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A fibril-specific, conformation-dependent antibody recognizes a subset of Abeta plaques in Alzheimer disease, Down syndrome and Tg2576 transgenic mouse brain.

Sarsoza F, Saing T, Kayed R, Dahlin R, Dick M, Broadwater-Hollifield C, Mobley S, Lott I, Doran E, Gillen D, Anderson-Bergman C, Cribbs DH, Glabe C, Head E - Acta Neuropathol. (2009)

Bottom Line: Our results show that accumulation of fibrillar immunoreactivity is significantly increased in AD relative to nondemented aged subjects and those with select cognitive impairments (p < 0.0001).Further, there was a significant correlation between the extent of frontal cortex fibrillar deposit accumulation and dementia severity (MMSE r = -0.72).These results suggest that fibrillar deposits are associated with disease in both AD and in adults with DS and their distribution within early Abeta pathology associated with diffuse plaques and correlation with MMSE suggest that these deposits may not be as benign as previously thought.

View Article: PubMed Central - PubMed

Affiliation: Institute for Brain Aging and Dementia, University of California, Irvine, CA 92697, USA.

ABSTRACT
Beta-amyloid (Abeta) is thought to be a key contributor to the pathogenesis of Alzheimer disease (AD) in the general population and in adults with Down syndrome (DS). Different assembly states of Abeta have been identified that may be neurotoxic. Abeta oligomers can assemble into soluble prefibrillar oligomers, soluble fibrillar oligomers and insoluble fibrils. Using a novel antibody, OC, recognizing fibrils and soluble fibrillar oligomers, we characterized fibrillar Abeta deposits in AD and DS cases. We further compared human specimens to those obtained from the Tg2576 mouse model of AD. Our results show that accumulation of fibrillar immunoreactivity is significantly increased in AD relative to nondemented aged subjects and those with select cognitive impairments (p < 0.0001). Further, there was a significant correlation between the extent of frontal cortex fibrillar deposit accumulation and dementia severity (MMSE r = -0.72). In DS, we observe an early age of onset and age-dependent accumulation of fibrillar OC immunoreactivity with little pathology in similarly aged non-DS individuals. Tg2576 mice show fibrillar accumulation that can be detected as young as 6 months. Interestingly, fibril-specific immunoreactivity was observed in diffuse, thioflavine S-negative Abeta deposits in addition to more mature neuritic plaques. These results suggest that fibrillar deposits are associated with disease in both AD and in adults with DS and their distribution within early Abeta pathology associated with diffuse plaques and correlation with MMSE suggest that these deposits may not be as benign as previously thought.

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Formic acid pretreatment has little effect on OC labeling intensity. Increasing concentrations of formic acid pretreatment (a none, b 10%, c 50%, d 70%, e 90%) were used in an AD case (frontal cortex) to illustrate no change in OC (red fluorescence) immunolabeling but an increase in 6E10 (green fluorescence) labeling. Note that with increasing formic acid and corresponding increase in 6E10 labeling, the extent of co-localization of the two markers also increases (orange fluorescence). In comparison, a control case shows neither significant OC nor 6E10 immunolabeling (f). However, a subset of OC-positive deposits (g and i) was negative for 6E10 (h and i)
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Fig1: Formic acid pretreatment has little effect on OC labeling intensity. Increasing concentrations of formic acid pretreatment (a none, b 10%, c 50%, d 70%, e 90%) were used in an AD case (frontal cortex) to illustrate no change in OC (red fluorescence) immunolabeling but an increase in 6E10 (green fluorescence) labeling. Note that with increasing formic acid and corresponding increase in 6E10 labeling, the extent of co-localization of the two markers also increases (orange fluorescence). In comparison, a control case shows neither significant OC nor 6E10 immunolabeling (f). However, a subset of OC-positive deposits (g and i) was negative for 6E10 (h and i)

Mentions: To determine if OC labeling was sensitive to formic acid pretreatment, a procedure used to improve immunostaining for fibrils [39], serial sections from an AD case were pretreated with 0, 10, 50, 70 and 90% formic acid for 4 min prior to incubation in OC antibody. After visualization with anti-rabbit conjugated to Alex Fluor 568, sections were washed and then incubated in 6E10, which shows an increase in immunolabeling with increasing formic acid. Figure 1 shows confocal images from a similar region in each serial section illustrating that increasing formic acid concentration leads to increasingly extensive 6E10 labeling but there is no change in OC labeling. We next examined whether OC immunoreactivity co-localizes with thioflavine-S, a marker for beta-pleated sheet fibrils but that there would also be distinct deposits. Figure 2 shows that some OC-positive deposits are also positive for thioflavin S suggesting an association with mature plaques (63.4% of thioflavin S was positive for OC). However, additional thioflavin-negative deposits were detected by the OC antibody, particularly at the periphery of mature plaques. It is possible that the OC antibody can detect other types of amyloid such as, for example, fibrillar oligomers that are thioflavine S-negative or alpha synuclein [35]. Further, OC-positive deposits had a distinct morphology from thioflavine S-positive fibrils (Fig. 2a–c). Using tissue from a nondemented elderly subject (Fig. 2d–f) and a younger individual with DS (Fig. 2g–i), both having primarily diffuse plaques (thioflavine S-negative), we observed that diffuse plaques are also OC-positive (9.3% of OC-positive plaques were thioflavin S-positive).Fig. 1


A fibril-specific, conformation-dependent antibody recognizes a subset of Abeta plaques in Alzheimer disease, Down syndrome and Tg2576 transgenic mouse brain.

Sarsoza F, Saing T, Kayed R, Dahlin R, Dick M, Broadwater-Hollifield C, Mobley S, Lott I, Doran E, Gillen D, Anderson-Bergman C, Cribbs DH, Glabe C, Head E - Acta Neuropathol. (2009)

Formic acid pretreatment has little effect on OC labeling intensity. Increasing concentrations of formic acid pretreatment (a none, b 10%, c 50%, d 70%, e 90%) were used in an AD case (frontal cortex) to illustrate no change in OC (red fluorescence) immunolabeling but an increase in 6E10 (green fluorescence) labeling. Note that with increasing formic acid and corresponding increase in 6E10 labeling, the extent of co-localization of the two markers also increases (orange fluorescence). In comparison, a control case shows neither significant OC nor 6E10 immunolabeling (f). However, a subset of OC-positive deposits (g and i) was negative for 6E10 (h and i)
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2737113&req=5

Fig1: Formic acid pretreatment has little effect on OC labeling intensity. Increasing concentrations of formic acid pretreatment (a none, b 10%, c 50%, d 70%, e 90%) were used in an AD case (frontal cortex) to illustrate no change in OC (red fluorescence) immunolabeling but an increase in 6E10 (green fluorescence) labeling. Note that with increasing formic acid and corresponding increase in 6E10 labeling, the extent of co-localization of the two markers also increases (orange fluorescence). In comparison, a control case shows neither significant OC nor 6E10 immunolabeling (f). However, a subset of OC-positive deposits (g and i) was negative for 6E10 (h and i)
Mentions: To determine if OC labeling was sensitive to formic acid pretreatment, a procedure used to improve immunostaining for fibrils [39], serial sections from an AD case were pretreated with 0, 10, 50, 70 and 90% formic acid for 4 min prior to incubation in OC antibody. After visualization with anti-rabbit conjugated to Alex Fluor 568, sections were washed and then incubated in 6E10, which shows an increase in immunolabeling with increasing formic acid. Figure 1 shows confocal images from a similar region in each serial section illustrating that increasing formic acid concentration leads to increasingly extensive 6E10 labeling but there is no change in OC labeling. We next examined whether OC immunoreactivity co-localizes with thioflavine-S, a marker for beta-pleated sheet fibrils but that there would also be distinct deposits. Figure 2 shows that some OC-positive deposits are also positive for thioflavin S suggesting an association with mature plaques (63.4% of thioflavin S was positive for OC). However, additional thioflavin-negative deposits were detected by the OC antibody, particularly at the periphery of mature plaques. It is possible that the OC antibody can detect other types of amyloid such as, for example, fibrillar oligomers that are thioflavine S-negative or alpha synuclein [35]. Further, OC-positive deposits had a distinct morphology from thioflavine S-positive fibrils (Fig. 2a–c). Using tissue from a nondemented elderly subject (Fig. 2d–f) and a younger individual with DS (Fig. 2g–i), both having primarily diffuse plaques (thioflavine S-negative), we observed that diffuse plaques are also OC-positive (9.3% of OC-positive plaques were thioflavin S-positive).Fig. 1

Bottom Line: Our results show that accumulation of fibrillar immunoreactivity is significantly increased in AD relative to nondemented aged subjects and those with select cognitive impairments (p < 0.0001).Further, there was a significant correlation between the extent of frontal cortex fibrillar deposit accumulation and dementia severity (MMSE r = -0.72).These results suggest that fibrillar deposits are associated with disease in both AD and in adults with DS and their distribution within early Abeta pathology associated with diffuse plaques and correlation with MMSE suggest that these deposits may not be as benign as previously thought.

View Article: PubMed Central - PubMed

Affiliation: Institute for Brain Aging and Dementia, University of California, Irvine, CA 92697, USA.

ABSTRACT
Beta-amyloid (Abeta) is thought to be a key contributor to the pathogenesis of Alzheimer disease (AD) in the general population and in adults with Down syndrome (DS). Different assembly states of Abeta have been identified that may be neurotoxic. Abeta oligomers can assemble into soluble prefibrillar oligomers, soluble fibrillar oligomers and insoluble fibrils. Using a novel antibody, OC, recognizing fibrils and soluble fibrillar oligomers, we characterized fibrillar Abeta deposits in AD and DS cases. We further compared human specimens to those obtained from the Tg2576 mouse model of AD. Our results show that accumulation of fibrillar immunoreactivity is significantly increased in AD relative to nondemented aged subjects and those with select cognitive impairments (p < 0.0001). Further, there was a significant correlation between the extent of frontal cortex fibrillar deposit accumulation and dementia severity (MMSE r = -0.72). In DS, we observe an early age of onset and age-dependent accumulation of fibrillar OC immunoreactivity with little pathology in similarly aged non-DS individuals. Tg2576 mice show fibrillar accumulation that can be detected as young as 6 months. Interestingly, fibril-specific immunoreactivity was observed in diffuse, thioflavine S-negative Abeta deposits in addition to more mature neuritic plaques. These results suggest that fibrillar deposits are associated with disease in both AD and in adults with DS and their distribution within early Abeta pathology associated with diffuse plaques and correlation with MMSE suggest that these deposits may not be as benign as previously thought.

Show MeSH
Related in: MedlinePlus