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U1 small nuclear ribonucleoproteins (snRNPs) aggregate in Alzheimer's disease due to autosomal dominant genetic mutations and trisomy 21.

Hales CM, Seyfried NT, Dammer EB, Duong D, Yi H, Gearing M, Troncoso JC, Mufson EJ, Thambisetty M, Levey AI, Lah JJ - Mol Neurodegener (2014)

Bottom Line: U1-70k and other snRNPs were biochemically enriched in the insoluble fraction of human brain from subjects with presenilin 1 (PS1) mutations.Ultrastructural analysis with electron microscopy in an APP mutation case demonstrated snRNP immunogold labeling of paired helical filaments (PHF).These studies identify U1 snRNP pathologic changes in brain of early onset genetic forms of AD.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neurology, Emory University School of Medicine, Atlanta 30322, Georgia. jlah@emory.edu.

ABSTRACT

Background: We recently identified U1 small nuclear ribonucleoprotein (snRNP) tangle-like aggregates and RNA splicing abnormalities in sporadic Alzheimer's disease (AD). However little is known about snRNP biology in early onset AD due to autosomal dominant genetic mutations or trisomy 21 in Down syndrome. Therefore we investigated snRNP biochemical and pathologic features in these disorders.

Findings: We performed quantitative proteomics and immunohistochemistry in postmortem brain from genetic AD cases. Electron microscopy was used to characterize ultrastructural features of pathologic aggregates. U1-70k and other snRNPs were biochemically enriched in the insoluble fraction of human brain from subjects with presenilin 1 (PS1) mutations. Aggregates of U1 snRNP-immunoreactivity formed cytoplasmic tangle-like structures in cortex of AD subjects with PS1 and amyloid precursor protein (APP) mutations as well as trisomy 21. Ultrastructural analysis with electron microscopy in an APP mutation case demonstrated snRNP immunogold labeling of paired helical filaments (PHF).

Conclusions: These studies identify U1 snRNP pathologic changes in brain of early onset genetic forms of AD. Since dominant genetic mutations and trisomy 21 result in dysfunctional amyloid processing, the findings suggest that aberrant β-amyloid processing may influence U1 snRNP aggregate formation.

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Immunohistochemistry of U1 snRNPs in FAD and Down syndrome. DAB immunohistochemistry staining of postmortem human frontal cortex (50 μm free floating sections) from control, PS1 mutation carrier, APP mutation carrier, and Down syndrome patient with (A-D) U1-70k, (E-H) Sm-D1, and (I-L) U1-A. Black arrows designate U1 snRNP tangle-like aggregates. (M-P) PHF and (Q-T) β-amyloid provided as reference for other AD pathologies. Representative sections shown. Scale bar = 10 μm.
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Figure 2: Immunohistochemistry of U1 snRNPs in FAD and Down syndrome. DAB immunohistochemistry staining of postmortem human frontal cortex (50 μm free floating sections) from control, PS1 mutation carrier, APP mutation carrier, and Down syndrome patient with (A-D) U1-70k, (E-H) Sm-D1, and (I-L) U1-A. Black arrows designate U1 snRNP tangle-like aggregates. (M-P) PHF and (Q-T) β-amyloid provided as reference for other AD pathologies. Representative sections shown. Scale bar = 10 μm.

Mentions: To examine early onset genetic AD brain tissues for evidence of U1 snRNP cytoplasmic aggregates similar to those seen in sporadic AD cases [3], we performed immunohistochemistry of fixed human frontal cortex to localize U1 snRNP in human PS1 and APP pathogenic mutation carriers. We also examined Down syndrome (DS, trisomy 21) cases as patients with DS have an extra copy of amyloid precursor protein and invariably develop Alzheimer’s disease later in life. U1-70k-labeled neurofibrillary structures were observed in the cytoplasm of cortical neurons in most genetic AD cases (PS1, 5/8; APP, 2/2; DS, 5/6; Figure 2). Although Sm-D1 only showed a trend for biochemical enrichment in the FAD insoluble proteome (Figure 1; Additional file 1: Table S1), Sm-D1 immunoreactivity was strongly associated with tangle-like structures in all cases (PS1-6/6, APP-2/2, Down 6/6) (Figure 2). In contrast to our observations in sporadic AD cases [3], U1-A maintained a normal nuclear distribution in genetic AD cases with only rare U1-A tangle structures observed in some Down syndrome cases. β-amyloid positive plaques and hyperphosphorylated tau positive neurofibrillary tangles are shown for reference.


U1 small nuclear ribonucleoproteins (snRNPs) aggregate in Alzheimer's disease due to autosomal dominant genetic mutations and trisomy 21.

Hales CM, Seyfried NT, Dammer EB, Duong D, Yi H, Gearing M, Troncoso JC, Mufson EJ, Thambisetty M, Levey AI, Lah JJ - Mol Neurodegener (2014)

Immunohistochemistry of U1 snRNPs in FAD and Down syndrome. DAB immunohistochemistry staining of postmortem human frontal cortex (50 μm free floating sections) from control, PS1 mutation carrier, APP mutation carrier, and Down syndrome patient with (A-D) U1-70k, (E-H) Sm-D1, and (I-L) U1-A. Black arrows designate U1 snRNP tangle-like aggregates. (M-P) PHF and (Q-T) β-amyloid provided as reference for other AD pathologies. Representative sections shown. Scale bar = 10 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4022210&req=5

Figure 2: Immunohistochemistry of U1 snRNPs in FAD and Down syndrome. DAB immunohistochemistry staining of postmortem human frontal cortex (50 μm free floating sections) from control, PS1 mutation carrier, APP mutation carrier, and Down syndrome patient with (A-D) U1-70k, (E-H) Sm-D1, and (I-L) U1-A. Black arrows designate U1 snRNP tangle-like aggregates. (M-P) PHF and (Q-T) β-amyloid provided as reference for other AD pathologies. Representative sections shown. Scale bar = 10 μm.
Mentions: To examine early onset genetic AD brain tissues for evidence of U1 snRNP cytoplasmic aggregates similar to those seen in sporadic AD cases [3], we performed immunohistochemistry of fixed human frontal cortex to localize U1 snRNP in human PS1 and APP pathogenic mutation carriers. We also examined Down syndrome (DS, trisomy 21) cases as patients with DS have an extra copy of amyloid precursor protein and invariably develop Alzheimer’s disease later in life. U1-70k-labeled neurofibrillary structures were observed in the cytoplasm of cortical neurons in most genetic AD cases (PS1, 5/8; APP, 2/2; DS, 5/6; Figure 2). Although Sm-D1 only showed a trend for biochemical enrichment in the FAD insoluble proteome (Figure 1; Additional file 1: Table S1), Sm-D1 immunoreactivity was strongly associated with tangle-like structures in all cases (PS1-6/6, APP-2/2, Down 6/6) (Figure 2). In contrast to our observations in sporadic AD cases [3], U1-A maintained a normal nuclear distribution in genetic AD cases with only rare U1-A tangle structures observed in some Down syndrome cases. β-amyloid positive plaques and hyperphosphorylated tau positive neurofibrillary tangles are shown for reference.

Bottom Line: U1-70k and other snRNPs were biochemically enriched in the insoluble fraction of human brain from subjects with presenilin 1 (PS1) mutations.Ultrastructural analysis with electron microscopy in an APP mutation case demonstrated snRNP immunogold labeling of paired helical filaments (PHF).These studies identify U1 snRNP pathologic changes in brain of early onset genetic forms of AD.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neurology, Emory University School of Medicine, Atlanta 30322, Georgia. jlah@emory.edu.

ABSTRACT

Background: We recently identified U1 small nuclear ribonucleoprotein (snRNP) tangle-like aggregates and RNA splicing abnormalities in sporadic Alzheimer's disease (AD). However little is known about snRNP biology in early onset AD due to autosomal dominant genetic mutations or trisomy 21 in Down syndrome. Therefore we investigated snRNP biochemical and pathologic features in these disorders.

Findings: We performed quantitative proteomics and immunohistochemistry in postmortem brain from genetic AD cases. Electron microscopy was used to characterize ultrastructural features of pathologic aggregates. U1-70k and other snRNPs were biochemically enriched in the insoluble fraction of human brain from subjects with presenilin 1 (PS1) mutations. Aggregates of U1 snRNP-immunoreactivity formed cytoplasmic tangle-like structures in cortex of AD subjects with PS1 and amyloid precursor protein (APP) mutations as well as trisomy 21. Ultrastructural analysis with electron microscopy in an APP mutation case demonstrated snRNP immunogold labeling of paired helical filaments (PHF).

Conclusions: These studies identify U1 snRNP pathologic changes in brain of early onset genetic forms of AD. Since dominant genetic mutations and trisomy 21 result in dysfunctional amyloid processing, the findings suggest that aberrant β-amyloid processing may influence U1 snRNP aggregate formation.

Show MeSH
Related in: MedlinePlus