Secretory PLA2-IIA: a new inflammatory factor for Alzheimer's disease - PubMed (original) (raw)

Secretory PLA2-IIA: a new inflammatory factor for Alzheimer's disease

Guna S D Moses et al. J Neuroinflammation. 2006.

Abstract

Secretory phospholipase A2-IIA (sPLA2-IIA) is an inflammatory protein known to play a role in the pathogenesis of many inflammatory diseases. Although this enzyme has also been implicated in the pathogenesis of neurodegenerative diseases, there has not been a direct demonstration of its expression in diseased human brain. In this study, we show that sPLA2-IIA mRNA is up-regulated in Alzheimer's disease (AD) brains as compared to non-demented elderly brains (ND). We also report a higher percentage of sPLA2-IIA-immunoreactive astrocytes present in AD hippocampus and inferior temporal gyrus (ITG). In ITG, the majority of sPLA2-IIA-positive astrocytes were associated with amyloid beta (Abeta)-containing plaques. Studies with human astrocytes in culture demonstrated the ability of oligomeric Abeta1-42 and interleukin-1beta (IL-1beta) to induce sPLA2-IIA mRNA expression, indicating that this gene is among those induced by inflammatory cytokines. Since exogenous sPLA2-IIA has been shown to cause neuronal injury, understanding the mechanism(s) and physiological consequences of sPLA2-IIA upregulation in AD brain may facilitate the development of novel therapeutic strategies to inhibit the inflammatory responses and to retard the progression of the disease.

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Figures

Figure 1

Figure 1

sPLA2-IIA immunoreactivity in human postmortem brain tissues. Double immunostaining depicting sPLA2-IIA immunoreactivity in dark blue color and GFAP immunoreactivity in brown color is shown in panels A-D (using 20X and 40X objective lenses). Panel A demonstrates that little sPLA2-IIA immunoreactivity is present in a cluster of GFAP immunoreactive astrocytes in ND hippocampus. Panel B shows many GFAP-positive astrocytes (white arrow) labeled with intense immunoreactivity for sPLA2-IIA (dark immunoreactive products, red arrow) in AD hippocampus. At higher magnification (Panel C), sPLA2-IIA immunoreactivity is shown in an astrocyte cell body in granular-like structures (red arrow). Panel D shows that immunoreactivity for sPLA2-IIA (red arrows) is also present in GFAP-positive astrcoytes (white arrows) surrounding microvessels in AD hippocampus. We also detected sPLA2 immunoreactivity in hippocampal neurons (black arrows) in ND (Panel A) and AD (Panel D) hippocampus. In Panel E, several sPLA2-IIA immunoreactivitve profiles (red arrows) are co-localized with an amyloid plaque (brown immunoreactive area) detected by immunohistochemistry with an antibody to Aβ.

Figure 2

Figure 2

Co-localization of sPLA2-IIA-positive astrocytes with thioflavin S-positive plaques. Double immunostaining of sPLA2-IIA and GFAP combined with thioflavin S staining shows the presence of sPLA2-IIA (red arrows) in GFAP-positive astrocytes (panels A and B) and their association with thioflavin S-positive amyloid plaques (green fluorescent area in panel A) in an ITG section from an AD case.

Figure 3

Figure 3

Induction of sPLA2-IIA mRNA expression by cytokines and Aβ 1–42 in cultured human astrocytes. Phase contrast micrographs show human astrocytes in control (panel A) and IL-1β-stimulated cultures (panel B) for 24 hours. Human postmortem astrocytes were used for the sPLA2-IIA RNA study. Experiments were performed using cultures derived from 3 neuropathologically confirmed AD cases. A representative gel depicting PCR-amplified fragments for sPLA2-IIA and β-actin is shown in panel C. Gel lanes 1–5 represent the following treatments used in the astrocyte cultures: 1. control; 2. IFNγ (100 ng/ml); 3. Aβ1–42 (2.5 μM); 4. IL-1β (20 ng/ml); 5. IL-1β and Aβ1–42. Twenty-four hours after treatment, RNA was extracted from cells, reverse transcribed, and RT-PCR was carried out as described in methods. Panel D shows a bar graph depicting relative units of sPLA2-IIA expression after normalization with β-actin. Significant differences (*) comparing treatment groups with controls were obtained by one-way ANOVA followed by Tukey multiple comparison post hoc test.

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