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. 2009 Oct;23(7):1003-13.
doi: 10.1016/j.bbi.2009.05.061. Epub 2009 Jun 6.

Disturbed Distribution of Proliferative Brain Cells During Lupus-Like Disease

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Free PMC article

Disturbed Distribution of Proliferative Brain Cells During Lupus-Like Disease

Mile Stanojcic et al. Brain Behav Immun. .
Free PMC article

Abstract

Brain atrophy and neuronal degeneration of unknown etiology are frequent and severe concomitants of the systemic autoimmune disease lupus erythematosus (SLE). Using the murine MRL/lpr model, we examined populations of proliferative brain cells during the development of SLE-like disease and brain atrophy. The disease onset was associated with reduced expression of Ki67 and BrdU proliferation markers in the dorsal part of the rostral migratory stream, enhanced Fluoro Jade C staining in the subgranular zone of the dentate gyrus, and paradoxical increase in density of Ki67(+)/BrdU(-) cells in the paraventricular nucleus. Protuberances containing clusters of BrdU(+) cells were frequent along the lateral ventricles and in some cases were bridging ventricular walls. Cells infiltrating the choroid plexus were Ki67(+)/BrdU(+), suggesting proliferative leukocytosis in this cerebrospinal fluid-producing organ. The above results further support the hypothesis that systemic autoimmune disease induces complex CNS pathology, including impaired neurogenesis in the hippocampus. Moreover, changes in the paraventricular nucleus implicate a metabolic dysfunction in the hypothalamus-pituitary-adrenal axis, which may account for altered hormonal status and psychiatric manifestations in SLE.

Figures

Figure 1
Figure 1
Mean lateral ventricle to brain area ratio at different ages. (A) In comparison to MRL +/+ controls, a significant increase in ratio was noted in the diseased 5-month-old MRL/lpr group. In addition, occasional enlargement in specific sections was seen at younger ages when T-test was applied (indicated by asterixes). (B) Representative low-power images illustrating enlarged and irregularly shaped lateral ventricles in a MRL/lpr mouse. Section locations: 1 = 1.42 to 0.74 mm, 2 = 0.62 to 0.14 mm, 3 = 0.02 to −0.70 mm, 4 = −0.82 to −1.34 mm, 5 = −1.58 to −2.18 mm, 6 = −2.30 to −2.80 mm, relative to Bregma. Abbreviations: Cg2, cingulate cortex area 2; cc, corpus callosum; LV, lateral ventricle.
Figure 2
Figure 2
Representative photos of ventricular protuberances in the 4-month-old MRL brain. (A) The BrdU+ protuberances were commonly seen in the wall of lateral ventricles from both MRL/lpr and MRL +/+ mice (not shown). (B) In some cases, opposing protuberances appeared “fused” (interconnected) by large processes. (C) Protuberances were absent in young mice and more frequent at the onset of disease in MRL/lpr mice.
Figure 3
Figure 3
Representative images of the choroid plexus (CP) in the third ventricle stained with fluorescent markers. (A) The CP abundant with Ki67+ cells in diseased MRL/lpr mice. (B) A lack of proliferating cells in the CP of MRL +/+ mice. (C) Lack of co-localization between BrdU+ and CD3+ cells in CP and adjacent brain parenchyma in MRL/lpr brains. (D) Lack of co-localization for the BrdU+ and NeuN+ cells at the hippocampal level. The above observations suggest that proliferative cells are neither T-lymphocytes nor neurons. Abbreviations: D3V, dorsal third ventricle; IVF, interventricular foramen.
Figure 4
Figure 4
The assessment of proliferation in RMS. (A) Representative image illustrating reduced spline length (red line), i.e. diameter of RMS and patchy accumulation of BrdU+ cells in a diseased MRL/lpr brain (Inset: location of brain sections used in quantitative analysis). (B) Elongated and continuous projection of BrdU+ cells in an age-matched MRL +/+ mouse. Dashed border shows approximate location of the signal area counting frame. (C) Lack of BrdU and NeuN co-localization, confirming that the migrating cells are not adult neurons. (D) Dissimilar patterns of Ki67+ expression between MRL/lpr and MRL +/+ mice during first five months of life. The density of Ki67+cells remain relatively constant in MRL/lpr mice, whereas significant fluctuations occur in the MRL +/+ group. Consistent with the notion of impaired capacity of the brain at the onset of systemic autoimmunity, 4-month-old MRL/lpr mice showed decreased numbers of Ki67+ and BrdU+ cells (24h after last injection) in comparison to age-matched controls. Abbreviations: RMS, rostral migratory stream; LV, lateral ventricle; SVZ, subventricular zone of the lateral ventricle.
Figure 5
Figure 5
FJC staining in the hippocampus. (A). A representative photo showing FJC+ neurons along the continuous SGZ of the dentate gyrus of MRL/lpr mouse and automated length assessment by AxioVision 4.6 (in red). (B) Higher magnification confirmed the selective involvement of the SGZ. (C) Four-month-old autoimmune mice showed increased FJC staining, followed by a similar increase in older MRL +/+ mice.
Figure 6
Figure 6
Age-dependent changes in the dentate gyrus (DG). (A) The length of the SGZ declined continuously with age, but this decrease was steeper in diseased MRL/lpr mice. (B) The BrdU+ cell counts in the SGZ of 4-month-old MRL/lpr mice were higher but showed a sharper decline one month later in comparison to age-matched MRL +/+ controls. (Inset: The sum of NeuN+ cells relative to the total number of BrdU+ cells in DG region from −1.58 to −2.54 mm from Bregma). (C) The increased lateral ventricle to brain area ratio at the level of hippocampus was associated with smaller SGZ length, suggesting that ventricular enlargement is accompanied by reductions in this proliferative zone (* p ≤ .05, *** p < .001).
Figure 7
Figure 7
Population of Ki67+cells in the paraventricular nucleus (PVN). (A) The Ki67+ cells were present in both 1-month-old MRL/lpr and MRL +/+ mice (photo not shown). (B) This signal intensified at the onset of autoimmune disease in 4-month-old MRL/lpr mice. (C) A detectable but less abundant signal was present in age-matched MRL +/+ controls. (D) A faint signal, undetectable to the imaging software, was also seen in 5-month-old healthy C57 controls. Abbreviations: 3V, ventral third ventricle
Figure 8
Figure 8
Quantification of the Ki67 signal in the PVN. (A) The area of Ki67 signal was comparable before the onset of autoimmune disease in MRL/lpr mice. However, it became significantly larger with increasing age. (B) The increased lateral ventricle to brain area ratio at the level of PVN sections was positively associated with the size of Ki67+ area, suggesting that ventricular enlargement was accompanied by enhanced expression of this unexpected signal.
Figure 9
Figure 9
Ki67 signal distribution in PVN-neighboring regions. (A) Standard immunofluorescence revealed a lack of co-localization between Ki67 and NeuN signals in the PVN (Inset: Confocal microscopy confirmed adjacent cells distinctly labeled with Ki67 or NeuN). (B) The Ki67 staining identified cells in the supraoptic nucleus of both MRL/lpr (shown) and MRL +/+ mice at all ages. (C) Similarly, supraoptic decussation and (D) median eminence contained sparse, but clearly labeled Ki67+/NeuN cells. Abbreviations: 3V, ventral third ventricle; SO, supraoptic nucleus; opt, optic tract; sox, supraoptic decussation; ME, median eminence.
Figure 10
Figure 10
Representative photos of GFAP and DCX signal distributions in SVZ and PVN regions of an MRL/lpr brain. (A) GFAP+ cells projecting from the lateral ventricle along the RMS. (B) The same section revealed a rim pattern staining around the third ventricle, but no signal was detected in the PVN. (C) As expected, the SVZ region showed a population of DCX+ cells. (D) Conversely, the same brain section demonstrated a lack of the same signal in the PVN. Abbreviations: 3V, ventral third ventricle; LV, lateral ventricle; RMS, rostral migratory stream.

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