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. 2014 Apr 28:9:15.
doi: 10.1186/1750-1326-9-15.

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

Chadwick M Hales, Nicholas T Seyfried, Eric B Dammer, Duc Duong, Hong Yi, Marla Gearing, Juan C Troncoso, Elliott J Mufson, Madhav Thambisetty, Allan I Levey, James J Lah  1
Affiliations

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

Chadwick M Hales et al. Mol Neurodegener. .

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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Figures

Figure 1
Figure 1
U1 snRNPs enriched in PS1 insoluble proteome. (A) Heat map showing quantitative proteomics of frontal cortex from 5 pathology free controls and 6 carriers of pathogenic PS1 mutations (insoluble fraction) demonstrated enrichment (yellow color) of RNA splicing factors and other AD associated proteins in PS1 mutation carriers (FAD-PS1). Log2 of mean of the extracted ion intensities (XIC; normalized protein intensities based on raw signal to noise ratio; Additional file 1: Table S1) in the insoluble fraction from individual cases are shown. (B) Western blot showing insoluble U1-70k in two sporadic (sAD) and two control cases with calnexin loading control. (C) Western blot showing insoluble U1-70k in 6 PS1 mutation carriers with α-tubulin as loading control.
Figure 2
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.
Figure 3
Figure 3
U1-70k and Sm-D1 immunogold labeling of paired helical filaments in APP mutation carrier. Transmission electron microscopy was performed on adjacent 50 μm vibratome free-floating sections from an APP mutation carrier following immunogold labeling with (A, D, G) U1-70k, (B, E, H) Sm-D1 and (C, F, I) PHF. Silver enhancement was utilized to label ultrastructural features. Gold particles specifically labeled filamentous structures with all 3 antibodies. N-nuclei, C-cytoplasm, L-lipofuscin granules, black arrows point to immuno-gold particles (D-I), black arrowheads point to nuclear U1-70k (D). Contents of dashed box in A-C presented in D-F, respectively. Scale bar (A-C) 1 μm, (D-F) 0.2 μm, (G-I) 0.1 μm.
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