Imaging the Breakdown of the BBB and Neuroinflammation in Models of
Neurodegeneration
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1
University of Belgrade, Center for laser microscopy, School of Biology, Serbia
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2
Universita Cattolica del Sacro Cuore, Institute for Anatomy and Cell Biology, Italy
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3
Polish Academy of Sciences, Laboratory of Ischemic and Neurodegenerative Brain Research, Poland
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4
University of Belgrade, Faculty of Physical Chemistry, Serbia
Magnetic resonance imaging (MRI) is the only non-invasive technique that provides structural information on cell loss, metabolic changes and state of the BBB altogether. Reliable biomarkers in neurological diseases are still lacking. For further research progress reliable animal models are needed. To this aim we have used the clinical MRI to assess neurodegenerative processes in the hSOD-1G93A ALS model, the trimethyltin (TMT) - treated model of Alzheimer’s-like disease and the ischemia-reperfusion (after cardiac arrest) long-term survival model. All were rat models that due to larger size as compered to mice are advantageous for MRI especially in a wide bore magnet setup. All three neurodegenerative pathologies have suspected BBB compromise that should be checked as a possible disease marker. Immunocytochemistry and confocal microscopy was used as a complementary imaging approach.
In the ALS model mutated SOD1 expression within motor neurons was shown to be a primary determinant of disease onset but using the murine model it was demonstrated [1] that the presence of mSOD1 in microglia had an effect on the later disease progression. In line with these non-cell-autonomous mechanisms in ALS it was worth noting that in the spinal cord and brain of rodent models [2] as well as of ALS patients [3,4], infiltration of T-cell lymphocytes, monocyte-derived macrophages and dendritic cells occurs. These observations, in addition to IgG deposits in the neural tissue as well as in the CSF of ALS patients [5] may point to a critical role of immune cell factors in neuroinflammation followed by motor neuron damage. Moreover, it has been recently shown that CD4+ T cells play a key role in glial neuroprotection and suppression of neuroinflammatory processes in hSOD1G93A mice [6]. These findings also indicate an altered vascular barrier permeability in ALS which has recently been validated [7]
T2-weighted (T2W) hyperintensive neurodegenerative foci were found in the brainstem of the ALS rat with apparent lateral ventricle dilation. Degenerative processes in these areas were also confirmed by confocal images of GFAP-positive astrogliosis. In addition, microglial activation was studied by immunocytochemistry. MRI of USPIO labeled T cells revealed CD4+ lymphocyte infiltration (Fig. 1) in the midbrain-interbrain region also near dilated ventricles, while the CD8+ cells were more confined to the brainstem region. With the Gd-contrast it was also confirmed that the BBB was compromised. Moreover, it was revealed that the regions of BBB breakthrough were congruent with the MRI foci of T-cell infiltration. Immunocytochemistry revealed microglial activation fusion/phagocytic interactions with neurons in the hippocampus and brainstem.
Trimethyltin (TMT) model is based on the induction by the toxicant of selective neuronal death, reactive astrogliosis and microglial activation in the limbic system, especially in the hippocampus [8,9]. Behavioral manifestations of TMT intoxication include increased seizure susceptibility, hyperactivity, aggression, and learning impairment. Because of these characteristics, TMT intoxication is regarded as a suitable model of chronic neurodegeneration with cognitive impairment, and is therefore useful in the study of Alzheimer’s disease [10].
MRI of the TMT-treated rats also revealed the dilation of lateral ventricles. Expected deterioration in the hippocampus was not observed by clinical MRI, but immunocytochemistry could reveal significant redistribution of macro- and micro-glia in this structure (Fig 2.). In addition, MRI with USPIO-labeled CD4+ cells revealed points of T2* hypointensity near dilated ventricles, suggesting the possible presence of labeled lymphocytes. In order to check for the possible pathway of inflammatory cells entrance the BBB was tested by Gd-DTPA i.v.i. and MRI investigation showed a positive enhancement in the frontal sections, corresponding to the level of the maximal dilation of the lateral ventricles and to the vicinity of the anterior dorsal hippocampus (Fig. 2).
Studies on the ischemia-reperfusion long-term model (1 year after insult) point to a hampered BBB that may still lead to infiltration of immune cells that are predominantly of helper type (CD4+ T cells). In addition, immunocytochemistry showed apparent microglial activation in the rat hippocampus, striatum, thalamic lateral dorsal nuclei and the subventricular zone (SVZ; Fig. 3). The presence of this activated microglia even up to one year after the ischemic insult can be explained by a persistent dysfunction of the BBB that facilitates a secondary inflammatory process. These creeping degenerative phenomena specifically in the hippocampal area may lead to formation of amyloid plaques and Alzheimer’s type dementia which has already been proposed for this model [11].
In all three models Gd-DTPA contrast revealed a compromised BBB that may serve as the passage for inflammatory immune cells in the vicinity of dilated lateral ventricles. Moreover, the midbrain region of the dorsal hippocampus seamed to be the mutual target of the BBB compromise, thus revealing a potentially vulnerable point that can be the primary target of neurodegeneration in the CNS.
References
1. Boillee S. et al. Science 312, 1389 (2006)
2. Alexianu ME et al. Neurology 57, 1282 (2001)
3. Appel SH, Simpson EP. Curr Neurol Neurosci Rep 1, 303 (2001)
4. Henkel JS et al. Ann Neurol 55, 221 (2004)
5. Zhang R et al. J Neuroimmunol 159, 215 (2005)
6. Beers DR et al. Proc Natl Acad Sci U S A 105, 15558 (2008)
7. Zhong Z et al. Nat Neurosci 11, 420 (2008)
8. Brown AW et al. Am J Pathol 97, 59 (1979)
9. Geloso M. et al. Neurosci Lett 357, 103 (2004)
10. Dyer RS et al. Neurobehav Toxicol Teratol 4,
141(1982)
11. Pluta R, Curr Neurovasc Res 4, 121 (2007)
Keywords:
Neuroinflammation,
neurodegeneration,
MRI imaging,
BBB,
CNS
Conference:
Pharmacology and Toxicology of the Blood-Brain Barrier: State of the Art, Needs for Future Research and Expected Benefits for the EU, Brussels, Belgium, 11 Feb - 12 Feb, 2010.
Presentation Type:
Oral Presentation
Topic:
Presentations
Citation:
Andjus
PR,
Michetti
F,
Pluta
R and
Bačić
G
(2010). Imaging the Breakdown of the BBB and Neuroinflammation in Models of
Neurodegeneration.
Front. Pharmacol.
Conference Abstract:
Pharmacology and Toxicology of the Blood-Brain Barrier: State of the Art, Needs for Future Research and Expected Benefits for the EU.
doi: 10.3389/conf.fphar.2010.02.00023
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Received:
11 Mar 2010;
Published Online:
11 Mar 2010.
*
Correspondence:
Pavle R Andjus, University of Belgrade, Center for laser microscopy, School of Biology, Belgrade, Serbia, pandjus@bio.bg.ac.rs