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Microglia and astrocytes may participate in strain selection because the agent evolved, stabilized, and reproducibly provoked BSE-like disease in subsequent passages. Early vacuolar change involving activated microglia and astrocytes preceded significant PrP-res accumulation by more than 50 days. These studies reveal several inflammatory host reactions to an exogenous agent.<\/jats:p>","DOI":"10.1126\/science.277.5322.94","type":"journal-article","created":{"date-parts":[[2002,7,27]],"date-time":"2002-07-27T09:44:47Z","timestamp":1027763087000},"page":"94-98","source":"Crossref","is-referenced-by-count":115,"title":["Evolution of a Strain of CJD That Induces BSE-Like Plaques"],"prefix":"10.1126","volume":"277","author":[{"given":"Laura","family":"Manuelidis","sequence":"first","affiliation":[{"name":"Section of Neuropathology, Yale Medical School, 310 Cedar Street, New Haven, CT 06510, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Fritch","sequence":"additional","affiliation":[{"name":"Section of Neuropathology, Yale Medical School, 310 Cedar Street, New Haven, CT 06510, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"You-Gen","family":"Xi","sequence":"additional","affiliation":[{"name":"Section of Neuropathology, Yale Medical School, 310 Cedar Street, New Haven, CT 06510, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_1_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/382779a0"},{"key":"e_1_3_1_3_2","first-page":"338","volume":"127","author":"Dawson M.","year":"1990","unstructured":"Dawson M., Wells G., Parker B., Scott A., Vet. 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The congophilic plaques described in P1 mice and rats from this progenitor strain were associated with the inoculation site and adjacent subependyma and white matter but were not reproduced on serial passage ["},{"key":"e_1_3_1_13_4","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1002\/ana.410150313","volume":"15","author":"Tateishi J.","year":"1984","unstructured":"Tateishi J., Nagara H., Hikita K., Sato Y., Ann. Neurol. 15, 278 (1984)].","journal-title":"Ann. Neurol."},{"key":"e_1_3_1_14_2","unstructured":"These people also lack any of the other relatively infrequent PrP mutations thought to enhance susceptibility to CJD or GSS although they do have an unrelated Met 129 homozygosity a polymorphism present in 38% of the human population."},{"key":"e_1_3_1_15_2","unstructured":"P. Brown in Immunologic Mechanisms in Neurologic and Psychiatric Disease B. Waksman Ed. (Raven New York 1990) pp. 305\u2013313; S. Prusiner Sci. Am. 272 30 (January 1995)."},{"key":"e_1_3_1_16_2","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1006\/viro.1996.0033","volume":"215","author":"Manuelidis L.","year":"1996","unstructured":"Manuelidis L., Fritch W., Virology 215, 46 (1996);","journal-title":"Virology"},{"key":"e_1_3_1_16_3","unstructured":". The fastest strain will preferentially survive during the >15-year passage. Because the determined doubling time is 7.5 days each year of continuous passage (two or more per year) represents \u223c248 doublings. Additionally cross-species transmission can mimic strain selection by limiting dilution (7) because P1 incubation times and \u201ctakes\u201d correspond to about one infectious dose."},{"key":"e_1_3_1_17_2","unstructured":"Sprague-Dawley rats were inoculated intracerebrally with 50 \u03bcl of a 10% SY\u2013infected hamster brain. For serial passage a slice of rat frontal cortex was homogenized. Five-micrometer deparafinized sections were used for antibody binding with standard alkaline phosphatase or peroxidase detectors. Primary antibodies were diluted >1:1000 except HLA-DR which was diluted 1:300. Because standard methods for histological detection of PrP-res (hydrolytic autoclaving formic acid treatment and proteinase K digestion) produced artifactual vacuoles we developed other pretreatments. Autoclaving 5-m paraffin sections for 12 min in 0.2 M citrate (pH 6.0) preserved neuropil structure gave little PrP background in controls and did not alter the staining pattern of other antibodies in double detections. For double labeling polyclonal antibody P8-1 (against gel-purified PrP-res) was first detected with peroxidase development (\u223c5 min) with alakaline phosphatase for the second mononclonal antibody (\u223c5 min). Reversed detection showed the same pattern of labeling."},{"key":"e_1_3_1_18_2","unstructured":"Normally microglia are found around vessels but rarely within the grey parenchyma and we used a KS antibody to delineate activated microglia. In accord with Fig. 1B KS antibody to released chondroitin sulfate (clone 5D4; ICN Costa Mesa CA) can stain a few \u201cramified\u201d microglia in the normal rat cortex ["},{"key":"e_1_3_1_18_3","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1177\/41.4.8450191","volume":"41","author":"Bertolotto A.","year":"1993","unstructured":"Bertolotto A., et al., J. Histochem. Cytochem. 41, 481 (1993);","journal-title":"J. Histochem. Cytochem."},{"key":"e_1_3_1_18_4","unstructured":"]. The numerous reactive microglia in infected rats were enlarged and had many processes making them morphologically comparable to activated HLA-DR (class II) microglia in Alzheimer's disease (25). Additionally invariant chains (associated with major histocompatibility class II molecules in antigen presentation) are modified by chondroitin sulfate ["},{"key":"e_1_3_1_18_5","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/0092-8674(93)90417-O","volume":"74","author":"Naujokas M. F.","year":"1993","unstructured":"Naujokas M. F., et al., Cell 74, 245 (1993);","journal-title":"Cell"},{"key":"e_1_3_1_18_6","unstructured":"]. It has not yet been determined whether the increase in activated microglia shown here represents migrating or proliferating populations; the association of many KS microglia with thin-walled vessels in later passages could suggest entry (macrophage derivatives) from the bloodstream. Some KS-positive cells may be phagocytic as PrP-res increased in the cytoplasm at later passages but these cells were negative for the macrophage marker ED-1."},{"key":"e_1_3_1_19_2","doi-asserted-by":"crossref","first-page":"5937","DOI":"10.1073\/pnas.84.16.5937","volume":"84","author":"Manuelidis L.","year":"1987","unstructured":"Manuelidis L., Tesin D. M., Sklaviadis T., Manuelidis E. E., Proc. Natl. Acad. Sci. U.S.A. 84, 5937 (1987).","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"e_1_3_1_20_2","first-page":"223","volume":"73","author":"Manuelidis E. E.","year":"1976","unstructured":"Manuelidis E. E., Kim J., Angelo J., Manuelidis L., ibid. 73, 223 (1976).","journal-title":"ibid."},{"key":"e_1_3_1_21_2","unstructured":"At early stages of clinical disease (\u223c307 days) rats could not right themselves when hung on a cage grid upside down. About a week later a footprint test documented tight circling and wobbling whereas older control rats ran straight off the filter paper. As in P1 and P2 terminal rats were hunched and thin with ruffled fur."},{"key":"e_1_3_1_22_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1237933"},{"key":"e_1_3_1_22_3","unstructured":". Rat plaques with \u201cvery faint\u201d Congo Red birefringence ["},{"key":"e_1_3_1_22_4","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1007\/BF00686649","volume":"8","author":"Field E.","year":"1967","unstructured":"Field E., Raine C., Joyce G., Acta Neuropathol. 8, 47 (1967);","journal-title":"Acta Neuropathol."},{"key":"e_1_3_1_22_5","unstructured":"] and in three aged Sprague-Dawley rats [D. Vaughan and A. Peters J. Neuropath. Exp. Neurol. 40 (1981)] have not been reproducible. Moreover many other scrapie isolates propagated in rats (7) ["},{"key":"e_1_3_1_22_6","doi-asserted-by":"crossref","first-page":"1875","DOI":"10.1099\/0022-1317-68-7-1875","volume":"68","author":"Kimberlin R.","year":"1987","unstructured":"Kimberlin R., Cole S., Walker C., J. Gen. Virol. 68, 1875 (1987);","journal-title":"J. Gen. Virol."},{"key":"e_1_3_1_22_7","unstructured":"] have shown only short incubation times (<200 days) and vacuolar change. In contrast the plaques here developed only after serial propagation and were widespread and unrelated to the inoculation site."},{"key":"e_1_3_1_23_2","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/0304-3940(94)90478-2","volume":"166","author":"Gomi H.","year":"1994","unstructured":"Gomi H., et al., Neurosci. Lett. 166, 171 (1994);","journal-title":"Neurosci. Lett."},{"key":"e_1_3_1_23_3","doi-asserted-by":"publisher","DOI":"10.1038\/382180a0"},{"key":"e_1_3_1_23_4","unstructured":". Alignment of GenBank sequences also shows only a single Ile-to-Leu difference in rat versus mice at codon 139."},{"key":"e_1_3_1_24_2","unstructured":"For time course experiments two random rats were killed and the uninoculated halves of the brains were fixed in formalin (16). Submitted images and controls for ubiquitin ApoJ APLP and ApoE will be reported in detail elsewhere (27). The other halves were used for blots. A small slice of unfixed cerebellum and cortex from each brain was pooled and homogenized in saline for studies of PrP on blots whereas the remaining unfixed half-brains were used for isolation of RNA and Northern (RNA) blotting as described (18). Proteinase K production of PrP-res was optimized for yield and maximum detection sensitivity by quantitative chemiluminesce (15). With polyclonal P8-1 diluted 1:2400 longer exposures made 1 in 20 000 PrP molecules visually obvious whereas 16-bit digitization with standards indicated a detection sensitivity approaching 5 logs. Use of other antibodies to PrP peptides gave the same pattern of PrP-res accumulation."},{"key":"e_1_3_1_25_2","unstructured":"The slightly lesser value for KS microglia as compared with that for vacuoles at 150 days is due to our exclusion of vacuolated cerebellum in scoring because the internal granule layer normally contains some KS+ cells."},{"key":"e_1_3_1_26_2","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1017\/S0317167100029863","volume":"16","author":"McGeer P.","year":"1989","unstructured":"McGeer P., Akiyama S., Itagaki S., McGeer E., Can. J. Neurol. Sci. 16, 516 (1989);","journal-title":"Can. J. Neurol. 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Outram in Slow Virus Diseases of Animals and Man R. Kimberlin Ed. (North-Holland Amsterdam 1976); R. Kimberlin and P. Cunnington Microbiol. Lett. 3 169- (1978);"},{"key":"e_1_3_1_40_4","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1038\/384529a0","volume":"384","author":"Fauci A.","year":"1996","unstructured":"Fauci A., Nature 384, 529 (1996).","journal-title":"Nature"},{"key":"e_1_3_1_41_2","unstructured":"We thank I. Shvayetsky Z. Y. Lu for technical assistance and I. Alafuzoff for suggesting citrate autoclaving. The human GSS and BSE blocks were generously provided by J. Tateishi and J. Ironside respectively. Supported by NIH grants NS12674 and NS34569."}],"container-title":["Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/science.277.5322.94","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,13]],"date-time":"2024-01-13T04:34:10Z","timestamp":1705120450000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/science.277.5322.94"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1997,7,4]]},"references-count":76,"journal-issue":{"issue":"5322","published-print":{"date-parts":[[1997,7,4]]}},"alternative-id":["10.1126\/science.277.5322.94"],"URL":"https:\/\/doi.org\/10.1126\/science.277.5322.94","relation":{},"ISSN":["0036-8075","1095-9203"],"issn-type":[{"value":"0036-8075","type":"print"},{"value":"1095-9203","type":"electronic"}],"subject":[],"published":{"date-parts":[[1997,7,4]]}}}