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• W2149304421 abstract "Apolipoprotein E4 (ApoE4) is associated with Alzheimer's disease by unknown mechanisms. We generated six transgenic mice strains expressing human ApoE4 in combination with mutant amyloid precursor protein (APP) and mutant presenilin-1 (PS1) in single-, double-, or triple-transgenic combinations. Diffuse, but not dense, amyloid plaque-load in subiculum and cortex was increased by neuronal but not glial ApoE4 in old (15 months) double-transgenic mice, whereas both diffuse and dense plaques formed in thalamus in both genotypes. Neuronal and glial ApoE4 promoted cerebral amyloid angiopathy as extensively as mutant PS1 but with pronounced regional differences: cortical angiopathy was induced by neuronal ApoE4 while thalamic angiopathy was again independent of ApoE4 source. Angiopathy correlated more strongly with soluble Aβ40 and Aβ42 levels in cortex than in thalamus throughout the six genotypes. Neither neuronal nor glial ApoE4 affected APP proteolytic processing, as opposed to mutant PS1. Neuronal ApoE4 increased soluble amyloid levels more than glial ApoE4, but the Aβ42/40 ratios were similar, although significantly higher than in single APP transgenic mice. We conclude that although the cellular origin of ApoE4 differentially affects regional amyloid pathology, ApoE4 acts on the disposition of amyloid peptides downstream from their excision from APP but without induction of tauopathy. Apolipoprotein E4 (ApoE4) is associated with Alzheimer's disease by unknown mechanisms. We generated six transgenic mice strains expressing human ApoE4 in combination with mutant amyloid precursor protein (APP) and mutant presenilin-1 (PS1) in single-, double-, or triple-transgenic combinations. Diffuse, but not dense, amyloid plaque-load in subiculum and cortex was increased by neuronal but not glial ApoE4 in old (15 months) double-transgenic mice, whereas both diffuse and dense plaques formed in thalamus in both genotypes. Neuronal and glial ApoE4 promoted cerebral amyloid angiopathy as extensively as mutant PS1 but with pronounced regional differences: cortical angiopathy was induced by neuronal ApoE4 while thalamic angiopathy was again independent of ApoE4 source. Angiopathy correlated more strongly with soluble Aβ40 and Aβ42 levels in cortex than in thalamus throughout the six genotypes. Neither neuronal nor glial ApoE4 affected APP proteolytic processing, as opposed to mutant PS1. Neuronal ApoE4 increased soluble amyloid levels more than glial ApoE4, but the Aβ42/40 ratios were similar, although significantly higher than in single APP transgenic mice. We conclude that although the cellular origin of ApoE4 differentially affects regional amyloid pathology, ApoE4 acts on the disposition of amyloid peptides downstream from their excision from APP but without induction of tauopathy. Alzheimer's disease (AD) is characterized by pathological accumulations in the brain of extracellular amyloid plaques and intraneuronal accumulations of protein tau known as neurofibrillary tangles. The amyloid peptides Aβ40 and Aβ42 are the major components of the amyloid deposits in parenchyma and vasculature.1Glenner GG Wong CW Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein.Biochem Biophys Res Commun. 1984; 120: 885-890Crossref PubMed Scopus (4244) Google Scholar The amyloid peptides are excised from the integral membrane protein amyloid precursor protein (APP) by sequential endoproteolytic cleavages by β- and γ-secretases.2Dewachter I Van Leuven F Secretases as targets for the treatment of Alzheimer's disease: the prospects.Lancet Neurol. 2002; 1: 409-416Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar The exact causes and consequences, in terms of normal processes and mechanisms that are disturbed by the amyloid peptides and causing neurodegeneration, remain primarily unclear.3Selkoe DJ Defining molecular targets to prevent Alzheimer disease.Arch Neurol. 2005; 2: 192-195Crossref Scopus (140) Google Scholar Besides APP and presenilins (PS1, PS2), the apolipoprotein E (ApoE) is genetically linked to AD.4Corder EH Saunders AM Strittmatter WJ Schmechel DE Gaskell PC Small GW Roses AD Haines JL Pericak-Vance MA Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families.Science. 1993; 261: 921-923Crossref PubMed Scopus (7342) Google Scholar The ApoE4 lipoprotein or its encoding ε4 allele, are epidemiologically associated with AD and confer an increased risk and earlier age of onset relative to the more common ApoE3 protein or ε3 allele.5Bales KR Dodart JC DeMattos RB Holtzman DM Paul SM Apolipoprotein E, amyloid, and Alzheimer disease.Mol Interv. 2002; 6: 363-375Crossref Scopus (109) Google Scholar, 6Tanzi RE Bertram L Twenty years of the Alzheimer's disease amyloid hypothesis: a genetic perspective.Cell. 2005; 120: 545-555Abstract Full Text Full Text PDF PubMed Scopus (1508) Google Scholar, 7St George-Hyslop PH Petit A Molecular biology and genetics of Alzheimer's disease.C R Biol. 2005; 328: 119-130Crossref PubMed Scopus (171) Google Scholar ApoE is a 34-kd protein abundantly expressed in liver and brain. In the circulation, ApoE-lipoproteins mediate transport of lipids and cholesterol from and to liver and extrahepatic tissues. In contrast to the peripheral functions of ApoE that are well understood, details of its actions in the central nervous system remain primarily unknown. Actually, the epidemiological association of the ε4-allele to AD provided a strong impetus to research, by pointing out our lack of understanding the physiology of lipid and cholesterol homeostasis and of their transport in brain, in particular the contribution of ApoE and various ApoE receptors.8Beffert U Stolt PC Herz J Functions of lipoprotein receptors in neurons.J Lipid Res. 2004; 45: 403-409Crossref PubMed Scopus (127) Google Scholar, 9Poirier J Apolipoprotein E, cholesterol transport and synthesis in sporadic Alzheimer's disease.Neurobiol Aging. 2005; 26: 355-361Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar Similar to the physiology of ApoE, its pathological contributions to amyloid and tau pathology in AD have been studied in different types of transgenic mouse models, either deficient in murine ApoE and/or overexpressing human ApoE isoforms. Combination in double-transgenic models carrying also a mutant human APP has revealed shortcomings and even conflicts into the contributions in the pathogenesis of AD, while many aspects and data, including the cholesterol conundrum, remain intriguing if not controversial.10Holtzman DM In vivo effects of ApoE and clusterin on amyloid-beta metabolism and neuropathology.J Mol Neurosci. 2004; 23: 247-254Crossref PubMed Scopus (121) Google Scholar, 11DeMattos RB Apolipoprotein E dose-dependent modulation of beta-amyloid deposition in a transgenic mouse model of Alzheimer's disease.J Mol Neurosci. 2004; 23: 255-262Crossref PubMed Scopus (43) Google Scholar, 12Sambamurti K Granholm AC Kindy MS Bhat NR Greig NH Lahiri DK Mintzer JE Cholesterol and Alzheimer's disease: clinical and experimental models suggest interactions of different genetic, dietary and environmental risk factors.Curr Drug Targets. 2004; 5: 517-528Crossref PubMed Scopus (52) Google Scholar The deficiency of endogenous murine ApoE in combination with mutant APP in double-transgenic mice, significantly delayed amyloid deposition overall, with less parenchymal and almost no vascular amyloid.13Holtzman DM Bales KR Wu S Bhat P Parsadanian M Fagan AM Chang LK Sun Y Paul SM Expression of human apolipoprotein E reduces amyloid-β deposition in a mouse model of Alzheimer's disease.J Clin Invest. 1999; 103: 15-21Crossref Scopus (293) Google Scholar, 14Bales KR Verina T Cummins DJ Du Y Dodel RC Saura J Fishman CE DeLong CA Piccardo P Petegnief V Ghetti B Paul SM Apolipoprotein E is essential for amyloid deposition in the APP(V717F) transgenic mouse model of Alzheimer's disease.Proc Natl Acad Sci USA. 1999; 96: 15233-15238Crossref PubMed Scopus (416) Google Scholar, 15Irizarry MC Cheung BS Rebeck GW Paul SM Bales KR Hyman BT Apolipoprotein E affects the amount, form, and anatomical distribution of amyloid beta-peptide deposition in homozygous APP(V717F) transgenic mice.Acta Neuropathol (Berl). 2000; 100: 451-458Crossref PubMed Scopus (79) Google Scholar, 16Fagan AM Watson M Parsadanian M Bales KR Paul SM Holtzman DM Human and murine ApoE markedly alters Aβ metabolism before and after plaque formation in a mouse model of Alzheimer's disease.Neurobiol Dis. 2002; 9: 305-318Crossref PubMed Scopus (222) Google Scholar, 17Fryer JD Taylor JW DeMattos RB Bales KR Paul SM Parsadanian M Holtzman DM Apolipoprotein E markedly facilitates age-dependent cerebral amyloid angiopathy and spontaneous hemorrhage in amyloid precursor protein transgenic mice.J Neurosci. 2003; 23: 7889-7896Crossref PubMed Google Scholar, 18Miao J Vitek MP Xu F Previti ML Davis J Van Nostrand WE Reducing cerebral microvascular amyloid-β protein deposition diminishes regional neuroinflammation in vasculotropic mutant amyloid precursor protein transgenic mice.J Neurosci. 2005; 25: 6271-6277Crossref PubMed Scopus (56) Google Scholar Thereby, ApoE was proposed to cause aggregation of amyloid and/or induce conformational changes in the amyloid peptides to form fibrils. In contrast, deposition of amyloid was also delayed by expression of human ApoE, in an isoform-specific manner, while ApoE even appeared to affect the metabolism of APP before plaques developed.13Holtzman DM Bales KR Wu S Bhat P Parsadanian M Fagan AM Chang LK Sun Y Paul SM Expression of human apolipoprotein E reduces amyloid-β deposition in a mouse model of Alzheimer's disease.J Clin Invest. 1999; 103: 15-21Crossref Scopus (293) Google Scholar, 16Fagan AM Watson M Parsadanian M Bales KR Paul SM Holtzman DM Human and murine ApoE markedly alters Aβ metabolism before and after plaque formation in a mouse model of Alzheimer's disease.Neurobiol Dis. 2002; 9: 305-318Crossref PubMed Scopus (222) Google Scholar, 17Fryer JD Taylor JW DeMattos RB Bales KR Paul SM Parsadanian M Holtzman DM Apolipoprotein E markedly facilitates age-dependent cerebral amyloid angiopathy and spontaneous hemorrhage in amyloid precursor protein transgenic mice.J Neurosci. 2003; 23: 7889-7896Crossref PubMed Google Scholar Another study demonstrated, however, that expression of human ApoE4 but not of ApoE3, both under control of the transferrin gene promoter, accelerated deposition of amyloid in APP/Swe transgenic mice.19Carter DB Dunn E McKinley DD Stratman NC Boyle TP Kuiper SL Oostveen JA Weaver RJ Boller JA Gurney ME Human apolipoprotein E4 accelerates beta-amyloid deposition in APPsw transgenic mouse brain.Ann Neurol. 2001; 50: 468-475Crossref PubMed Scopus (59) Google Scholar In a similar study, overexpression of either ApoE isoform under control of the prion gene promoter neither accelerated nor increased the amyloid burden, nor markedly affected the metabolism before amyloid deposition even in the presence of mutant presenilin-1 in triple-transgenic mice.20Lesuisse C Xu G Anderson J Wong M Jankowsky J Holtz G Gonzalez V Wong PCY Price DL Tang F Wagner S Borchelt DR Hyper-expression of human apolipoprotein E4 in astroglia and neurons does not enhance amyloid deposition in transgenic mice.Hum Mol Genet. 2001; 10: 2525-2537Crossref PubMed Scopus (47) Google Scholar In addition to parenchymal amyloid plaques, the vascular deposits presenting as cerebral congophilic amyloid angiopathy (CAA) are a major pathological sign in AD21Weller RO Nicoll JA Cerebral amyloid angiopathy: pathogenesis and effects on the ageing and Alzheimer brain.Neurol Res. 2003; 25: 611-616Crossref PubMed Scopus (104) Google Scholar with a prevalence of more than 90% in the oldest patients.22Jellinger KA Attems J Prevalence and pathogenic role of cerebrovascular lesions in Alzheimer disease.J Neurol Sci. 2005; 229–230: 37-41Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar The severity of CAA was, in contrast to parenchymal amyloidosis, strongly associated with the presence of ApoE4 alleles,23Chalmers K Wilcock GK Love S APOE ɛ4 influences the pathological phenotype of Alzheimer's disease by favouring cerebrovascular over parenchymal accumulation of Aβ protein.Neuropathol Appl Neurol. 2003; 29: 231-238Crossref PubMed Scopus (136) Google Scholar similar to reduced Aβ42 levels in cerebrospinal fluid.24Prince JA Zetterberg H Andreasen N Marcusson J Blennow K APOE epsilon4 allele is associated with reduced cerebrospinal fluid levels of Abeta42.Neurology. 2004; 62: 2116-2118Crossref PubMed Scopus (118) Google Scholar Although not consistent throughout all studies, the combined clinical, pathological, and experimental findings suggest that ApoE4 favors vascular over parenchymal deposition of amyloid, although the mechanisms are unclear. The shift in amyloid deposition from the parenchyma to the vasculature by human ApoE4 in brain of double-transgenic APP×ApoE4 knockin mice, corroborates this hypothesis.25Fryer JD Simmons K Parsadanian M Bales KR Paul SM Sullivan PM Holtzman DM Human apolipoprotein E4 alters the amyloid-β40:42 ratio and promotes the formation of cerebral amyloid angiopathy in an amyloid precursor protein transgenic model.J Neurosci. 2005; 25: 2803-2810Crossref PubMed Scopus (232) Google Scholar ApoE is synthesized and secreted mainly by nonneuronal glial cells and is taken up by neurons by receptor-mediated endocytosis.8Beffert U Stolt PC Herz J Functions of lipoprotein receptors in neurons.J Lipid Res. 2004; 45: 403-409Crossref PubMed Scopus (127) Google Scholar, 9Poirier J Apolipoprotein E, cholesterol transport and synthesis in sporadic Alzheimer's disease.Neurobiol Aging. 2005; 26: 355-361Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar, 26Fryer JD Demattos RB McCormick LM O'dell MA Spinner ML Bales KR Paul SM Sullivan PM Parsadanian M Bu G Holtzman DM The low-density lipoprotein receptor regulates the level of CNS human and murine apolipoprotein E but does not modify amyloid plaque pathology in PDAPP mice.J Biol Chem. 2005; 280: 25754-25759Crossref PubMed Scopus (113) Google Scholar Neurons can synthesize ApoE as observed in human and mouse brain.27Xu PT Gilbert JR Qiu HL Ervin J Rothrock-Christian TR Hulette C Schmechel DE Specific regional transcription of apolipoprotein E in human brain neurons.Am J Pathol. 1999; 154: 601-611Abstract Full Text Full Text PDF PubMed Google Scholar, 28Tesseur I Van Dorpe J Spittaels K Van den Haute C Moechars D Van Leuven F Expression of human apolipoprotein E4 in neurons causes hyperphosphorylation of protein tau in the brains of transgenic mice.Am J Pathol. 2000; 156: 951-964Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar, 29Tesseur I Van Dorpe J Bruynseels K Bronfman F Sciot R Van Lommel A Van Leuven F Prominent axonopathy and disruption of axonal transport in transgenic mice expressing human apolipoprotein E4 in neurons of brain and spinal cord.Am J Pathol. 2000; 157: 1495-1510Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar, 30Harris FM Tesseur I Brecht WJ Xu Q Mullendorff K Chang S Wyss-Coray T Mahley RW Huang Y Astroglial regulation of apolipoprotein E expression in neuronal cells. Implications for Alzheimer's disease.J Biol Chem. 2004; 279: 3862-3868Crossref PubMed Scopus (104) Google Scholar Interestingly, brain regions that express ApoE in neurons also correlate with more severe amyloid and neurofibrillary tangle pathology in AD. The exact contribution or even the importance of neuronal expression of ApoE to amyloid or tau pathology is unknown. We have previously tested this hypothesis in vivo, by deriving transgenic mice that differentially expressed ApoE4 in neurons or glia.28Tesseur I Van Dorpe J Spittaels K Van den Haute C Moechars D Van Leuven F Expression of human apolipoprotein E4 in neurons causes hyperphosphorylation of protein tau in the brains of transgenic mice.Am J Pathol. 2000; 156: 951-964Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar, 29Tesseur I Van Dorpe J Bruynseels K Bronfman F Sciot R Van Lommel A Van Leuven F Prominent axonopathy and disruption of axonal transport in transgenic mice expressing human apolipoprotein E4 in neurons of brain and spinal cord.Am J Pathol. 2000; 157: 1495-1510Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar Neuronal but not glial expression of ApoE4 resulted in hyperphosphorylation of protein tau and caused prominent axonopathy by disruption of axonal transport.28Tesseur I Van Dorpe J Spittaels K Van den Haute C Moechars D Van Leuven F Expression of human apolipoprotein E4 in neurons causes hyperphosphorylation of protein tau in the brains of transgenic mice.Am J Pathol. 2000; 156: 951-964Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar, 29Tesseur I Van Dorpe J Bruynseels K Bronfman F Sciot R Van Lommel A Van Leuven F Prominent axonopathy and disruption of axonal transport in transgenic mice expressing human apolipoprotein E4 in neurons of brain and spinal cord.Am J Pathol. 2000; 157: 1495-1510Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar A recent independent study not only confirmed our data, but additionally reported proteolytic cleavage of ApoE4 to be involved.31Brecht WJ Harris FM Chang S Tesseur I Yu GQ Xu Q Fish JD Wyss-Coray T Buttini M Mucke L Mahley RW Huang Y Neuron-specific apolipoprotein E4 proteolysis is associated with increased tau phosphorylation in brains of transgenic mice.J Neurosci. 2004; 24: 2527-2534Crossref PubMed Scopus (310) Google Scholar We investigated the pathological contributions of different cellular origins of ApoE4 further and report here the in-depth analysis of six transgenic mouse strains expressing human ApoE4 in combination with mutant APP[V717I] and mutant PS1[A246E] in either single-, double-, or triple-transgenic combinations. The aim was to assess the contribution of the differential expression of ApoE4 in either neurons or glia cells on the amyloid pathology in parenchyma and vasculature relative to the parental APP[V717I] transgenic mice.32Moechars D Dewachter I Lorent K Reversé D Baekelandt V Naidu A Tesseur I Spittaels K Van Den Haute C Checler F Godaux E Cordell B Van Leuven F Early phenotypic changes in transgenic mice that overexpress different mutants of amyloid precursor protein in brain.J Biol Chem. 1999; 274: 6483-6492Crossref PubMed Scopus (614) Google Scholar, 33Van Dorpe J Smeijers L Dewachter I Nuyens D Spittaels K Van den Haute C Mercken M Moechars D Laenen I Kuiperi C Bruynseels K Tesseur I Loos R Vanderstichele H Checler F Van Leuven F Prominent cerebral amyloid angiopathy in transgenic mice overexpressing the London mutant of human APP in neurons.Am J Pathol. 2000; 157: 1283-1298Abstract Full Text Full Text PDF PubMed Google Scholar, 34Dewachter I Van Dorpe J Smeijers L Gilis M Kuiperi C Laenen I Caluwaerts N Moechars D Checler F Vanderstichele H Van Leuven F Aging increased amyloid peptide and caused amyloid plaques in brain of old APP/V717I transgenic mice by a different mechanism than mutant presenilin1.J Neurosci. 2000; 20: 6452-6458Crossref PubMed Google Scholar We explored with progressing age, the differential effects of neuronal versus glial ApoE on amyloid pathology, and analyzed the processing of APP as well as the eventual emergence of tauopathy. The data demonstrate that the cellular origin of ApoE4 differentially modulated the amyloid pathology in brain parenchyma and in the vasculature, without affecting the processing of APP. Moreover, despite hyperphosphorylation of protein tau at different AD-related epitopes, no tauopathy was induced by the neuronal expression of ApoE4, demonstrating that the major, if not only, pathological effect of ApoE4 is to be situated in the cellular or extracellular handling of the amyloid peptides, subsequently to their excision from APP. Transgenic mice with neuronal and glial overexpression of human ApoE4, respectively, driven by the mouse thy1 gene promoter and by the GFAP gene promoter, were generated previously.28Tesseur I Van Dorpe J Spittaels K Van den Haute C Moechars D Van Leuven F Expression of human apolipoprotein E4 in neurons causes hyperphosphorylation of protein tau in the brains of transgenic mice.Am J Pathol. 2000; 156: 951-964Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar, 29Tesseur I Van Dorpe J Bruynseels K Bronfman F Sciot R Van Lommel A Van Leuven F Prominent axonopathy and disruption of axonal transport in transgenic mice expressing human apolipoprotein E4 in neurons of brain and spinal cord.Am J Pathol. 2000; 157: 1495-1510Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar Two different strategies were used to generate offspring in a F1 background of FVB/N × C57BL6 and with co-expression of human ApoE4 with APP-V717I and PS1-A246E. Homozygous thy1-ApoE4 mice and hemizygous GFAP-ApoE4 transgenic mice in the C57BL6 genetic background28Tesseur I Van Dorpe J Spittaels K Van den Haute C Moechars D Van Leuven F Expression of human apolipoprotein E4 in neurons causes hyperphosphorylation of protein tau in the brains of transgenic mice.Am J Pathol. 2000; 156: 951-964Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar, 29Tesseur I Van Dorpe J Bruynseels K Bronfman F Sciot R Van Lommel A Van Leuven F Prominent axonopathy and disruption of axonal transport in transgenic mice expressing human apolipoprotein E4 in neurons of brain and spinal cord.Am J Pathol. 2000; 157: 1495-1510Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar were crossed with APP[V717I] single-transgenic mice and with APP[V717I] × PS1[A246E] double-transgenic mice both in the FVB/N background.32Moechars D Dewachter I Lorent K Reversé D Baekelandt V Naidu A Tesseur I Spittaels K Van Den Haute C Checler F Godaux E Cordell B Van Leuven F Early phenotypic changes in transgenic mice that overexpress different mutants of amyloid precursor protein in brain.J Biol Chem. 1999; 274: 6483-6492Crossref PubMed Scopus (614) Google Scholar, 33Van Dorpe J Smeijers L Dewachter I Nuyens D Spittaels K Van den Haute C Mercken M Moechars D Laenen I Kuiperi C Bruynseels K Tesseur I Loos R Vanderstichele H Checler F Van Leuven F Prominent cerebral amyloid angiopathy in transgenic mice overexpressing the London mutant of human APP in neurons.Am J Pathol. 2000; 157: 1283-1298Abstract Full Text Full Text PDF PubMed Google Scholar, 34Dewachter I Van Dorpe J Smeijers L Gilis M Kuiperi C Laenen I Caluwaerts N Moechars D Checler F Vanderstichele H Van Leuven F Aging increased amyloid peptide and caused amyloid plaques in brain of old APP/V717I transgenic mice by a different mechanism than mutant presenilin1.J Neurosci. 2000; 20: 6452-6458Crossref PubMed Google Scholar Genotyping by polymerase chain reaction identified all six possible genotypes, ie, double ApoE4 × APP and triple ApoE4 × APP × PS1 transgenic mice, respectively with ApoE4 driven by either the mouse thy1 gene promoter or by the GFAP gene promoter. Importantly, all transgenic mice analyzed in this study were all females, all hemizygous for the transgenes they express, and moreover, were all from the F1 generations of different crossings resulting in all having an identical mixed FVB/N × C57BL6 genetic background (Table 1). The time line of analysis was defined at ages 4, 6, 8, and 15 months, based on the characteristics of the four parental mouse strains28Tesseur I Van Dorpe J Spittaels K Van den Haute C Moechars D Van Leuven F Expression of human apolipoprotein E4 in neurons causes hyperphosphorylation of protein tau in the brains of transgenic mice.Am J Pathol. 2000; 156: 951-964Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar, 29Tesseur I Van Dorpe J Bruynseels K Bronfman F Sciot R Van Lommel A Van Leuven F Prominent axonopathy and disruption of axonal transport in transgenic mice expressing human apolipoprotein E4 in neurons of brain and spinal cord.Am J Pathol. 2000; 157: 1495-1510Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar, 32Moechars D Dewachter I Lorent K Reversé D Baekelandt V Naidu A Tesseur I Spittaels K Van Den Haute C Checler F Godaux E Cordell B Van Leuven F Early phenotypic changes in transgenic mice that overexpress different mutants of amyloid precursor protein in brain.J Biol Chem. 1999; 274: 6483-6492Crossref PubMed Scopus (614) Google Scholar, 33Van Dorpe J Smeijers L Dewachter I Nuyens D Spittaels K Van den Haute C Mercken M Moechars D Laenen I Kuiperi C Bruynseels K Tesseur I Loos R Vanderstichele H Checler F Van Leuven F Prominent cerebral amyloid angiopathy in transgenic mice overexpressing the London mutant of human APP in neurons.Am J Pathol. 2000; 157: 1283-1298Abstract Full Text Full Text PDF PubMed Google Scholar, 34Dewachter I Van Dorpe J Smeijers L Gilis M Kuiperi C Laenen I Caluwaerts N Moechars D Checler F Vanderstichele H Van Leuven F Aging increased amyloid peptide and caused amyloid plaques in brain of old APP/V717I transgenic mice by a different mechanism than mutant presenilin1.J Neurosci. 2000; 20: 6452-6458Crossref PubMed Google Scholar and a total of 112 transgenic mice, ie, three or four transgenic mice per age group per genotype, were analyzed. Genotyping of all transgenic offspring for human APP, human PS1, and human ApoE4 was performed by six independent polymerase chain reaction assays on DNA extracted from tail biopsies as described.28Tesseur I Van Dorpe J Spittaels K Van den Haute C Moechars D Van Leuven F Expression of human apolipoprotein E4 in neurons causes hyperphosphorylation of protein tau in the brains of transgenic mice.Am J Pathol. 2000; 156: 951-964Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar, 32Moechars D Dewachter I Lorent K Reversé D Baekelandt V Naidu A Tesseur I Spittaels K Van Den Haute C Checler F Godaux E Cordell B Van Leuven F Early phenotypic changes in transgenic mice that overexpress different mutants of amyloid precursor protein in brain.J Biol Chem. 1999; 274: 6483-6492Crossref PubMed Scopus (614) Google Scholar, 33Van Dorpe J Smeijers L Dewachter I Nuyens D Spittaels K Van den Haute C Mercken M Moechars D Laenen I Kuiperi C Bruynseels K Tesseur I Loos R Vanderstichele H Checler F Van Leuven F Prominent cerebral amyloid angiopathy in transgenic mice overexpressing the London mutant of human APP in neurons.Am J Pathol. 2000; 157: 1283-1298Abstract Full Text Full Text PDF PubMed Google Scholar, 34Dewachter I Van Dorpe J Smeijers L Gilis M Kuiperi C Laenen I Caluwaerts N Moechars D Checler F Vanderstichele H Van Leuven F Aging increased amyloid peptide and caused amyloid plaques in brain of old APP/V717I transgenic mice by a different mechanism than mutant presenilin1.J Neurosci. 2000; 20: 6452-6458Crossref PubMed Google ScholarTable 1The Six Genotypes of Transgenic Mice AnalyzedGenotypeExpression of human ApoE4NotationAPP[V717I]APPAPP[V717I] × PS1[A246E]APP.PS1Thy1-ApoE4 × APP[V717I]NeuronAPP.TE4GFAP-ApoE4 × APP[V717I]AstrocyteAPP.GE4Thy1-ApoE4 × APP[V717I] × PS1[A246E]NeuronAPP.PS1.TE4GFAP-ApoE4 × APP[V717I] ×PS1[A246E]AstrocyteAPP.PS1.GE4 Open table in a new tab Anesthetized mice were perfused transcardiacally with ice-cold saline and their brain was rapidly excised. One hemisphere was immersion-fixed overnight in 10 vol of 4% paraformaldehyde in phosphate-buffered saline (PBS) at 4°C, rinsed, and stored in PBS containing 0.1% azide at 4°C. Sagittal free-floating vibratome sections (40 μm) were transferred to microtiter plates, and kept in PBS containing 0.1% azide at 4°C. The other hemisphere was snap-frozen in liquid N2 and used for biochemical analysis by differential extraction. Hemispheres were homogenized with a Potter-type mechanical homogenizer (Zipperer GmbH, Staufen, Germany), in 10 vol of ice-cold Tris-proteinase/phosphatase-inhibitor buffer (TPI-buffer), containing 20 mmol/L Tris-HCl (pH 8.5), 20 mmol/L ethylenediaminetetraacetic acid, 10 mmol/L ortho-phenanthroline, 20 mmol/L NaF, 200 μmol/L Na3VO4, and a cocktail of proteinase inhibitors (Roche Diagnostics GmbH, Germany). A portion equivalent to 2 vol of the total homogenate was stored at −70°C and the remainder was centrifuged (100,000 × g, 4°C, 80 minutes). The supernatant, designated as soluble fraction was aliquoted and stored at −70°C. The pellet containing the membranes was resuspended in 500 μl of ice-cold TPI-buffer containing 1% Triton X-100 (v/v) and after complete solubilization was centrifuged again (100,000 × g, 4°C, 80 minutes). The supernatant, designated as Triton-soluble membrane fraction (MT) was aliquoted and stored at −70°C. The pellet was solubilized in formic acid (80%) and after centrifugation (20,000 × g, 4°C, 60 minutes) the supernatant was dried under vacuum and the residue solubilized by boiling in sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis (PAGE) sample buffer. Western blotting was performed to quantify full-length human APP (APPm) and the C-terminal fragments of APP (α- and β-CTF, or C83 and C99) as described.34Dewachter I Van Dorpe J Smeijers L Gilis M Kuiperi C Laenen I Caluwaerts N Moechars D Checler F Vanderstichele H Van Leuven F Aging increased amyloid peptide and caused amyloid plaques in brain of old APP/V717I transgenic mice by a different mechanism than mutant presenilin1.J Neurosci. 2000; 20: 6452-6458Crossref PubMed Google Scholar, 35Dewachter I Reversé D Caluwaerts N Ris L Kuipéri C Van den Haute C Spittaels K Umans L Serneels L Thiry E Moechars D Mercken M Godaux E Van Leuven F Neuronal deficiency of presenilin 1 inhibits amyloid plaque formation and corrects hippocampal long-term potentiation but not a cognitive defect of amyloid precursor protein [V717I] transgenic mice.J Ne" @default.
• W2149304421 created "2016-06-24" @default.
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• W2149304421 date "2006-01-01" @default.
• W2149304421 modified "2023-09-26" @default.
• W2149304421 title "Neuronal or Glial Expression of Human Apolipoprotein E4 Affects Parenchymal and Vascular Amyloid Pathology Differentially in Different Brain Regions of Double- and Triple-Transgenic Mice" @default.
• W2149304421 cites W1511142149 @default.
• W2149304421 cites W1586465707 @default.
• W2149304421 cites W1619610860 @default.
• W2149304421 cites W1667748077 @default.
• W2149304421 cites W1973017204 @default.
• W2149304421 cites W1975404558 @default.
• W2149304421 cites W1977274382 @default.
• W2149304421 cites W1978831666 @default.
• W2149304421 cites W1980362319 @default.
• W2149304421 cites W1983670592 @default.
• W2149304421 cites W1987816913 @default.
• W2149304421 cites W1988453500 @default.
• W2149304421 cites W1991607389 @default.
• W2149304421 cites W1993121285 @default.
• W2149304421 cites W1996447834 @default.
• W2149304421 cites W2000558306 @default.
• W2149304421 cites W2000983899 @default.
• W2149304421 cites W2002520289 @default.
• W2149304421 cites W2004131059 @default.
• W2149304421 cites W2004646459 @default.
• W2149304421 cites W2005681172 @default.
• W2149304421 cites W2007821406 @default.
• W2149304421 cites W2024564106 @default.
• W2149304421 cites W2032452147 @default.
• W2149304421 cites W2032920422 @default.
• W2149304421 cites W2036362108 @default.
• W2149304421 cites W2040772218 @default.
• W2149304421 cites W2041192235 @default.
• W2149304421 cites W2041378923 @default.
• W2149304421 cites W2041396523 @default.
• W2149304421 cites W2041512773 @default.
• W2149304421 cites W2043736979 @default.
• W2149304421 cites W2044222926 @default.
• W2149304421 cites W2048975745 @default.
• W2149304421 cites W2056609113 @default.
• W2149304421 cites W2063505049 @default.
• W2149304421 cites W2063661531 @default.
• W2149304421 cites W2066601928 @default.
• W2149304421 cites W2068394373 @default.
• W2149304421 cites W2072891357 @default.
• W2149304421 cites W2074709695 @default.
• W2149304421 cites W2077674018 @default.
• W2149304421 cites W2087109004 @default.
• W2149304421 cites W2095745901 @default.
• W2149304421 cites W2096898082 @default.
• W2149304421 cites W2098055591 @default.
• W2149304421 cites W2101985994 @default.
• W2149304421 cites W2103126689 @default.
• W2149304421 cites W2107538859 @default.
• W2149304421 cites W2126019582 @default.
• W2149304421 cites W2129327581 @default.
• W2149304421 cites W2130393399 @default.
• W2149304421 cites W2131819352 @default.
• W2149304421 cites W2132810311 @default.
• W2149304421 cites W2138955227 @default.
• W2149304421 cites W2141653500 @default.
• W2149304421 cites W2145017801 @default.
• W2149304421 cites W2152192643 @default.
• W2149304421 cites W2156998090 @default.
• W2149304421 cites W2157973003 @default.
• W2149304421 cites W2159367229 @default.
• W2149304421 cites W2163457087 @default.
• W2149304421 cites W2169308121 @default.
• W2149304421 cites W2170218376 @default.
• W2149304421 cites W2171264766 @default.
• W2149304421 cites W2171960085 @default.
• W2149304421 cites W2234898823 @default.
• W2149304421 cites W2250575986 @default.
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