Dendritic BC200 RNA in aging and in Alzheimer's disease - PubMed (original) (raw)
Comparative Study
. 2007 Jun 19;104(25):10679-84.
doi: 10.1073/pnas.0701532104. Epub 2007 Jun 6.
Affiliations
- PMID: 17553964
- PMCID: PMC1965572
- DOI: 10.1073/pnas.0701532104
Comparative Study
Dendritic BC200 RNA in aging and in Alzheimer's disease
El Mus et al. Proc Natl Acad Sci U S A. 2007.
Abstract
Small untranslated BC1 and BC200 RNAs are translational regulators that are selectively targeted to somatodendritic domains of neurons. They are thought to operate as modulators of local protein synthesis in postsynaptic dendritic microdomains, in a capacity in which they would contribute to the maintenance of long-term synaptic plasticity. Because plasticity failure has been proposed to be a starting point for the neurodegenerative changes that are seen in Alzheimer's disease (AD), we asked whether somatodendritic levels of human BC200 RNA are deregulated in AD brains. We found that in normal aging, BC200 levels in cortical areas were reduced by >60% between the ages of 49 and 86. In contrast, BC200 RNA was significantly up-regulated in AD brains, in comparison with age-matched normal brains. This up-regulation in AD was specific to brain areas that are involved in the disease. Relative BC200 levels in those areas increased in parallel with the progression of AD, as reflected by Clinical Dementia Rating scores. In more advanced stages of the disease, BC200 RNA often assumed a clustered perikaryal localization, indicating that dendritic loss is accompanied by somatic overexpression. Mislocalization and overexpression of BC200 RNA may be reactive-compensatory to, or causative of, synaptodendritic deterioration in AD neurons.
Conflict of interest statement
The authors declare no conflict of interest.
Figures
Fig. 1.
Differential expression of BC200 RNA in normal aging (10 left lanes) and in AD (two right lanes). Total RNA from Brodmann's area 9 was probed by using Northern hybridization. (A) A substantial relative decrease in BC200 levels is observed after age 49. In contrast, no such decrease is apparent in AD brains. Relative signal intensities are indicated for each lane (intensity at age 49 set to 100 in the left lanes). (B) 18S and 28S rRNAs were monitored to ensure uniform sample loading.
Fig. 2.
BC200 expression in Brodmann's areas 9 and 17 in normal and AD brains. Quantitative analysis showed that in AD, BC200 levels were significantly elevated in area 9, but not in area 17, compared with either area in normal brains. [One-way ANOVA, P < 0.001, n = 12; Scheffé's multiple comparison post hoc analysis (comparison with normal area 9), P < 0.001 for AD area 9]. Levels of 7SL RNA showed no significant differences. Ages (left to right): 77 and 78 (normal); 90, 88, 62, and 79 (AD).
Fig. 3.
Expression levels of BC200 RNA in association with CDR status in AD brains. Results are shown for six patients with CDRs ranging from 0 (no dementia) to 5 (terminal dementia). BC200 expression was analyzed in Brodmann's area 9 (prefrontal association cortex), area 17 (primary visual cortex), and the hippocampus for each patient (18 samples total). BC200 expression is significantly increased in area 9 and in the hippocampus, but not in area 17, and the degree of this increase correlates with CDR status. Ages (in order of ascending CDR scores): 96, 93, 94, 77, 85, and 67. See Table 1 for a quantitative analysis of the entire data set.
Fig. 4.
Increase of BC200 expression levels relative with CDR status. The bar diagram is based on the same data set as Table 1, and it was derived from the data shown in the table by normalizing BC200 expression levels in area 17 to a relative value of 1.0 for each CDR data set.
Fig. 5.
Altered distribution of BC200 RNA in terminal AD. In situ hybridization reveals differential expression of BC200 RNA in Brodmann's area 9 of terminal AD brain (A and C–F) and normal brain (B). (A–C and E) Autoradiographic signal appears as white-silver grains in darkfield photomicrographs. (B) In area 9 of normal brain, BC200 signal was found diffusely distributed, reflecting a somatodendritic distribution, as has been reported earlier (2). (A and C–F) In contrast, in area 9 of terminal AD brains, labeling often appeared in high intensity clusters. (A) A low-magnification overview. (C) An area 9 region at higher magnification. (D) A brightfield photomicrograph showing H&E counterstaining of the region shown in C. (E) A high-magnification darkfield photomicrograph. (F) An epifluorescence photomicrograph showing DAPI-counterstained nuclei of the region shown in E. Outside of high-intensity BC200 clusters, regions in Brodmann's area 9 frequently showed lower BC200 levels than average levels in non-AD cases. (Scale bars: A and B, 100 μm; C and D, 30 μm; E and F, 15 μm.)
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