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. 2007 May-Jun;11(3):569-79.
doi: 10.1111/j.1582-4934.2007.00047.x.

Occludin is overexpressed in Alzheimer's disease and vascular dementia

Mihaela Oana Romanitan  1 , Bogdan O Popescu, Bengt Winblad, Ovidiu Alexandru Bajenaru, Nenad Bogdanovic
Affiliations

Occludin is overexpressed in Alzheimer's disease and vascular dementia

Mihaela Oana Romanitan et al. J Cell Mol Med. 2007 May-Jun.

Abstract

The tight junctions (TJs) are key players in the control of blood-brain barrier (BBB) properties, the most complex TJs in the vascular system being found in the endothelial cells of brain capillaries. One of the main TJs proteins is occludin, which anchors plasma membranes of neighbour cells and is present in large amounts in the brain endothelia. Previous studies demonstrated that disruption of BBB in various pathological situations associates with changes in occludin expression, and this change could be responsible for malfunction of BBB. Therefore in this study, applying an immunohistochemical approach, we decided to explore the occludin expression in frontal cortex (FC) and basal ganglia in ageing control, Alzheimer's disease (AD), and vascular dementia (VD) brains, as far as all these pathologies associate microangiopathy and disruption of BBB. Strikingly, we found selected neurons, astrocytes and oligodendrocytes expressing occludin, in all cases studied. To estimate the number of occludin-expressing neurons, we applied a stereological approach with random systematic sampling and the unbiased optical fractionator method. We report here a significant increase in ratio of occludin-expressing neurons in FC and basal ganglia regions in both AD and VD as compared to ageing controls. Within the cerebral cortex, occludin was selectively expressed by pyramidal neurons, which are the ones responsible for cognitive processes and affected by AD pathology. Our findings could be important in unravelling new pathogenic pathways in dementia disorders and new functions of occludin and TJs.

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Figures

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Expression of occludin in control (CON, A, B), Alzheimer's disease (AD, C, D), vascular dementia (VD, E, F), CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, G, GG, H, HH) and CAA (congophilic amyloid angiopathy, I, II, J) brains, in the frontal medial gyrus Brodmann's area 9 (left panels, A, C, E, G, GG, I, II), and basal ganglia, nucleus caudatus (right panels, B, D, F, H, HH, J). Occludin-expressing cells are brownish, as a result of the immunohistochemical staining method with anti-occludin serum detected with avidin–biotin-peroxidase complex kit and DAB substrate. As compared to control brain, in AD and VD brains, occludin expression was increased in neurons and neuronal fibres in the frontal cortex (left panels, A, C, E, G), and in the glial cells of the basal ganglia (right panels, B, D, F, H). Inserts show occludin expression within the brain microvasculature (transversal sections) which is seen only in selected endothelial cells in AD (C) and CAA (I) and in the entire vessel wall in CADASIL (GG). The occludin expression pattern in neurons, astrocytes and oligodendrocytes was similar to control for both CADASIL and CAA cases. Conversely, as compared to control, a more intense occludin expression was noted in the endothelium of CADASIL and CAA cases, mainly in the frontal cortex region. Occludin expression was noticed only in the pyramidal neurons (layer III in the figure) in AD and VD, but not in controls, CADASIL or CAA. Some selected oligodendroglial cells were occludin-positive in the frontal cortex region (arrow in A) in all cases analysed. Occludin-positive astrocytes were identified in VD (E, insert) and in CAA (II). Occludin expression was detected in the microvasculature of frontal cortex in AD (C, insert), CADASIL (GG) and sparsely in CAA (I), but not in control or VD. In the basal ganglia region, intranuclear staining was found almost only in astrocytes in control (B, double arrows, absence in oligodendrocytes denoted by single arrow), AD (D), VD (F) and CADASIL (H) brains. Occludin expression was undetectable in arteries of basal ganglia (nucleus caudatus) in all control and diseased brains (CADASIL, HH and CAA, J). Bars: 5 μm in B, D, F, H and II, 10 μm in E insert, G insert, GG, HH, I and J, 15 μm in A, C, E and G and 20 μm in C, insert.
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Comparative ratios between number of occludin-expressing neurons and total number of neurons in frontal cortex and striatum regions in control (five cases), Alzheimer's disease (AD, four cases) and vascular dementia (VD, six cases). The ratio was calculated with the formula: Ratio = (number of occludin-positive neurons/total number of neurons) × 100. Error bars indicate standard deviation (SD). SD in VD is higher due to the differences in vascular subtype pattern among VD cases. Statistical significance is marked by the following symbols: ‘§’ for comparison between frontal cortex and striatum regions in the control group (p < 0.01), ‘#’ for comparison between frontal region of each AD and VD groups and frontal region in control group (p < 0.05) and ‘*’ for comparison between striatal region of each AD and VD groups and striatal region in control group (p < 0.05).
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Expression of occludin in control, Alzheimer's disease (AD) and vascular dementia (VD) brains, in the frontal white matter. As compared to control brain, in AD and VD brains, occludin expression is increased in oligodendrocytes and astrocytes (brownish, immunohis-tochemical staining method with anti-occludin serum detected with avidin–biotin-peroxidase complex kit and DAB substrate). Quantification was not performed in this study.
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