Altered Machinery of Protein Synthesis in Alzheimer's: From the Nucleolus to the Ribosome - PubMed (original) (raw)
. 2016 Sep;26(5):593-605.
doi: 10.1111/bpa.12335. Epub 2015 Dec 14.
Affiliations
- PMID: 26512942
- PMCID: PMC8029302
- DOI: 10.1111/bpa.12335
Altered Machinery of Protein Synthesis in Alzheimer's: From the Nucleolus to the Ribosome
Karina Hernández-Ortega et al. Brain Pathol. 2016 Sep.
Abstract
Ribosomes and protein synthesis have been reported to be altered in the cerebral cortex at advanced stages of Alzheimer's disease (AD). Modifications in the hippocampus with disease progression have not been assessed. Sixty-seven cases including middle-aged (MA) and AD stages I-VI were analyzed. Nucleolar chaperones nucleolin, nucleophosmin and nucleoplasmin 3, and upstream binding transcription factor RNA polymerase I gene (UBTF) mRNAs are abnormally regulated and their protein levels reduced in AD. Histone modifications dimethylated histone H3K9 (H3K9me2) and acetylated histone H3K12 (H3K12ac) are decreased in CA1. Nuclear tau declines in CA1 and dentate gyrus (DG), and practically disappears in neurons with neurofibrillary tangles. Subunit 28 ribosomal RNA (28S rRNA) expression is altered in CA1 and DG in AD. Several genes encoding ribosomal proteins are abnormally regulated and protein levels of translation initiation factors eIF2α, eIF3η and eIF5, and elongation factor eEF2, are altered in the CA1 region in AD. These findings show alterations in the protein synthesis machinery in AD involving the nucleolus, nucleus and ribosomes in the hippocampus in AD some of them starting at first stages (I-II) preceding neuron loss. These changes may lie behind reduced numbers of dendritic branches and reduced synapses of CA1 and DG neurons which cause hippocampal atrophy.
Keywords: Alzheimer's disease; elongation factors of protein synthesis; histones; initiation factors; nuclear tau; nucleolin; nucleolus; nucleophosmin; nucleoplasmin; nucleus; protein synthesis; ribosomal proteins; ribosome; upstream binding transcription factor RNA polymerase I.
© 2015 International Society of Neuropathology.
Figures
Figure 1
NPM1, NPM3 and NCL in MA cases and AD at different stages of disease progression . A–D. NPM1/B23 in CA1 (A–D), in MA (A) and AD cases stages I–II (B), III–IV (C) and V–VI (D). E–H. NPM3 in the CA1 region of the hippocampus in MA (E), AD stage I‐II (F), IV (G) and V (H) of Braak and Braak. I–K. Nucleolin in CA1 in MA (I) and AD stage V–VI (J, K). Decreased numbers of nucleoli and reduced nucleolar NPM1, NPM3 and NCL immunoreactivity in remaining nucleoli is observed in neurons at stages III–IV and V–VI when compared with MA and AD cases stages I–II. A few CA1 neurons show, in addition to weak nucleolar staining, NCL immunoreactivity. Cytoplasmic granules in neurons with granulovacuolar degeneration are strongly NCL immunoreactive. Paraffin sections without haematoxylin counterstaining permit a perfect visualization of the nucleolus, bar = 25 µm.
Figure 2
UBF in MA cases and AD at different stages of disease progression. A–D. MA; E–H. AD stage III–IV; I–L. AD stage V–VI of Braak and Braak. A, E, I: CA1 region of the hippocampus; B, F, J: dentate gyrus; C, G, K: entorhinal cortex; D, H, L: temporal cortex. UBF‐immunoreactive nucleoli decrease and UBF nucleolar immunostaining fades at staged III–IV and V–VI when compared with MA cases. This is particularly evident in neurons bearing NFTs. Moreover UBF immunoreactivity locates to the cytoplasm and decorates NFTs. Paraffin sections without haematoxylin counterstaining, bar = 25 µm.
Figure 3
Histone modifications in AD. A–D. H3K9m2, E–H. H4K12ac; CA1 region of the hippocampus. A, E: MA individuals; AD stages I–II (B), III–IV (C, F) and V–VI (D, G, H). Individual selective loss of nuclear neuronal immunoreactivity and rare formation of H4K12ac‐immunoreactive globules and bars at advanced stages of AD. Paraffin sections without haematoxylin counterstaining, bar = 25 µm
Figure 4
Tau‐100 immunohistochemistry. A–D. CA1 region of the hippocampus; E–H. dentate gyrus; I–L. hilus; M, N. entorhinal cortex; O, P. temporal cortex layer V. A, E, I, M: Middle‐aged (MA); B, F, J: AD stage II of Braak and Braak; C, G, K, N: stage III of Braak; D, H, L, P: stage V. Tau‐100 immunoreactivity is present in the nucleus of neurons and glial cells in MA brains. Decreased tau‐100 nuclear immunoreactivity occurs in AD with disease progression. Almost complete absence of tau‐100 immunoreactivity in the nucleus is seen in neurons with NFTs in CA1, entorhinal cortex, and temporal neocortex. Note that reduced nuclear tau‐100 immunoreactivity is not necessarily accompanied by NFT formation. Tau‐100 also decorates dystrophic neurites of senile plaques (D). Paraffin sections without haematoxylin counterstaining, bar = 25 µm
Figure 5
Eukaryotic translation factors in the CA1 region of MA and AD cases. A. Representative western blots and densitometric analysis of the content of eIF2 α, eIF3η, eiF5 in the CA1 region of MA, AD I–II, AD III–IV, and AD V–VI cases. B. Western blot analysis of eEF1A and eEF2 in the CA1 region of MA, AD I–II, AD III–IV, and AD V–VI cases. β‐actin levels are used to normalize total protein content. The values represent the mean ± standard error of the mean (SEM) of 6–7 cases for group. *P > 0.05, **P > 0.01 compared with MA.
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