mild Alzheimer’s Disease. [Research Support, Non-U.S. Gov’t Review]. J Prev Alzheimers Dis 5(2):149–154. https://doi.org/10.14283/jpad.2018.18
Carrano A, Hoozemans JJ, van der Vies SM, Rozemuller AJ, van Horssen J, de Vries HE (2011) Amyloid Beta induces oxidative stress-mediated blood-brain barrier changes in capillary amyloid angiopathy. [Research Support, Non-U.S. Gov’t]. Antioxid Redox Signal 15(5):1167–1178. https://doi.org/10.1089/ars.2011.3895
Cirrito JR, Deane R, Fagan AM, Spinner ML, Parsadanian M, Finn MB, Holtzman DM (2005) P-glycoprotein deficiency at the blood-brain barrier increases amyloid-beta deposition in an Alzheimer disease mouse model. [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov’t, Non-P.H.S.]. J Clin Investig 115(11):3285–3290. https://doi.org/10.1172/JCI25247
Citron M, Vigo-Pelfrey C, Teplow DB, Miller C, Schenk D, Johnston J, Selkoe DJ (1994) Excessive production of amyloid beta-protein by peripheral cells of symptomatic and presymptomatic patients carrying the Swedish familial Alzheimer disease mutation. [Research Support, Non-U.S. Gov’t Research Support, U.S. Gov’t, P.H.S.]. Proc Natl Acad Sci U S A 91(25):11993–11997. https://doi.org/10.1073/pnas.91.25.11993
Cullen KM, Kocsi Z, Stone J (2005) Pericapillary haem-rich deposits: evidence for microhaemorrhages in aging human cerebral cortex. J Cereb Blood Flow Metab 25(12):1656–1667. https://doi.org/10.1038/sj.jcbfm.9600155
Da Mesquita S, Louveau A, Vaccari A, Smirnov I, Cornelison RC, Kingsmore KM, Kipnis J (2018) Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease. [Research Support, N.I.H., Extramural]. Nature 560(7717):185–191. https://doi.org/10.1038/s41586-018-0368-8
Daneman R, Zhou L, Kebede AA, Barres BA (2010) Pericytes are required for blood-brain barrier integrity during embryogenesis. Nature 468(7323):562–566. https://doi.org/10.1038/nature09513
Deane R, Du Yan S, Submamaryan RK, LaRue B, Jovanovic S, Hogg E, Zlokovic B (2003) RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain. Nat Med 9(7):907–913. https://doi.org/10.1038/nm890
Deane R, Sagare A, Hamm K, Parisi M, LaRue B, Guo H, Zlokovic BV (2005) IgG-assisted age-dependent clearance of Alzheimer’s amyloid beta peptide by the blood-brain barrier neonatal Fc receptor. [Comparative Study Research Support, N.I.H., Extramural]. J Neurosci 25(50):11495–11503. https://doi.org/10.1523/JNEUROSCI.3697-05.2005
Deane R, Sagare A, Hamm K, Parisi M, Lane S, Finn MB, Zlokovic BV (2008) apoE isoform-specific disruption of amyloid beta peptide clearance from mouse brain. [Research Support, N.I.H., Extramural]. J Clin Invest 118(12):4002–4013. https://doi.org/10.1172/JCI36663
Deane R, Singh I, Sagare AP, Bell RD, Ross NT, LaRue B, Zlokovic BV (2012) A multimodal RAGE-specific inhibitor reduces amyloid beta-mediated brain disorder in a mouse model of Alzheimer disease. J Clin Investig 122(4):1377–1392. https://doi.org/10.1172/JCI58642
Deo AK, Borson S, Link JM, Domino K, Eary JF, Ke B, Unadkat JD (2014) Activity of P-glycoprotein, a beta-amyloid transporter at the blood-brain barrier, is compromised in patients with mild Alzheimer Disease. [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t]. J Nucl Med 55(7):1106–1111. https://doi.org/10.2967/jnumed.113.130161
Devraj K, Poznanovic S, Spahn C, Schwall G, Harter PN, Mittelbronn M, Liebner S (2016) BACE-1 is expressed in the blood-brain barrier endothelium and is upregulated in a murine model of Alzheimer's disease. [Research Support, Non-U.S. Gov’t]. J Cereb Blood Flow Metab 36(7):1281–1294. https://doi.org/10.1177/0271678X15606463
Do TM, Noel-Hudson MS, Ribes S, Besengez C, Smirnova M, Cisternino S, Bourasset F (2012) ABCG2- and ABCG4-mediated efflux of amyloid-beta peptide 1-40 at the mouse blood-brain barrier. J Alzheimers Dis 30(1):155–166. https://doi.org/10.3233/JAD-2012-112189
Do TM, Bedussi B, Chasseigneaux S, Dodacki A, Yapo C, Chacun H, Bourasset F (2013) Oatp1a4 and an L-thyroxine-sensitive transporter mediate the mouse blood-brain barrier transport of amyloid-beta peptide. J Alzheimers Dis 36(3):555–561. https://doi.org/10.3233/JAD-121891
Edgren G, Hjalgrim H, Rostgaard K, Lambert P, Wikman A, Norda R, Nyren O (2016) Transmission of neurodegenerative disorders through blood transfusion: a cohort study. [Observational Study]. Ann Intern Med 165(5):316–324. https://doi.org/10.7326/M15-2421
Eisele YS, Bolmont T, Heikenwalder M, Langer F, Jacobson LH, Yan ZX, Jucker M (2009) Induction of cerebral beta-amyloidosis: intracerebral versus systemic Abeta inoculation. [Comparative Study Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t]. Proc Natl Acad Sci U S A 106(31):12926–12931. https://doi.org/10.1073/pnas.0903200106
Eisele YS, Obermuller U, Heilbronner G, Baumann F, Kaeser SA, Wolburg H, Jucker M (2010) Peripherally applied Abeta-containing inoculates induce cerebral beta-amyloidosis. [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't]. Science 330(6006):980–982. https://doi.org/10.1126/science.1194516
Eisele YS, Fritschi SK, Hamaguchi T, Obermuller U, Fuger P, Skodras A, Jucker M (2014) Multiple factors contribute to the peripheral induction of cerebral beta-amyloidosis. [Research Support, Non-U.S. Gov’t]. J Neurosci 34(31):10264–10273. https://doi.org/10.1523/JNEUROSCI.1608-14.2014
Frackowiak J, Potempska A, LeVine H, Haske T, Dickson D, Mazur-Kolecka B (2005) Extracellular deposits of a beta produced in cultures of Alzheimer disease brain vascular smooth muscle cells. [Comparative Study Research Support, Non-U.S. Gov’t Research Support, U.S. Gov’t, P.H.S.]. J Neuropathol Exp Neurol 64(1):82–90. https://doi.org/10.1093/jnen/64.1.82
Gindorf M, Storck SE, Ohler A, Scharfenberg F, Becker-Pauly C, Pietrzik CU (2020) Meprin beta: a novel regulator of blood-brain barrier integrity. J Cereb Blood Flow Metab:271678X20905206. https://doi.org/10.1177/0271678X20905206
Gowert NS, Donner L, Chatterjee M, Eisele YS, Towhid ST, Munzer P, Elvers M (2014) Blood platelets in the progression of Alzheimer’s disease. [Research Support, Non-U.S. Gov’t]. PLoS One 9(2):e90523. https://doi.org/10.1371/journal.pone.0090523
Halliday MR, Rege SV, Ma Q, Zhao Z, Miller CA, Winkler EA, Zlokovic BV (2016) Accelerated pericyte degeneration and blood-brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer’s disease. J Cereb Blood Flow Metab 36(1):216–227. https://doi.org/10.1038/jcbfm.2015.44
Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere ML, Williams J (2009) Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nat Genet 41(10):1088–1093. https://doi.org/10.1038/ng.440
Hartz AM, Bauer B, Soldner EL, Wolf A, Boy S, Backhaus R, Schlachetzki F (2012) Amyloid-beta contributes to blood-brain barrier leakage in transgenic human amyloid precursor protein mice and in humans with cerebral amyloid angiopathy. [Research Support, Non-U.S. Gov’t]. Stroke 43(2):514–523. https://doi.org/10.1161/STROKEAHA.111.627562
Hudson N, Celkova L, Hopkins A, Greene C, Storti F, Ozaki E, Campbell M (2019) Dysregulated claudin-5 cycling in the inner retina causes retinal pigment epithelial cell atrophy. [Research Support, Non-U.S. Gov’t]. JCI Insight 4(15). https://doi.org/10.1172/jci.insight.130273
Iadecola C (2004) Neurovascular regulation in the normal brain and in Alzheimer’s disease. [Research Support, U.S. Gov’t, P.H.S. Review]. Nat Rev Neurosci 5(5):347–360. https://doi.org/10.1038/nrn1387
Iadecola C (2016) Vascular and Metabolic Factors in Alzheimer’s Disease and Related Dementias: Introduction. Cell Mol Neurobiol. https://doi.org/10.1007/s10571-015-0319-y
Iliff J, Simon M (2019) CrossTalk proposal: the glymphatic system supports convective exchange of cerebrospinal fluid and brain interstitial fluid that is mediated by perivascular aquaporin-4. J Physiol. https://doi.org/10.1113/JP277635
Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, Nedergaard M (2012) A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t Research Support, U.S. Gov’t, Non-P.H.S.]. Sci Transl Med 4(147):147ra111. https://doi.org/10.1126/scitranslmed.3003748
Iturria-Medina Y, Sotero RC, Toussaint PJ, Mateos-Perez JM, Evans AC, Alzheimer’s Disease Neuroimaging, I (2016) Early role of vascular dysregulation on late-onset Alzheimer’s disease based on multifactorial data-driven analysis. Nat Commun 7:11934. https://doi.org/10.1038/ncomms11934
Jiang S, Zhang M, Ren D, Tang G, Lin S, Qian Y, Wang D (2003) Enhanced production of amyloid precursor protein mRNA by peripheral mononuclear blood cell in Alzheimer’s disease. [Comparative Study Research Support, Non-U.S. Gov’t]. Am J Med Genet B Neuropsychiatr Genet 118B(1):99–102. https://doi.org/10.1002/ajmg.b.10067
Jun G, Naj AC, Beecham GW, Wang LS, Buros J, Gallins PJ, Schellenberg GD (2010) Meta-analysis confirms CR1, CLU, and PICALM as alzheimer disease risk loci and reveals interactions with APOE genotypes. Arch Neurol 67(12):1473–1484. https://doi.org/10.1001/archneurol.2010.201
Kalaria RN, Harik SI (1989) Reduced glucose transporter at the blood-brain barrier and in cerebral cortex in Alzheimer disease. J Neurochem 53(4):1083–1088
Kanekiyo T, Liu CC, Shinohara M, Li J, Bu G (2012) LRP1 in brain vascular smooth muscle cells mediates local clearance of Alzheimer’s amyloid-beta. [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t]. J Neurosci 32(46):16458–16465. https://doi.org/10.1523/JNEUROSCI.3987-12.2012
Kang DE, Pietrzik CU, Baum L, Chevallier N, Merriam DE, Kounnas MZ, Koo EH (2000) Modulation of amyloid beta-protein clearance and Alzheimer’s disease susceptibility by the LDL receptor-related protein pathway. [Research Support, Non-U.S. Gov’t Research Support, U.S. Gov’t, P.H.S.]. J Clin Investig 106(9):1159–1166. https://doi.org/10.1172/JCI11013
Kariolis MS, Wells RC, Getz JA, Kwan W, Mahon CS, Tong R, Zuchero YJY (2020) Brain delivery of therapeutic proteins using an Fc fragment blood-brain barrier transport vehicle in mice and monkeys. Sci Transl Med 12(545). https://doi.org/10.1126/scitranslmed.aay1359
Keaney J, Walsh DM, O’Malley T, Hudson N, Crosbie DE, Loftus T, Campbell M (2015) Autoregulated paracellular clearance of amyloid-beta across the blood-brain barrier. Sci Adv 1(8):e1500472. https://doi.org/10.1126/sciadv.1500472
Kitazume S, Tachida Y, Kato M, Yamaguchi Y, Honda T, Hashimoto Y, Taniguchi N (2010) Brain endothelial cells produce amyloid {beta} from amyloid precursor protein 770 and preferentially secrete the O-glycosylated form. [Research Support, Non-U.S. Gov’t]. J Biol Chem 285(51):40097–40103. https://doi.org/10.1074/jbc.M110.144626
Kress BT, Iliff JJ, Xia M, Wang M, Wei HS, Zeppenfeld D, Nedergaard M (2014) Impairment of paravascular clearance pathways in the aging brain. [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t]. Ann Neurol 76(6):845–861. https://doi.org/10.1002/ana.24271
Krohn M, Lange C, Hofrichter J, Scheffler K, Stenzel J, Steffen J, Pahnke J (2011) Cerebral amyloid-beta proteostasis is regulated by the membrane transport protein ABCC1 in mice. [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t]. J Clin Investig 121(10):3924–3931. https://doi.org/10.1172/JCI57867
Lamartiniere Y, Boucau MC, Dehouck L, Krohn M, Pahnke J, Candela P, Fenart L (2018) ABCA7 downregulation modifies cellular cholesterol homeostasis and decreases amyloid-beta peptide efflux in an in vitro model of the blood-brain barrier. J Alzheimers Dis 64(4):1195–1211. https://doi.org/10.3233/JAD-170883
Lee JH, Cheng R, Barral S, Reitz C, Medrano M, Lantigua R, Mayeux R (2011) Identification of novel loci for Alzheimer disease and replication of CLU, PICALM, and BIN1 in Caribbean Hispanic individuals. [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t]. Arch Neurol 68(3):320–328. https://doi.org/10.1001/archneurol.2010.292
Leinenga G, Gotz J (2015) Scanning ultrasound removes amyloid-beta and restores memory in an Alzheimer’s disease mouse model. [Research Support, Non-U.S. Gov't]. Sci Transl Med 7(278):278ra233. https://doi.org/10.1126/scitranslmed.aaa2512
Li Y, Lu W, Marzolo MP, Bu G (2001) Differential functions of members of the low density lipoprotein receptor family suggested by their distinct endocytosis rates. [Research Support, Non-U.S. Gov’t Research Support, U.S. Gov’t, P.H.S.]. J Biol Chem 276(21):18000–18006. https://doi.org/10.1074/jbc.M101589200
Lipsman N, Meng Y, Bethune AJ, Huang Y, Lam B, Masellis M, Black SE (2018) Blood-brain barrier opening in Alzheimer’s disease using MR-guided focused ultrasound. [Clinical Trial, Phase I Research Support, Non-U.S. Gov’t]. Nat Commun 9(1):2336. https://doi.org/10.1038/s41467-018-04529-6
Liu CC, Hu J, Zhao N, Wang J, Wang N, Cirrito JR, Bu G (2017) Astrocytic LRP1 mediates brain Abeta clearance and impacts amyloid deposition. J Neurosci 37(15):4023–4031. https://doi.org/10.1523/JNEUROSCI.3442-16.2017
Long JM, Holtzman DM (2019) Alzheimer Disease: an update on pathobiology and treatment strategies. [Research Support, N.I.H., Extramural Review]. Cell 179(2):312–339. https://doi.org/10.1016/j.cell.2019.09.001
Mandrekar-Colucci S, Karlo JC, Landreth GE (2012) Mechanisms underlying the rapid peroxisome proliferator-activated receptor-gamma-mediated amyloid clearance and reversal of cognitive deficits in a murine model of Alzheimer’s disease. [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t]. J Neurosci 32(30):10117–10128. https://doi.org/10.1523/JNEUROSCI.5268-11.2012
Mattsson-Carlgren N, Andersson E, Janelidze S, Ossenkoppele R, Insel P, Strandberg O, Hansson O (2020) Abeta deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease. Sci Adv 6(16):eaaz2387. https://doi.org/10.1126/sciadv.aaz2387
Mawuenyega KG, Sigurdson W, Ovod V, Munsell L, Kasten T, Morris JC, Bateman RJ (2010) Decreased clearance of CNS beta-amyloid in Alzheimer’s disease. [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t]. Science 330(6012):1774. https://doi.org/10.1126/science.1197623
Meng Y, MacIntosh BJ, Shirzadi Z, Kiss A, Bethune A, Heyn C, Lipsman N (2019) Resting state functional connectivity changes after MR-guided focused ultrasound mediated blood-brain barrier opening in patients with Alzheimer’s disease. [Research Support, Non-U.S. Gov’t]. NeuroImage 200:275–280. https://doi.org/10.1016/j.neuroimage.2019.06.060
Meyer EP, Ulmann-Schuler A, Staufenbiel M, Krucker T (2008) Altered morphology and 3D architecture of brain vasculature in a mouse model for Alzheimer’s disease. Proc Natl Acad Sci U S A 105(9):3587–3592. https://doi.org/10.1073/pnas.0709788105
Milikovsky DZ, Ofer J, Senatorov VV Jr, Friedman AR, Prager O, Sheintuch L, Friedman A (2019) Paroxysmal slow cortical activity in Alzheimer’s disease and epilepsy is associated with blood-brain barrier dysfunction. [Research Support, Non-U.S. Gov’t]. Sci Transl Med 11(521). https://doi.org/10.1126/scitranslmed.aaw8954
Montagne A, Barnes SR, Sweeney MD, Halliday MR, Sagare AP, Zhao Z, Zlokovic BV (2015) Blood-brain barrier breakdown in the aging human hippocampus. [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t]. Neuron 85(2):296–302. https://doi.org/10.1016/j.neuron.2014.12.032
Montagne A, Nation DA, Sagare AP, Barisano G, Sweeney MD, Chakhoyan A, Zlokovic BV (2020) APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline. Nature 581(7806):71–76. https://doi.org/10.1038/s41586-020-2247-3
Nikolakopoulou AM, Montagne A, Kisler K, Dai Z, Wang Y, Huuskonen MT, Zlokovic BV (2019) Pericyte loss leads to circulatory failure and pleiotrophin depletion causing neuron loss. Nat Neurosci 22(7):1089–1098. https://doi.org/10.1038/s41593-019-0434-z
Nisbet RM, Van der Jeugd A, Leinenga G, Evans HT, Janowicz PW, Gotz J (2017) Combined effects of scanning ultrasound and a tau-specific single chain antibody in a tau transgenic mouse model. Brain 140(5):1220–1230. https://doi.org/10.1093/brain/awx052
Osgood D, Miller MC, Messier AA, Gonzalez L, Silverberg GD (2017) Aging alters mRNA expression of amyloid transporter genes at the blood-brain barrier. Neurobiol Aging 57:178–185. https://doi.org/10.1016/j.neurobiolaging.2017.05.011
Park SW, Kim JH, Mook-Jung I, Kim KW, Park WJ, Park KH, Kim JH (2014) Intracellular amyloid beta alters the tight junction of retinal pigment epithelium in 5XFAD mice. Neurobiol Aging 35(9):2013–2020. https://doi.org/10.1016/j.neurobiolaging.2014.03.008
Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP (2013) The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dement 9(1):63–75 e62. https://doi.org/10.1016/j.jalz.2012.11.007
Purro SA, Farrow MA, Linehan J, Nazari T, Thomas DX, Chen Z, Collinge J (2018) Transmission of amyloid-beta protein pathology from cadaveric pituitary growth hormone. [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t]. Nature 564(7736):415–419. https://doi.org/10.1038/s41586-018-0790-y
Raina P, Santaguida P, Ismaila A, Patterson C, Cowan D, Levine M, Oremus M (2008) Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline. [Meta-Analysis Research Support, Non-U.S. Gov’t Research Support, U.S. Gov’t, P.H.S. Review]. Ann Intern Med 148(5):379–397. https://doi.org/10.7326/0003-4819-148-5-200803040-00009
Rauch JN, Luna G, Guzman E, Audouard M, Challis C, Sibih YE, Kosik KS (2020) LRP1 is a master regulator of tau uptake and spread. Nature 580(7803):381–385. https://doi.org/10.1038/s41586-020-2156-5
Roher AE, Debbins JP, Malek-Ahmadi M, Chen K, Pipe JG, Maze S, Beach TG (2012) Cerebral blood flow in Alzheimer’s disease. Vasc Health Risk Manag 8:599–611. https://doi.org/10.2147/VHRM.S34874
Sagare A, Deane R, Bell RD, Johnson B, Hamm K, Pendu R, Zlokovic BV (2007) Clearance of amyloid-beta by circulating lipoprotein receptors. [Research Support, N.I.H., Extramural]. Nat Med 13(9):1029–1031. https://doi.org/10.1038/nm1635
Schlenzig D, Cynis H, Hartlage-Rubsamen M, Zeitschel U, Menge K, Fothe A, Demuth HU (2018) Dipeptidyl-peptidase activity of Meprin beta links N-truncation of Abeta with Glutaminyl cyclase-catalyzed pGlu-Abeta formation. [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t]. J Alzheimers Dis 66(1):359–375. https://doi.org/10.3233/JAD-171183
Schneider L (2020) A resurrection of aducanumab for Alzheimer’s disease. Lancet Neurol 19(2):111–112. https://doi.org/10.1016/S1474-4422(19)30480-6
Schonherr C, Bien J, Isbert S, Wichert R, Prox J, Altmeppen H, Pietrzik CU (2016) Generation of aggregation prone N-terminally truncated amyloid beta peptides by meprin beta depends on the sequence specificity at the cleavage site. [Research Support, Non-U.S. Gov’t]. Mol Neurodegener 11:19. https://doi.org/10.1186/s13024-016-0084-5
Senatorov VV Jr, Friedman AR, Milikovsky DZ, Ofer J, Saar-Ashkenazy R, Charbash A, Kaufer D (2019) Blood-brain barrier dysfunction in aging induces hyperactivation of TGFbeta signaling and chronic yet reversible neural dysfunction. [Research Support, Non-U.S. Gov’t Research Support, N.I.H., Extramural Research Support, U.S. Gov’t, Non-P.H.S.]. Sci Transl Med 11(521). https://doi.org/10.1126/scitranslmed.aaw8283
Sengillo JD, Winkler EA, Walker CT, Sullivan JS, Johnson M, Zlokovic BV (2013) Deficiency in mural vascular cells coincides with blood-brain barrier disruption in Alzheimer's disease. Brain Pathol 23(3):303–310. https://doi.org/10.1111/bpa.12004
Shackleton B, Crawford F, Bachmeier C (2016) Inhibition of ADAM10 promotes the clearance of Abeta across the BBB by reducing LRP1 ectodomain shedding. Fluids Barr CNS 13(1):14. https://doi.org/10.1186/s12987-016-0038-x
Shibata M, Yamada S, Kumar SR, Calero M, Bading J, Frangione B, Zlokovic BV (2000) Clearance of Alzheimer's amyloid-ss(1-40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. [Research Support, U.S. Gov’t, P.H.S.]. J Clin Investig 106(12):1489–1499. https://doi.org/10.1172/JCI10498
Silverberg GD, Messier AA, Miller MC, Machan JT, Majmudar SS, Stopa EG, Johanson CE (2010a) Amyloid efflux transporter expression at the blood-brain barrier declines in normal aging. [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t]. J Neuropathol Exp Neurol 69(10):1034–1043. https://doi.org/10.1097/NEN.0b013e3181f46e25
Silverberg GD, Miller MC, Messier AA, Majmudar S, Machan JT, Donahue JE, Johanson CE (2010b) Amyloid deposition and influx transporter expression at the blood-brain barrier increase in normal aging. [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t]. J Neuropathol Exp Neurol 69(1):98–108. https://doi.org/10.1097/NEN.0b013e3181c8ad2f
Smith AJ, Verkman AS (2019) CrossTalk opposing view: going against the flow: interstitial solute transport in brain is diffusive and aquaporin-4 independent. J Physiol. https://doi.org/10.1113/JP277636
Stitt AW, Burke GA, Chen F, McMullen CB, Vlassara H (2000) Advanced glycation end-product receptor interactions on microvascular cells occur within caveolin-rich membrane domains. FASEB J 14(15):2390–2392. https://doi.org/10.1096/fj.00-0289fje
Storck SE, Pietrzik CU (2017) Endothelial LRP1 – a potential target for the treatment of Alzheimer's Disease : theme: drug discovery, development and delivery in Alzheimer’s Disease guest editor: Davide Brambilla. [Review]. Pharm Res 34(12):2637–2651. https://doi.org/10.1007/s11095-017-2267-3
Storck SE, Pietrzik CU (2018) The blood brain-barrier and its role in Alzheimer’s disease. e-Neuroforum 24(4):A197–A205. https://doi.org/10.1515/nf-2018-A014
Storck SE, Meister S, Nahrath J, Meissner JN, Schubert N, Di Spiezio A, Pietrzik CU (2016) Endothelial LRP1 transports amyloid-beta1-42 across the blood-brain barrier. J Clin Investig 126(1):123–136. https://doi.org/10.1172/JCI81108
Storck SE, Hartz AMS, Bernard J, Wolf A, Kachlmeier A, Mahringer A, Pietrzik CU (2018) The concerted amyloid-beta clearance of LRP1 and ABCB1/P-gp across the blood-brain barrier is linked by PICALM. Brain Behav Immun. https://doi.org/10.1016/j.bbi.2018.07.017
Tarasoff-Conway JM, Carare RO, Osorio RS, Glodzik L, Butler T, Fieremans E, de Leon MJ (2015) Clearance systems in the brain-implications for Alzheimer disease. Nat Rev Neurol 11(8):457–470. https://doi.org/10.1038/nrneurol.2015.119
Thuenauer R, Muller SK, Romer W (2017) Pathways of protein and lipid receptor-mediated transcytosis in drug delivery. [Review]. Expert Opin Drug Deliv 14(3):341–351. https://doi.org/10.1080/17425247.2016.1220364
Van Gool B, Storck SE, Reekmans SM, Lechat B, Gordts P, Pradier L, Roebroek AJM (2019) LRP1 has a predominant role in production over clearance of Abeta in a mouse model of Alzheimer’s Disease. Mol Neurobiol 56(10):7234–7245. https://doi.org/10.1007/s12035-019-1594-2
Walter S, Jumpertz T, Huttenrauch M, Ogorek I, Gerber H, Storck SE, Weggen S (2019) The metalloprotease ADAMTS4 generates N-truncated Abeta4-x species and marks oligodendrocytes as a source of amyloidogenic peptides in Alzheimer’s disease. [Research Support, Non-U.S. Gov’t]. Acta Neuropathol 137(2):239–257. https://doi.org/10.1007/s00401-018-1929-5
Yamanaka M, Ishikawa T, Griep A, Axt D, Kummer MP, Heneka MT (2012) PPARgamma/RXRalpha-induced and CD36-mediated microglial amyloid-beta phagocytosis results in cognitive improvement in amyloid precursor protein/presenilin 1 mice. [Research Support, Non-U.S. Gov’t]. J Neurosci 32(48):17321–17331. https://doi.org/10.1523/JNEUROSCI.1569-12.2012
Yan SD, Chen X, Fu J, Chen M, Zhu H, Roher A, Schmidt AM (1996) RAGE and amyloid-beta peptide neurotoxicity in Alzheimer’s disease. [Research Support, Non-U.S. Gov’t Research Support, U.S. Gov’t, P.H.S.]. Nature 382(6593):685–691. https://doi.org/10.1038/382685a0
Yang AC, Stevens MY, Chen MB, Lee DP, Stahli D, Gate D, Wyss-Coray T (2020) Physiological blood-brain transport is impaired with age by a shift in transcytosis. Nature 583(7816):425–430. https://doi.org/10.1038/s41586-020-2453-z
Zandl-Lang M, Fanaee-Danesh E, Sun Y, Albrecher NM, Gali CC, Cancar I, Panzenboeck U (2018) Regulatory effects of simvastatin and apoJ on APP processing and amyloid-beta clearance in blood-brain barrier endothelial cells. [Research Support, Non-U.S. Gov’t]. Biochim Biophys Acta Mol Cell Biol Lipids 1863(1):40–60. https://doi.org/10.1016/j.bbalip.2017.09.008
Zhang SL, Yue Z, Arnold DM, Artiushin G, Sehgal A (2018) A circadian clock in the blood-brain barrier regulates xenobiotic efflux. [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t]. Cell 173(1):130–139 e110. https://doi.org/10.1016/j.cell.2018.02.017
Zhao J, O’Connor T, Vassar R (2011) The contribution of activated astrocytes to Abeta production: implications for Alzheimer’s disease pathogenesis. [Research Support, N.I.H., Extramural]. J Neuroinflammation 8:150. https://doi.org/10.1186/1742-2094-8-150
Zhao Z, Sagare AP, Ma Q, Halliday MR, Kong P, Kisler K, Zlokovic BV (2015) Central role for PICALM in amyloid-beta blood-brain barrier transcytosis and clearance. [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t]. Nat Neurosci 18(7):978–987. https://doi.org/10.1038/nn.4025
Zhu X, Raina AK, Perry G, Smith MA (2004) Alzheimer’s disease: the two-hit hypothesis. Lancet Neurol 3(4):219–226. https://doi.org/10.1016/S1474-4422(04)00707-0. PMID: 15039034
Zhu D, Su Y, Fu B, Xu H (2018) Magnesium reduces blood-brain barrier permeability and regulates amyloid-beta transcytosis. Mol Neurobiol 55(9):7118–7131. https://doi.org/10.1007/s12035-018-0896-0
Zlokovic BV (2005) Neurovascular mechanisms of Alzheimer’s neurodegeneration. [Research Support, U.S. Gov’t, P.H.S. Review]. Trends Neurosci 28(4):202–208. https://doi.org/10.1016/j.tins.2005.02.001
Zlokovic BV (2011) Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders. [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t Review]. Nat Rev Neurosci 12(12):723–738. https://doi.org/10.1038/nrn3114
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Storck, S.E., Hartz, A.M.S., Pietrzik, C.U. (2020). The Blood-Brain Barrier in Alzheimer’s Disease. In: Cader, Z., Neuhaus, W. (eds) Physiology, Pharmacology and Pathology of the Blood-Brain Barrier. Handbook of Experimental Pharmacology, vol 273. Springer, Cham. https://doi.org/10.1007/164_2020_418
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