ABCG2 Is Upregulated in Alzheimer's Brain with Cerebral Amyloid Angiopathy and May Act as a Gatekeeper at the Blood–Brain Barrier for Aβ1–40 Peptides

Alzheimer's disease (AD) is characterized by accumulation and deposition of Aβ peptides in the brain. Aβ deposition in cerebrovessels occurs in many AD patients and results in cerebral amyloid angiopathy (AD/CAA). Since Aβ can be transported across blood–brain barrier (BBB), aberrant Aβ trafficking across BBB may contribute to Aβ accumulation in the brain and CAA development. Expression analyses of 273 BBB-related genes performed in this study showed that the drug transporter, ABCG2, was significantly upregulated in the brains of AD/CAA compared with age-matched controls. Increased ABCG2 expression was confirmed by Q-PCR, Western blot, and immunohistochemistry. Abcg2 was also increased in mouse AD models, Tg-SwDI and 3XTg. Aβ alone or in combination with hypoxia/ischemia failed to stimulate ABCG2 expression in BBB endothelial cells; however, conditioned media from Aβ-activated microglia strongly induced ABCG2 expression. ABCG2 protein in AD/CAA brains interacted and coimmunoprecipitated with Aβ. Overexpression of hABCG2 reduced drug uptake in cells; however, interaction of Aβ1–40 with ABCG2 impaired ABCG2-mediated drug efflux. The role of Abcg2 in Aβ transport at the BBB was investigated in Abcg2-null and wild-type mice after intravenous injection of Cy5.5-labeled Aβ1–40 or scrambled Aβ40–1. Optical imaging analyses of live animals and their brains showed that Abcg2-null mice accumulated significantly more Aβ in their brains than wild-type mice. The finding was confirmed by immunohistochemistry. These results suggest that ABCG2 may act as a gatekeeper at the BBB to prevent blood Aβ from entering into brain. ABCG2 upregulation may serve as a biomarker of CAA vascular pathology in AD patients.

[1]  F. LaFerla,et al.  Genetically Altering Aβ Distribution from the Brain to the Vasculature Ameliorates Tau Pathology , 2009, Brain pathology.

[2]  L. Lue,et al.  Expression of inflammatory genes induced by beta-amyloid peptides in human brain endothelial cells and in Alzheimer's brain is mediated by the JNK-AP1 signaling pathway , 2009, Neurobiology of Disease.

[3]  E. Morii,et al.  Synergistic effect of interleukin-6 and endoplasmic reticulum stress inducers on the high level of ABCG2 expression in plasma cells , 2009, Laboratory Investigation.

[4]  Katie Hamm,et al.  apoE isoform-specific disruption of amyloid beta peptide clearance from mouse brain. , 2008, The Journal of clinical investigation.

[5]  E. Brunette,et al.  Dynamic Analysis of the Blood-Brain Barrier Disruption in Experimental Stroke Using Time Domain in Vivo Fluorescence Imaging , 2008, Molecular imaging.

[6]  J. Provias,et al.  Evidence for altered LRP/RAGE expression in Alzheimer lesion pathogenesis. , 2008, Current Alzheimer research.

[7]  D. Selkoe,et al.  Soluble oligomers of the amyloid β-protein impair synaptic plasticity and behavior , 2008, Behavioural Brain Research.

[8]  S. Hickman,et al.  Microglial Dysfunction and Defective β-Amyloid Clearance Pathways in Aging Alzheimer's Disease Mice , 2008, The Journal of Neuroscience.

[9]  L. Lue,et al.  Tg-SwDI transgenic mice exhibit novel alterations in AbetaPP processing, Abeta degradation, and resilient amyloid angiopathy. , 2008, The American journal of pathology.

[10]  R. Deane,et al.  The role of the cell surface LRP and soluble LRP in blood-brain barrier Abeta clearance in Alzheimer's disease. , 2008, Current pharmaceutical design.

[11]  Lih-Fen Lue,et al.  Human postmortem brain-derived cerebrovascular smooth muscle cells express all genes of the classical complement pathway: a potential mechanism for vascular damage in cerebral amyloid angiopathy and Alzheimer's disease. , 2008, Microvascular research.

[12]  John Woulfe,et al.  Cholesterol retention in Alzheimer's brain is responsible for high β- and γ-secretase activities and Aβ production , 2008, Neurobiology of Disease.

[13]  B. Zlokovic.  The Blood-Brain Barrier in Health and Chronic Neurodegenerative Disorders , 2008, Neuron.

[14]  E. Brunette,et al.  In Vivo Time Domain Optical Imaging of Renal Ischemia-Reperfusion Injury: Discrimination Based on Fluorescence Lifetime , 2007, Molecular imaging.

[15]  A. Goate,et al.  Clearance of amyloid-β by circulating lipoprotein receptors , 2007, Nature Medicine.

[16]  B. Solomon.  Antibody-mediated immunotherapy for Alzheimer's disease. , 2007, Current opinion in investigational drugs.

[17]  D. Holtzman,et al.  Transport Pathways for Clearance of Human Alzheimer's Amyloid β-Peptide and Apolipoproteins E and J in the Mouse Central Nervous System , 2007, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[18]  M. Frosch,et al.  Course of cerebral amyloid angiopathy–related inflammation , 2007, Neurology.

[19]  David S. Miller,et al.  Tumor Necrosis Factor α and Endothelin-1 Increase P-Glycoprotein Expression and Transport Activity at the Blood-Brain Barrier , 2007, Molecular Pharmacology.

[20]  Judianne Davis,et al.  Deficient cerebral clearance of vasculotropic mutant Dutch/Iowa Double Aß in human AßPP transgenic mice , 2006, Neurobiology of Aging.

[21]  H. Cui,et al.  Evidence that hypoxia-inducible factor-1 (HIF-1) mediates transcriptional activation of interleukin-1β (IL-1β) in astrocyte cultures , 2006, Journal of Neuroimmunology.

[22]  L. Lue,et al.  Gene expression changes by amyloid β peptide‐stimulated human postmortem brain microglia identify activation of multiple inflammatory processes , 2006, Journal of leukocyte biology.

[23]  Kaan E. Biron,et al.  Aβ peptide immunization restores blood‐brain barrier integrity in Alzheimer disease , 2006, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[24]  A. Fagan,et al.  P-glycoprotein deficiency at the blood-brain barrier increases amyloid-beta deposition in an Alzheimer disease mouse model. , 2005, The Journal of clinical investigation.

[25]  A. Prat,et al.  The Blood-Brain Barrier and Its Microenvironment : Basic Physiology to Neurological Disease , 2005 .

[26]  D. Stanimirovic,et al.  The Transport Systems of the Blood–Brain Barrier , 2005 .

[27]  Irene Otte-Höller,et al.  Cerebral microvascular amyloid beta protein deposition induces vascular degeneration and neuroinflammation in transgenic mice expressing human vasculotropic mutant amyloid beta precursor protein. , 2005, The American journal of pathology.

[28]  L. Lue,et al.  Investigations with cultured human microglia on pathogenic mechanisms of Alzheimer's disease and other neurodegenerative diseases , 2005, Journal of neuroscience research.

[29]  D. Holtzman,et al.  Human Apolipoprotein E4 Alters the Amyloid-β 40:42 Ratio and Promotes the Formation of Cerebral Amyloid Angiopathy in an Amyloid Precursor Protein Transgenic Model , 2005, The Journal of Neuroscience.

[30]  R. Deane,et al.  RAGE (Yin) Versus LRP (Yang) Balance Regulates Alzheimer Amyloid &bgr;-Peptide Clearance Through Transport Across the Blood–Brain Barrier , 2004, Stroke.

[31]  Peter J. Lenting,et al.  LRP/Amyloid β-Peptide Interaction Mediates Differential Brain Efflux of Aβ Isoforms , 2004, Neuron.

[32]  Julio J. Valdés,et al.  Permission is granted to quote short excerpts and to reproduce figures and tables from this report, provided that the source of such material is fully acknowledged. Data Mining of Gene Expression Changes in , 2003 .

[33]  R. Deane,et al.  Early-onset and Robust Cerebral Microvascular Accumulation of Amyloid β-Protein in Transgenic Mice Expressing Low Levels of a Vasculotropic Dutch/Iowa Mutant Form of Amyloid β-Protein Precursor* , 2004, Journal of Biological Chemistry.

[34]  D. Stanimirovic,et al.  Development of rapid staining protocols for laser-capture microdissection of brain vessels from human and rat coupled to gene expression analyses , 2004, Journal of Neuroscience Methods.

[35]  D. Selkoe,et al.  Alzheimer's disease: molecular understanding predicts amyloid-based therapeutics. , 2003, Annual review of pharmacology and toxicology.

[36]  L. Doyle,et al.  Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2) , 2003, Oncogene.

[37]  R. Weller,et al.  Cerebral amyloid angiopathy: Pathogenesis and effects on the ageing and Alzheimer brain , 2003, Neurological research.

[38]  M. Mattson,et al.  Triple-Transgenic Model of Alzheimer's Disease with Plaques and Tangles Intracellular Aβ and Synaptic Dysfunction , 2003, Neuron.

[39]  Ann Marie Schmidt,et al.  RAGE mediates amyloid-β peptide transport across the blood-brain barrier and accumulation in brain , 2003, Nature Medicine.

[40]  S. Love,et al.  APOEɛ4 influences the pathological phenotype of Alzheimer's disease by favouring cerebrovascular over parenchymal accumulation of Aβ protein , 2003 .

[41]  T. Strandberg.  Alzheimer's disease and angiogenesis , 2003, The Lancet.

[42]  S. D. Preston,et al.  Capillary and arterial cerebral amyloid angiopathy in Alzheimer's disease: defining the perivascular route for the elimination of amyloid β from the human brain , 2003, Neuropathology and applied neurobiology.

[43]  Jacob C Tony.  Alzheimer's disease and angiogenesis , 2003, The Lancet.

[44]  L. Lue,et al.  Modeling Alzheimer's disease immune therapy mechanisms: Interactions of human postmortem microglia with antibody‐opsonized amyloid beta peptide , 2002, Journal of neuroscience research.

[45]  K. Jellinger,et al.  Alzheimer disease and cerebrovascular pathology: an update , 2002, Journal of Neural Transmission.

[46]  D. Holtzman,et al.  Brain to Plasma Amyloid-β Efflux: a Measure of Brain Amyloid Burden in a Mouse Model of Alzheimer's Disease , 2002, Science.

[47]  L. Lue,et al.  Modeling microglial activation in Alzheimer’s disease with human postmortem microglial cultures , 2001, Neurobiology of Aging.

[48]  L. Lue,et al.  Gene expression profiling of amyloid beta peptide-stimulated human post-mortem brain microglia , 2001, Neurobiology of Aging.

[49]  David J. Cummins,et al.  Peripheral anti-Aβ antibody alters CNS and plasma Aβ clearance and decreases brain Aβ burden in a mouse model of Alzheimer's disease , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[50]  H. Hampel,et al.  Inflammatory repertoire of Alzheimer's disease and nondemented elderly microglia in vitro , 2001, Glia.

[51]  D. Selkoe.  Alzheimer's disease: genes, proteins, and therapy. , 2001, Physiological reviews.

[52]  Peter B. Reiner,et al.  β‐Amyloid efflux mediated by p‐glycoprotein , 2001 .

[53]  D. Holtzman,et al.  Clearance of Alzheimer's amyloid-ss(1-40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. , 2000, The Journal of clinical investigation.

[54]  B. Zlokovic,et al.  beta-amyloid-induced migration of monocytes across human brain endothelial cells involves RAGE and PECAM-1. , 2000, American journal of physiology. Cell physiology.

[55]  J. Durkin,et al.  The induction of ICAM-1 in human cerebromicrovascular endothelial cells (HCEC) by ischemia-like conditions promotes enhanced neutrophil/HCEC adhesion , 1997, Journal of Neuroimmunology.

[56]  B. Zlokovic.  Cerebrovascular transport of Alzheimer's amyloid beta and apolipoproteins J and E: possible anti-amyloidogenic role of the blood-brain barrier. , 1996, Life sciences.

[57]  L. Thal,et al.  The apolipoprotein E epsilon 4 allele is associated with increased neuritic plaques and cerebral amyloid angiopathy in Alzheimer's disease and Lewy body variant , 1996, Neurology.

[58]  D. T. Vernier,et al.  Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. , 1990, Journal of lipid research.

[59]  David S. Miller,et al.  Tumor necrosis factor alpha and endothelin-1 increase P-glycoprotein expression and transport activity at the blood-brain barrier. , 2007, Molecular pharmacology.

[60]  A. Goate,et al.  Clearance of amyloid-beta by circulating lipoprotein receptors. , 2007, Nature medicine.

[61]  Judianne Davis,et al.  Deficient cerebral clearance of vasculotropic mutant Dutch/Iowa Double A beta in human A betaPP transgenic mice. , 2006, Neurobiology of aging.

[62]  R. Deane,et al.  LRP/amyloid beta-peptide interaction mediates differential brain efflux of Abeta isoforms. , 2004, Neuron.

[63]  S. Love,et al.  APOE epsilon 4 influences the pathological phenotype of Alzheimer's disease by favouring cerebrovascular over parenchymal accumulation of A beta protein. , 2003, Neuropathology and applied neurobiology.

[64]  P. Reiner,et al.  beta-Amyloid efflux mediated by p-glycoprotein. , 2001, Journal of neurochemistry.

[65]  D. Holtzman,et al.  Peripheral anti-A beta antibody alters CNS and plasma A beta clearance and decreases brain A beta burden in a mouse model of Alzheimer's disease. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[66]  Hong Zhang,et al.  The FASEB Journal express article 10.1096/fj.02-1131fje. Published online September 4, 2003. Expression and functional characterization of ABCG2 in brain endothelial cells and vessels , 2022 .