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. 2014 Jun;40(4):489-501.
doi: 10.1111/nan.12056.

Phosphatidylinositol-4,5-bisphosphate is enriched in granulovacuolar degeneration bodies and neurofibrillary tangles

Tomokazu Nishikawa  1 , Tetsuya Takahashi, Masahiro Nakamori, Yu Yamazaki, Takashi Kurashige, Yoshito Nagano, Yoshihiko Nishida, Yuishin Izumi, Masayasu Matsumoto
Affiliations
Free PMC article

Phosphatidylinositol-4,5-bisphosphate is enriched in granulovacuolar degeneration bodies and neurofibrillary tangles

Tomokazu Nishikawa et al. Neuropathol Appl Neurobiol. 2014 Jun.
Free PMC article

Abstract

Aims: Among the pathological findings in Alzheimer's disease (AD), the temporal and spatial profiles of granulovacuolar degeneration (GVD) bodies are characteristic in that they seem to be related to those of neurofibrillary tangles (NFTs), suggesting a common mechanism underlying the pathogenesis of these structures. Flotillin-1, a marker of lipid rafts, accumulates in lysosomes of tangle-bearing neurones in AD patients. In addition, recent reports have shown that GVD bodies accumulate at the nexus of the autophagic and endocytic pathways. The aim of this study was to elucidate the distribution of the lipid component of lipid rafts, phosphatidylinositol-4,5-bisphosphate [PtdIns(4,5)P2], in AD and other neurodegenerative disorders.

Methods: We compared PtdIns(4,5)P2 immunoreactivity in the hippocampus, entorhinal cortex and neocortex of five AD cases, 17 cases of other neurodegenerative disorders and four controls. In addition, we performed double staining using markers of GVD, NFTs and lipid rafts for further characterization.

Results: Immunohistochemical analysis revealed that PtdIns(4,5)P2 was selectively enriched in GVD bodies and NFTs. Although immunoreactivity for PtdIns(4,5)P2 was also evident in NFTs composed of hyperphosphorylated tau, PtdIns(4,5)P2 was segregated from phosphorylated tau within NFTs by double immunofluorescence staining. In contrast, PtdIns(4,5)P2 colocalized with the lipid raft markers flotillin-1 and annexin 2, within GVD bodies and NFTs.

Conclusions: These results suggest that lipid raft components including PtdIns(4,5)P2 play a role in the formation of both GVD bodies and NFTs.

Keywords: 5-bisphosphate; Alzheimer's disease; granulovacuolar degeneration; lipid raft; neurofibrillary tangle; phosphatidylinositol-4.

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Figures

Figure 1
Figure 1
Immunohistochemistry for PtdIns(4,5)P2. Immunohistochemistry in AD, MyD, ALS and control cases. AD case (case 1): low-power fields in hippocampus (a,b) and neocortex (c). MyD case (case 6): low-power fields in hippocampus (d,e) and neocortex (f). ALS case (case 17): low-power fields in hippocampus (g,h) and neocortex (i). Control case (case 26): low-power fields in hippocampus (j,k) and neocortex (l). AD case (case 5): some of the detected structures are (m) GVD bodies, (n) ‘GVD bodies + NFTs’, and (o) NFTs. The specificity of immunoreactivity for PtdIns(4,5)P2 was verified using PLCδ1PH-GST on sections, which showed essentially the same staining pattern as the anti-PtdIns(4,5)P2 antibody (p–r). Scale bars: (a–l) 50 μm, (m–r) 20 μm.
Figure 2
Figure 2
PtdIns(4,5)P2-positive structures corresponding to GVD bodies and NFTs. In the hippocampus of an AD case, the cellular localization of PtdIns(4,5)P2 was compared among haematoxylin and eosin (H&E)–stained sections (a,c), sections subjected to immunohistochemical analysis with 2C11 [b,d; some of the structures are GVD bodies (arrowhead) and some are NFTs (arrow)], sections incubated without primary antibody (e), and sections incubated with 10 mM neomycin sulphate/PBS prior to immunohistochemical staining with 2C11 (f). Scale bars: 20 μm.
Figure 3
Figure 3
Three-dimensional image of PtdIns(4,5)P2-positive structures in the hippocampus. PtdIns(4,5)P2-immunopositive structures in the hippocampus in an AD case (case 1). (a) 2-dimensional serial images and (b) reconstituted 3-dimensional image. Some of the structures are GVD bodies (arrowhead) and some are NFTs (arrow).
Figure 4
Figure 4
Representative confocal laser scanning micrograph. Double immunofluorescence labeling for (a) CHMP2B (green) and PtdIns(4,5)P2 (red), (b) AT8 (green) and PtdIns(4,5)P2 (red), (c,d) CDK5 (green) and PtdIns(4,5)P2 (red), (e,f) flotillin-1 (green) and PtdIns(4,5)P2 (red), and (g,h) annexin 2 (green) and PtdIns(4,5)P2 (red) and merged images in sections from patients with AD. For optimum visualization of the relationship, images from two channels were assigned the pseudocolour red [568 nm, for PtdIns(4,5)P2 in (b) and (e,f)] or green (488 nm, for AT8 and flotillin-1) and merged. Scale bars:10 μm.
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