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• W2019574244 abstract "Occurrence of amyloid β (Aβ) dense-core plaques in the brain is one of the chief hallmarks of Alzheimer's disease (AD). It is not yet clear what factors are responsible for the aggregation of Aβ in the formation of these plaques. Using Tg2576 and PSAPP mouse models that exhibit age-related development of amyloid plaques similar to that observed in AD, we showed that ≈95% of dense plaques in Tg2576 and ≈85% in PSAPP mice are centered on vessel walls or in the immediate perivascular regions. Stereoscopy and simulation studies focusing on smaller plaques suggested that vascular associations for both Tg2576 and PSAPP mice were dramatically higher than those encountered by chance alone. We further identified ultrastructural microvascular abnormalities occurring in association with dense plaques. Although occurrence of gross cerebral hemorrhage was infrequent, we identified considerable infiltration of the serum proteins immunoglobulin and albumin in association with dense plaques. Together with earlier evidence of vascular clearance of Aβ, our data suggest that perturbed vascular transport and/or perivascular enrichment of Aβ leads to the formation of vasocentric dense plaques in Tg2576 and PSAPP mouse models of AD. Occurrence of amyloid β (Aβ) dense-core plaques in the brain is one of the chief hallmarks of Alzheimer's disease (AD). It is not yet clear what factors are responsible for the aggregation of Aβ in the formation of these plaques. Using Tg2576 and PSAPP mouse models that exhibit age-related development of amyloid plaques similar to that observed in AD, we showed that ≈95% of dense plaques in Tg2576 and ≈85% in PSAPP mice are centered on vessel walls or in the immediate perivascular regions. Stereoscopy and simulation studies focusing on smaller plaques suggested that vascular associations for both Tg2576 and PSAPP mice were dramatically higher than those encountered by chance alone. We further identified ultrastructural microvascular abnormalities occurring in association with dense plaques. Although occurrence of gross cerebral hemorrhage was infrequent, we identified considerable infiltration of the serum proteins immunoglobulin and albumin in association with dense plaques. Together with earlier evidence of vascular clearance of Aβ, our data suggest that perturbed vascular transport and/or perivascular enrichment of Aβ leads to the formation of vasocentric dense plaques in Tg2576 and PSAPP mouse models of AD. Alzheimer's disease (AD) is characterized by progressive deposition of the amyloid β protein (Aβ) in brain regions responsible for memory and cognition. The chief constituents of Aβ plaques are the Aβ peptides, Aβ40 and Aβ42, and according to the proposed amyloid hypothesis, Aβ is the key pathogenic molecule in the causation of AD.1Hardy JA Higgins GA Alzheimer's disease: the amyloid cascade hypothesis.Science. 1992; 256: 184-185Crossref PubMed Scopus (4810) Google Scholar Accordingly, mutations causing autosomal-dominant forms of AD identified within the Aβ precursor protein (APP) or presenilin proteins (PS1 and PS2)2Van Broeckhoven C Molecular genetics of Alzheimer disease: identification of genes and gene mutations.Eur Neurol. 1995; 35: 8-19Crossref PubMed Scopus (90) Google Scholar increase the production of total Aβ (Aβ40 and Aβ42) or Aβ42.3Selkoe DJ The cell biology of β-amyloid precursor protein and presenilin in Alzheimer's disease.Trends Cell Biol. 1998; 8: 447-453Abstract Full Text Full Text PDF PubMed Scopus (794) Google Scholar However, the precise mechanism by which Aβ is neurotoxic, or deposited in plaques, has not been, as yet, resolved. A variety of Aβ plaques are described in AD that range from diffuse to highly compacted plaques, the latter often contain a dense amyloid core and stain with fibril-binding dyes such as thioflavin S (ThS).4Dickson DW The pathogenesis of senile plaques.J Neuropathol Exp Neurol. 1997; 56: 321-339Crossref PubMed Scopus (598) Google Scholar Consistent with in vitro neurotoxic properties of fibrillar Aβ,5Yankner BA Duffy LK Kirschner DA Neurotrophic and neurotoxic effects of amyloid beta-protein—reversal by tachykinin neuropeptides.Science. 1990; 250: 279-282Crossref PubMed Scopus (1888) Google Scholar dense plaques are associated with neuronal loss and a significant amount of neuritic pathology in the form of dystrophic neurites with vesicular organelles, dense bodies, and paired helical filaments.4Dickson DW The pathogenesis of senile plaques.J Neuropathol Exp Neurol. 1997; 56: 321-339Crossref PubMed Scopus (598) Google Scholar A third form of Aβ deposition is in the walls of small arteries and arterioles within the leptomeninges and cortex as a segmental or concentric amyloid deposit (cerebral amyloid angiopathy, CAA).6Joachim CL Morris JH Selkoe DJ Clinically diagnosed Alzheimers-disease—autopsy results in 150 cases.Ann Neurol. 1988; 24: 50-56Crossref PubMed Scopus (326) Google Scholar, 7Scholtz W Studien zur Pathologie der Hirngefässe. II. Die drüsige Entartung der Hirnarterien und-capillären.Z Gesamte Neurol Psychiat. 1938; 162: 694-715Crossref Scopus (165) Google Scholar With the recognition of Aβ deposition in vessels, considerable efforts have been devoted to studying the relationship between vessels and parenchymal Aβ plaques.7Scholtz W Studien zur Pathologie der Hirngefässe. II. Die drüsige Entartung der Hirnarterien und-capillären.Z Gesamte Neurol Psychiat. 1938; 162: 694-715Crossref Scopus (165) Google Scholar, 8Ishii T Enzyme histochemical studies of senile plaques and the plaque-like degeneration of arteries and capillaries (Scholz).Acta Neuropathol (Berl). 1969; 14: 250-260Crossref PubMed Scopus (19) Google Scholar, 9Mandybur TI The incidence of cerebral amyloid angiopathy in Alzheimer's disease.Neurology. 1975; 25: 120-126Crossref PubMed Google Scholar, 10Glenner GG Amyloid deposits and amyloidosis.N Engl J Med. 1980; 302: 1283-1292Crossref PubMed Scopus (1294) Google Scholar, 11Miyakawa T Shimoji A Kuramoto R Higuchi Y The relationship between senile plaques and cerebral blood vessels in Alzheimer's disease and senile dementia. Morphological mechanism of senile plaque production.Virchows Arch B Cell Pathol Incl Mol Pathol. 1982; 40: 121-129Crossref PubMed Scopus (176) Google Scholar, 12Arai H Sagi N Noguchi I Haga S Ishii T Makino Y Kosaka K An immunohistochemical study of beta-protein in Alzheimer-type dementia brains.J Neurol. 1989; 236: 214-217Crossref PubMed Scopus (20) Google Scholar, 13Kawai M Kalaria RN Harik SI Perry G The relationship of amyloid plaques to cerebral capillaries in Alzheimer's disease.Am J Pathol. 1990; 137: 1435-1446PubMed Google Scholar, 14Iwamoto N Nishiyama E Ohwada J Arai H Distribution of amyloid deposits in the cerebral white matter of the Alzheimer's disease brain: relationship to blood vessels.Acta Neuropathol (Berl). 1997; 93: 334-340Crossref PubMed Scopus (49) Google Scholar, 15Kumar-Singh S Cras P Wang R Kros JM van Swieten J Lubke U Ceuterick C Serneels S Vennekens K Timmermans J-P Van Marck E Martin J-J van Duijn C Van Broeckhoven C Dense-core senile plaques in the Flemish variant of Alzheimer's disease are vasocentric.Am J Pathol. 2002; 161: 507-520Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar, 16Vinters HV Wang ZZ Secor DL Brain parenchymal and microvascular amyloid in Alzheimer's disease.Brain Pathol. 1996; 6: 179-195Crossref PubMed Scopus (151) Google Scholar However, to date only one such entity has been accepted as a bona fide but smaller version of parenchymal Aβ plaques called drusige Entartung der Hirnarterien und capillaren or dyshoric angiopathy.7Scholtz W Studien zur Pathologie der Hirngefässe. II. Die drüsige Entartung der Hirnarterien und-capillären.Z Gesamte Neurol Psychiat. 1938; 162: 694-715Crossref Scopus (165) Google Scholar, 17Morel F Wildi E General and cellular pathochemistry of senile and presenile alterations of the brain.Proc 1st Int Cong Neuropathol Rome. 1952; : 347-374Google Scholar These deposits involve smaller cortical arterioles and capillaries, and amyloid fibrils extend from the vessel into the surrounding neuropil and are associated with dystrophic neurites.18Peers MC Lenders MB Defossez A Delacourte A Mazzuca M Cortical angiopathy in Alzheimers-disease—the formation of dystrophic perivascular neurites is related to the exudation of amyloid fibrils from the pathological vessels.Virchows Arch A Pathol Anat Histopathol. 1988; 414: 15-20Crossref PubMed Scopus (20) Google Scholar In a rare familial AD associated with the Flemish APP substitution (Ala 692 Gly),19Hendriks L van Duijn CM Cras P Cruts M Van Hul W van Harskamp F Warren A McInnis MG Antonarakis SE Martin J-J Hofman A Van Broeckhoven C Presenile dementia and cerebral haemorrhage linked to a mutation at condon 692 of the β-amyloid precursor protein gene.Nat Genet. 1992; 1: 218-221Crossref PubMed Scopus (640) Google Scholar we recently reported that almost all dense-core plaques from various brain regions enclosed vessels or were associated with vessel walls.15Kumar-Singh S Cras P Wang R Kros JM van Swieten J Lubke U Ceuterick C Serneels S Vennekens K Timmermans J-P Van Marck E Martin J-J van Duijn C Van Broeckhoven C Dense-core senile plaques in the Flemish variant of Alzheimer's disease are vasocentric.Am J Pathol. 2002; 161: 507-520Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar Remarkably, dyshoric angiopathy was not only observed for capillaries and small arterioles, but also medium-sized arterioles.15Kumar-Singh S Cras P Wang R Kros JM van Swieten J Lubke U Ceuterick C Serneels S Vennekens K Timmermans J-P Van Marck E Martin J-J van Duijn C Van Broeckhoven C Dense-core senile plaques in the Flemish variant of Alzheimer's disease are vasocentric.Am J Pathol. 2002; 161: 507-520Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar Findings such as these have also been reported in rare familial forms of AD.20Dermaut B Kumar-Singh S De Jonghe C Cruts M Lofgren A Lubke U Cras P Dom R De Deyn PP Martin JJ Van Broeckhoven C Cerebral amyloid angiopathy is a pathogenic lesion in Alzheimer's disease due to a novel presenilin 1 mutation.Brain. 2001; 124: 2383-2392Crossref PubMed Scopus (74) Google Scholar Recently, transgenic mouse models have been developed that exhibit progressive age-related Aβ plaques and CAA similar to that observed in AD.21Games D Adams D Alessandrini R Barbour R Berthelette P Blackwell C Carr T Clemens J Donaldson T Gillespie F Guido T Hagopian S Johnsonwood K Khan K Lee M Leibowitz P Lieberburg I Little S Masliah E McConlogue L Montoyazavala M Mucke L Paganini L Penniman E Power M Schenk D Seubert P Snyder B Soriano F Tan H Vitale J Wadsworth S Wolozin B Zhao J Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein.Nature. 1995; 373: 523-527Crossref PubMed Scopus (2217) Google Scholar, 22Hsiao K Chapman P Nilsen S Eckman C Harigaya Y Younkin S Yang F Cole G Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice.Science. 1996; 274: 99-102Crossref PubMed Scopus (3635) Google Scholar, 23Holcomb L Gordon MN McGowan E Yu X Benkovic S Jantzen P Wright K Saad I Mueller R Morgan D Sanders S Zehr C O'Campo K Hardy J Prada CM Eckman C Younkin S Hsiao K Duff K Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes.Nat Med. 1998; 4: 97-100Crossref PubMed Scopus (824) Google Scholar, 24Sturchler-Pierrat C Abramowski D Duke M Wiederhold KH Mistl C Rothacher S Ledermann B Burki K Frey P Paganetti PA Waridel C Calhoun ME Jucker M Probst A Staufenbiel M Sommer B Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology.Proc Natl Acad Sci USA. 1997; 94: 13287-13292Crossref PubMed Scopus (1234) Google Scholar Specifically, the dense plaques closely resemble human pathology, with neuritic dystrophy and neuronal loss in the surrounding parenchyma.25Urbanc B Cruz L Le R Sanders J Ashe KH Duff K Stanley HE Irizarry MC Hyman BT Neurotoxic effects of thioflavin S-positive amyloid deposits in transgenic mice and Alzheimer's disease.Proc Natl Acad Sci USA. 2002; 99: 13990-13995Crossref PubMed Scopus (182) Google Scholar The aim of this study was to explore the anatomical relationship between vessels (or vascular Aβ) and dense plaques in transgenic AD mouse models. In addition, we explored changes in vascular densities and structural microvascular abnormalities described previously in AD.13Kawai M Kalaria RN Harik SI Perry G The relationship of amyloid plaques to cerebral capillaries in Alzheimer's disease.Am J Pathol. 1990; 137: 1435-1446PubMed Google Scholar, 26Farkas E Luiten PGM Cerebral microvascular pathology in aging and Alzheimer's disease.Prog Neurobiol. 2001; 64: 575-611Crossref PubMed Scopus (871) Google Scholar Using two AD mouse models—Tg2576 (APP/Sw or APPK670N/M671L; line Tg2576)22Hsiao K Chapman P Nilsen S Eckman C Harigaya Y Younkin S Yang F Cole G Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice.Science. 1996; 274: 99-102Crossref PubMed Scopus (3635) Google Scholar and bigenic PSAPP (APP/Sw X PS1M146L; line 6.2)23Holcomb L Gordon MN McGowan E Yu X Benkovic S Jantzen P Wright K Saad I Mueller R Morgan D Sanders S Zehr C O'Campo K Hardy J Prada CM Eckman C Younkin S Hsiao K Duff K Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes.Nat Med. 1998; 4: 97-100Crossref PubMed Scopus (824) Google Scholar, 27Duff K Eckman C Zehr C Yu X Prada CM Perez-tur J Hutton M Buee L Harigaya Y Yager D Morgan D Gordon MN Holcomb L Refolo L Zenk B Hardy J Younkin S Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1.Nature. 1996; 383: 710-713Crossref PubMed Scopus (1307) Google Scholar—we showed that the majority of the dense plaques are centered on vessel walls. We also showed considerable structural microvascular damage and blood-brain barrier (BBB) abnormalities in the vicinity of dense plaques. A total of 16 brains from hemizygous Tg2576 (n = 10, APPK670N/M671L)22Hsiao K Chapman P Nilsen S Eckman C Harigaya Y Younkin S Yang F Cole G Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice.Science. 1996; 274: 99-102Crossref PubMed Scopus (3635) Google Scholar and bigenic PSAPP (n = 6, Tg2576 X PS1M146L line 6.2)23Holcomb L Gordon MN McGowan E Yu X Benkovic S Jantzen P Wright K Saad I Mueller R Morgan D Sanders S Zehr C O'Campo K Hardy J Prada CM Eckman C Younkin S Hsiao K Duff K Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes.Nat Med. 1998; 4: 97-100Crossref PubMed Scopus (824) Google Scholar, 27Duff K Eckman C Zehr C Yu X Prada CM Perez-tur J Hutton M Buee L Harigaya Y Yager D Morgan D Gordon MN Holcomb L Refolo L Zenk B Hardy J Younkin S Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1.Nature. 1996; 383: 710-713Crossref PubMed Scopus (1307) Google Scholar mice were studied. Tg2576 mice comprised four males (15, 17, 24, and 25 months of age) and six females (10 months of age, n = 2; 13 months of age, n = 2; and 17 and 24 months of age, n = 1 each); and PSAPP mice were three males (5, 11, and 20 months of age) and three females (5 months of age, n = 1; and 11 months of age, n = 2). Tg2576 founder was made in Swiss Webster X C57BL6/DBA2 hybrid and subsequently backcrossed to C57BL6/SJL, Swiss Webster, or B5/SJL-Swiss Webster F1. PSAPP were chiefly in Swiss Webster/C57D2F1. Control nontransgenic mice in C57BL6/D2AF1 were 12, 18, and 24 months of age (n = 2 each). Mice were euthanized by cervical dislocation, and either the right or both hemispheres were immersion-fixed in 10% neutral buffered formalin (Tg2576) or 4% buffered paraformaldehyde for 18 hours (PSAPP) and embedded in paraffin, oriented coronally or sagittally. One PSAPP mouse that died immediately before being euthanized was also included in this study. In addition, tissue was also prepared for electron microscopy (see further). All animal experiments were approved by the University of Antwerp ethics committee and conducted according to the guidelines of the University of Antwerp and the National Institutes of Health. For Aβ immunohistochemistry, the following antibodies were used: biotinylated-4G8 (Aβ17-24; Signet, Dedham, MA); 6E10 (Aβ5-11, Signet); JRF/AβN/11 (Aβ1-7);28Kumar-Singh S De Jonghe C Cruts M Kleinert R Wang R Mercken M De Strooper B Vanderstichele H Lofgren A Vanderhoeven I Backhovens H Vanmechelen E Kroisel PM Van Broeckhoven C Nonfibrillar diffuse amyloid deposition due to a gamma(42)-secretase site mutation points to an essential role for N-truncated abeta(42) in Alzheimer's disease.Hum Mol Genet. 2000; 9: 2589-2598Crossref PubMed Google Scholar JRF/cAb40/10, R209, and FCA3340 (specific for Aβ40);28Kumar-Singh S De Jonghe C Cruts M Kleinert R Wang R Mercken M De Strooper B Vanderstichele H Lofgren A Vanderhoeven I Backhovens H Vanmechelen E Kroisel PM Van Broeckhoven C Nonfibrillar diffuse amyloid deposition due to a gamma(42)-secretase site mutation points to an essential role for N-truncated abeta(42) in Alzheimer's disease.Hum Mol Genet. 2000; 9: 2589-2598Crossref PubMed Google Scholar and, JRF/cAb42/12, R226, and FCA3542 (specific for Aβ42).28Kumar-Singh S De Jonghe C Cruts M Kleinert R Wang R Mercken M De Strooper B Vanderstichele H Lofgren A Vanderhoeven I Backhovens H Vanmechelen E Kroisel PM Van Broeckhoven C Nonfibrillar diffuse amyloid deposition due to a gamma(42)-secretase site mutation points to an essential role for N-truncated abeta(42) in Alzheimer's disease.Hum Mol Genet. 2000; 9: 2589-2598Crossref PubMed Google Scholar Different antibodies on serial sections gave consistent staining patterns for dense plaques, which were defined as dense circumscribed aggregates, chiefly composed of Aβ40, and larger than 5 μm in diameter with clear limiting margins. Dense plaques recognizable on immunohistochemistry were also ThS-positive (see further). Dense vascular deposits were rejected when Aβ was confined to the vessel walls. Dyshoric angiopathy in which Aβ deposition involves parenchyma was considered as dense plaques. Furthermore, based on high specificity and almost no background, biotinylated-4G8 with 70% formic acid pretreatment for 5 minutes at room temperature was used for plaque-vascular association studies. Utility of a panel of antibodies and lectins was explored as markers of murine vasculature: Ricinus communis agglutinin (RCA) I; Ulex europaeus agglutinin (UEA) I; Griffonia (Bandeiraea) simplicifolia (GSL I-B4) (Vector Laboratories, Peterborough, UK); anti-mouse collagen IV (Chemicon, Temecula, CA); human smooth muscle cell, SMA (DAKO, Glostrup, Denmark); and three anti-mouse CD31 (PharMingen, San Diego, CA; Chemicon; and Cymbus, Hants, UK). From these markers, GSL I-B4 and collagen IV emerged as the most efficient murine vascular markers and were subsequently used in this study. However, the reactivity of GSL I-B4 (as well as of other endothelial markers) was substantially reduced in areas of dense plaque deposition. On the other hand, collagen IV immunoreactivity although relatively stable in plaque-rich areas, did not recognize all small vessels. Hematoxylin and eosin (H&E) stain was invariably used in conjunction with immunostaining because it was useful in identifying degenerating microvessels. For some series, Verhoeff's-van Gieson elastica stain was also used with biotinylated-4G8 histochemistry. All immunohistochemical procedures were performed as detailed elsewhere.15Kumar-Singh S Cras P Wang R Kros JM van Swieten J Lubke U Ceuterick C Serneels S Vennekens K Timmermans J-P Van Marck E Martin J-J van Duijn C Van Broeckhoven C Dense-core senile plaques in the Flemish variant of Alzheimer's disease are vasocentric.Am J Pathol. 2002; 161: 507-520Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar Briefly, double immunohistochemistry was performed using species-specific or IgG subtype-specific secondary antibodies, conjugated to biotin for an additional amplification step or directly to horseradish peroxidase, alkaline phosphatase, or galactosidase. For monoclonal anti-Aβ antibodies, mouse-on-mouse kit (DAKO Ark system) was used. Color was developed with 3′3′diaminobenzidine (Roche, Nutley, NJ), 3-amino-9-ethylcarbazole (Roche), 5-bromo-4-chloro-3-indolyl-phosphate/nitro blue tetrazolium solution (Roche), or 5-bromo-4-chloro-3-indolyl-d-galactopyranoside (X-gal, Roche). Sections were counterstained with hematoxylin. For each specimen, 40 serial sections of 4 μm thickness were sliced for two to three such series, spaced ≈50 μm apart. Dense plaques were systematically sampled on 4 to 10 random fields (depending on the objective used, see below) from the rhinal, frontal, hindlimb motor, cingulate, occipital cortices, hippocampus, as well as thalamus. All plaques encountered in the 11th to 30th section (80 μm) of each series were followed serially. An additional 10 flanking sections (thus 40 μm further on each end) were used only to conclude the plaques already being analyzed. Those that could not be concluded were rejected. For two mice we studied the entire brain region. For this, all plaques appearing on coronal brain slices for a Tg2576–24m (n = 210 plaques) and sagittal slices for a PSAPP-5m (n = 258 plaques) were studied with the above strategy. Images were grabbed by a ×20 lens covering a field of 0.092 mm2 and occasionally by a ×40 (0.023 mm2), archived into AnalySIS (Soft Imaging System, Münster, Germany) with each plaque being assigned a unique identity, montaged, and studied serially. More than 350 montages were generated with ≈35 Gb of images. For vascular density assessments, two mice each of 11- to 13-month-old nontransgenic, Tg2576, and PSAPP mice were analyzed with GSL I-B4, collagen IV, and goat anti-mouse immunoglobulin (Ig; Southern Biotechnology Inc., Birmingham, AL). Three images were grabbed by a ×20 objective (0.092 mm2) from three serial sections from five cortical (rhinal, frontal, hindlimb motor, cingulated, occipital), hippocampal, and thalamic regions and were analyzed by densitometry as described earlier.29Kumar-Singh S Vermeulen PB Weyler J Segers K Weyn B Van Daele A Van Oosterom AT Dirix LY Van Marck E Evaluation of tumour angiogenesis as a prognostic marker in malignant mesothelioma.J Pathol. 1997; 182: 211-216Crossref PubMed Scopus (76) Google Scholar Sixteen Tg2576 and PSAPP mice grouped as young (≤3 months, n = 7), adult (15 to 20 months, n = 4), and old (24 to 25 months, n = 5) together with nontransgenic mice of 12, 18, and 24 months (n = 2 each) were investigated for fresh or late microvascular hemorrhage (by H&E and Pearls' Prussian blue, respectively) and for parenchymal serum protein infiltration (Ig and albumin immunostaining). For Ig staining, sections were treated with 1:50 biotinylated goat anti-mouse Ig (DAKO) overnight and detected by streptavidin-biotin-horseradish peroxidase and 3′3′diaminobenzidine. For albumin staining, utility of three polyclonal antibodies was tested: biotinylated rabbit anti-mouse albumin (Autogen Bioclear, Wilts, UK), goat anti-mouse albumin (Bethyl, Montgomery, TX) and rabbit anti-mouse albumin (ICN Pharmaceutical, Cincinnati, OH). Rabbit anti-mouse albumin (ICN) was further used and detected as described for Ig. Microhemorrhages and serum staining were semiquantitatively scored independently by two investigators as: 0 (no microhemorrhage or reactivity detected in the entire brain section), 1 (≤2), 2 (>2 to 10), or 3 (>10 such observations). A total of 10 such series spaced up to 40 sections apart were analyzed and the scores averaged. For investigating total and fibrillar Aβ content and comparing the staining patterns of dense plaques, two adjacent sections from each mouse were studied by Aβ immunolabeling and ThS. The sections were first stained with 1% solution of ThS (Sigma-Aldrich, Bornem, Belgium) and imaged using a Zeiss Axioskop 50 fluorescent microscope (Carl Zeiss NV, Zaventem, Brussels) equipped with specific filter sets (excitation, 395 to 440 nm; emission, 515 to 565 nm) connected to a UNIX workstation with an analysis program (Applied Imaging System, San Jose, CA). The sections were thereafter differentiated in 70% ethanol and processed further for Aβ histochemistry as described in the earlier section. Image analysis for Aβ- and ThS-stained sections was performed as described previously.29Kumar-Singh S Vermeulen PB Weyler J Segers K Weyn B Van Daele A Van Oosterom AT Dirix LY Van Marck E Evaluation of tumour angiogenesis as a prognostic marker in malignant mesothelioma.J Pathol. 1997; 182: 211-216Crossref PubMed Scopus (76) Google Scholar Co-localization of Ig or albumin with Aβ was performed on 16 Tg2576 and PSAPP mice. Three series of two consecutive sections sampled systematically as described above were double-labeled for Aβ (biotinylated-4G8 or a combination of R209/R226 antisera28Kumar-Singh S De Jonghe C Cruts M Kleinert R Wang R Mercken M De Strooper B Vanderstichele H Lofgren A Vanderhoeven I Backhovens H Vanmechelen E Kroisel PM Van Broeckhoven C Nonfibrillar diffuse amyloid deposition due to a gamma(42)-secretase site mutation points to an essential role for N-truncated abeta(42) in Alzheimer's disease.Hum Mol Genet. 2000; 9: 2589-2598Crossref PubMed Google Scholar) with either Ig or albumin. In parallel, similar series were also prepared for ThS with Ig or albumin staining for each mouse. Using Alexa 488- or Alexa 594-labeled anti-mouse, anti-rabbit, or streptavidin biotin (Molecular Probes, Leiden, The Netherlands) with specific combinations of excitation and emission filter sets, proportions of dense-plaques positively labeled for Ig or albumin were manually assessed. Frontal and posterior cortex as well as the hippocampus of three PSAPP (5 months, n = 2; and 11 months) and 20-month-old nontransgenic mice (n = 2) were fixed in 4% neutral buffered glutaraldehyde followed by 2% buffered osmium tetraoxide, embedded in araldite, and sectioned with a Reichert Jung microtome equipped with a section counter as described previously.15Kumar-Singh S Cras P Wang R Kros JM van Swieten J Lubke U Ceuterick C Serneels S Vennekens K Timmermans J-P Van Marck E Martin J-J van Duijn C Van Broeckhoven C Dense-core senile plaques in the Flemish variant of Alzheimer's disease are vasocentric.Am J Pathol. 2002; 161: 507-520Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar Approximately 250, 1-μm-thick sections were sliced serially for each block. Semithin sections were stained with metachromatic methylene blue. A few sections were also stained immunohistochemically for Aβ to confirm the tinctorial properties of methylene blue. For this, the epoxy resin was removed as described30Maxwell MH Two rapid and simple methods for the removal of resins from 1.0 micrometer thick epoxy sections.J Microsc. 1977; 112: 253-255Crossref Scopus (167) Google Scholar and processed as described for paraffin-embedded tissue. For ultrastructural microscopy, 0.1-μm-ultrathin sections were collected on copper grids before the start (prethin) and at the end (postthin) of each semithin series. Sections were contrasted with routine uranyl acetate and lead citrate, and analyzed by a Philips CM10 electron microscope equipped with a goniometric coordinator as described previously.15Kumar-Singh S Cras P Wang R Kros JM van Swieten J Lubke U Ceuterick C Serneels S Vennekens K Timmermans J-P Van Marck E Martin J-J van Duijn C Van Broeckhoven C Dense-core senile plaques in the Flemish variant of Alzheimer's disease are vasocentric.Am J Pathol. 2002; 161: 507-520Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar For immunogold labeling, tissue was fixed in 4% paraformaldehyde and 0.01% glutaraldehyde and embedded in Unicryl (BB Int., Cardiff, UK). Sections were collected on formvar-coated nickel grids (Ted Pella Inc., Redding, CA) and labeling performed with a polyclonal Aβ antibody (kind gift from Dr. Konrad Beyreuther, ZMBH, University Heidelberg, Germany (http://www.zmbh.uni-heidelberg.de/Beyreuther/)) using anti-rabbit linked with 10-nm gold particles (BB Int.). The following attributes were measured manually by a specific tool within the AnalySIS package for both thin (4 μm) and semithin (1 μm) section analysis: 1) the total plaque size in its largest dimension in any of the serial section; 2) size of the dense core(s); and, 3) total number and diameter of the associated vessels within 4 μm of dense plaque (vessel bifurcation was counted as two). The chance of encountering vessels was calculated as follows: for a given vascular density, minimum area (AT) containing at most one vessel was calculated by dividing AT by the mean vessel area in this region, AV, which provided a probability of a given vessel to be in this unique position (PV = AV/AT). Presuming AV to be circular, the probability of a circular plaque with radius RP that would either overlap or juxtapose the vessel within a circle of radius RP + RV + 4 μm was calculated (see Figure 4D). Because the number of vessels far exceeds the number of dense plaques, only one plaque could occur at one time. The probability for both events happening together is P = PV * PP and was deemed significant if <0.05. Simulations were performed by randomly pitching circles of diameters 10, 20, and 40 μm to mimic plaques of these sizes. Simulations pitching partly outside the measured field, and for transgenic mice, pitching on the plaques, were rejected. All statistical analysis was performed either on S-Plus (Splus; Insightful Co., Seattle, WA) or by SPSS (SPSS Inc., Chicago, IL) and has been addressed in relevant sections in Results. Multiple comparisons were adjusted acc" @default.
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• W2019574244 date "2005-08-01" @default.
• W2019574244 modified "2023-10-16" @default.
• W2019574244 title "Dense-Core Plaques in Tg2576 and PSAPP Mouse Models of Alzheimer's Disease Are Centered on Vessel Walls" @default.
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