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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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OC fibril labeling in Tg2576 animals. a Tg2576 animals show increasing OC accumulation with age while no OC was observed in comparably aged wild type animals. OC loads were obtained from the b frontoparietal cortex, c entorhinal cortex and d from area CA1 in the hippocampus of individual animals. Mean loads are plotted as a function of age for each brain region and show a dramatic increase after 12 months of age in cortical regions but with a slower more progressive rise in the hippocampus. Error bars represent standard errors of the mean (n = 5 animals/age group)
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Fig5: OC fibril labeling in Tg2576 animals. a Tg2576 animals show increasing OC accumulation with age while no OC was observed in comparably aged wild type animals. OC loads were obtained from the b frontoparietal cortex, c entorhinal cortex and d from area CA1 in the hippocampus of individual animals. Mean loads are plotted as a function of age for each brain region and show a dramatic increase after 12 months of age in cortical regions but with a slower more progressive rise in the hippocampus. Error bars represent standard errors of the mean (n = 5 animals/age group)

Mentions: Age-associated increases in OC labeling in individuals with DS may be due to overexpression of the human APP gene. To confirm and extend this hypothesis, we used tissue from Tg2576 mice, which overexpress mutant human APP [31]. In a study of the brains of 30 Tg2576 animals, we find a significant main effect of age on OC loads in the frontoparietal cortex (F(5,29) = 5.90, p = 0.001), in the entorhinal cortex (F(5,29) = 9.91, p < 0.0005) and in area CA1 of the hippocampus (F(5,29) = 9.94, p < 0.0005). Figure 5 shows that as with DS cases, there was a sudden rise in the extent of OC labeling after the age of 12 months in Tg2576 animals. Initial deposits were observed at 6 months in one animal and in 4/5 animals at 9 months of age. When 18- and 24-month old Tg2576 mice were directly compared to wild type animals of the same ages, the latter group had undetectable amounts of OC-positive deposits (data not shown).Fig. 5


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)

OC fibril labeling in Tg2576 animals. a Tg2576 animals show increasing OC accumulation with age while no OC was observed in comparably aged wild type animals. OC loads were obtained from the b frontoparietal cortex, c entorhinal cortex and d from area CA1 in the hippocampus of individual animals. Mean loads are plotted as a function of age for each brain region and show a dramatic increase after 12 months of age in cortical regions but with a slower more progressive rise in the hippocampus. Error bars represent standard errors of the mean (n = 5 animals/age group)
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2737113&req=5

Fig5: OC fibril labeling in Tg2576 animals. a Tg2576 animals show increasing OC accumulation with age while no OC was observed in comparably aged wild type animals. OC loads were obtained from the b frontoparietal cortex, c entorhinal cortex and d from area CA1 in the hippocampus of individual animals. Mean loads are plotted as a function of age for each brain region and show a dramatic increase after 12 months of age in cortical regions but with a slower more progressive rise in the hippocampus. Error bars represent standard errors of the mean (n = 5 animals/age group)
Mentions: Age-associated increases in OC labeling in individuals with DS may be due to overexpression of the human APP gene. To confirm and extend this hypothesis, we used tissue from Tg2576 mice, which overexpress mutant human APP [31]. In a study of the brains of 30 Tg2576 animals, we find a significant main effect of age on OC loads in the frontoparietal cortex (F(5,29) = 5.90, p = 0.001), in the entorhinal cortex (F(5,29) = 9.91, p < 0.0005) and in area CA1 of the hippocampus (F(5,29) = 9.94, p < 0.0005). Figure 5 shows that as with DS cases, there was a sudden rise in the extent of OC labeling after the age of 12 months in Tg2576 animals. Initial deposits were observed at 6 months in one animal and in 4/5 animals at 9 months of age. When 18- and 24-month old Tg2576 mice were directly compared to wild type animals of the same ages, the latter group had undetectable amounts of OC-positive deposits (data not shown).Fig. 5

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