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Ultrastructural differences in pretangles between Alzheimer disease and corticobasal degeneration revealed by comparative light and electron microscopy.

Tatsumi S, Uchihara T, Aiba I, Iwasaki Y, Mimuro M, Takahashi R, Yoshida M - Acta Neuropathol Commun (2014)

Bottom Line: With these methods, we were successful for the first time in demonstrating accurately that LM-defined pretangles are tau-positive straight filaments sparsely distributed throughout neuronal cytoplasm and neurites in both AD and CBD at the EM level.Notably, AD-pretangles showed a strong tendency to form fibrillary tangles even at an early stage, whereas pretangles or Pick-like inclusions in tissue from patients with CBD did not even at an advanced stage.In conclusion, AD-pretangles and CBD-pretangles showed essential differences at the EM level.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Structural Neuropathology, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya 156-8506, Tokyo, Japan. uchihara-ts@igakuken.or.jp.

ABSTRACT
Pretangles are defined under the light microscope as diffuse and granular tau immunoreactivity in neurons in tissue from patients with Alzheimer disease (AD) or corticobasal degeneration (CBD) and are considered to be a premature stage before neurofibrillary tangle formation. However, the ultrastructure of pretangles remains to be described. To clarify the similarities and differences between pretangles from patients with AD and CBD (AD-pretangles and CBD-pretangles, respectively), we examined cortical pretangles in tissue from patients with each of diseases. For direct light and electron microscopic (LM/EM) correlation of the pretangles, we used quantum dot nanocrystals (QDs) with dual fluorescent and electron-dense properties. We first identified tau-labeled pretangles on fluorescence LM and subsequently examined the same neurons on EM. Energy dispersive X-ray spectrometry (EDX) color mapping identified selenium (Se) and cadmium (Cd) as elementary components of QDs and highlighted each QD particle clearly against gray-scale EM images. With these methods, we were successful for the first time in demonstrating accurately that LM-defined pretangles are tau-positive straight filaments sparsely distributed throughout neuronal cytoplasm and neurites in both AD and CBD at the EM level. Notably, AD-pretangles showed a strong tendency to form fibrillary tangles even at an early stage, whereas pretangles or Pick-like inclusions in tissue from patients with CBD did not even at an advanced stage. In conclusion, AD-pretangles and CBD-pretangles showed essential differences at the EM level.

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Correlation of immunolabeled LM and EM images of Pick-like inclusions in two CBD cases. A densely packed round inclusion (Pick-like inclusion) from a CBD case (case 3) labeled with anti-PHF antibody (AT8) visualized with QD 655, also labeled with Alexa 488 for more precise confocal images (A). Correlated LM and EM images (B, C) showed that tau immunoreactivity around the cavity on LM corresponded to bundles of tau filaments that were not arranged as parallely as in AD (C, rectangle d; D). Note that these filaments were intermingled with ribosomes (D, arrow). (E) The ultrastructure of Pick-like inclusions in another case of CBD (case 4) also revealed randomly assembled tau filaments with occasional formation of paired helical filaments (a periodicity of 130 nm, arrow). Scale bars in A to C = 3 μm; D = 50 nm; E = 100 nm. A to D, case 3; E, case 4.
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Fig6: Correlation of immunolabeled LM and EM images of Pick-like inclusions in two CBD cases. A densely packed round inclusion (Pick-like inclusion) from a CBD case (case 3) labeled with anti-PHF antibody (AT8) visualized with QD 655, also labeled with Alexa 488 for more precise confocal images (A). Correlated LM and EM images (B, C) showed that tau immunoreactivity around the cavity on LM corresponded to bundles of tau filaments that were not arranged as parallely as in AD (C, rectangle d; D). Note that these filaments were intermingled with ribosomes (D, arrow). (E) The ultrastructure of Pick-like inclusions in another case of CBD (case 4) also revealed randomly assembled tau filaments with occasional formation of paired helical filaments (a periodicity of 130 nm, arrow). Scale bars in A to C = 3 μm; D = 50 nm; E = 100 nm. A to D, case 3; E, case 4.

Mentions: Densely packed round inclusions (Pick-like inclusions) were found mainly in the small neurons in the superficial layer of the cerebral cortex of CBD cases; their tau immunoreactivity was more compact and denser than that of CBD-pretangles. On confocal observation, we found that these inclusions often contained small cavities (Figure 6A-B). The correlation of LM and EM images revealed bundles of tau filaments around the cavities (Figure 6B-D). Tau-positive filaments were composed of straight filaments and PHFs with a periodicity of approximately 130 nm (Figure 6D-E). These filaments were loosely assembled and usually intermingled with cellular organellae, especially ribosomes (Figure 6D, arrow). Strictly speaking, the straight filaments were not oriented parallel to each other. The diameters of straight filaments in these inclusions ranged from 13 to 15 nm in case 3 and 15 to 16 nm in case 4. Similarities and differences among AD-pretangles, NFTs in AD, CBD-pretangles, and Pick-like inclusions in CBD are listed in Table 2.Figure 6


Ultrastructural differences in pretangles between Alzheimer disease and corticobasal degeneration revealed by comparative light and electron microscopy.

Tatsumi S, Uchihara T, Aiba I, Iwasaki Y, Mimuro M, Takahashi R, Yoshida M - Acta Neuropathol Commun (2014)

Correlation of immunolabeled LM and EM images of Pick-like inclusions in two CBD cases. A densely packed round inclusion (Pick-like inclusion) from a CBD case (case 3) labeled with anti-PHF antibody (AT8) visualized with QD 655, also labeled with Alexa 488 for more precise confocal images (A). Correlated LM and EM images (B, C) showed that tau immunoreactivity around the cavity on LM corresponded to bundles of tau filaments that were not arranged as parallely as in AD (C, rectangle d; D). Note that these filaments were intermingled with ribosomes (D, arrow). (E) The ultrastructure of Pick-like inclusions in another case of CBD (case 4) also revealed randomly assembled tau filaments with occasional formation of paired helical filaments (a periodicity of 130 nm, arrow). Scale bars in A to C = 3 μm; D = 50 nm; E = 100 nm. A to D, case 3; E, case 4.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4269873&req=5

Fig6: Correlation of immunolabeled LM and EM images of Pick-like inclusions in two CBD cases. A densely packed round inclusion (Pick-like inclusion) from a CBD case (case 3) labeled with anti-PHF antibody (AT8) visualized with QD 655, also labeled with Alexa 488 for more precise confocal images (A). Correlated LM and EM images (B, C) showed that tau immunoreactivity around the cavity on LM corresponded to bundles of tau filaments that were not arranged as parallely as in AD (C, rectangle d; D). Note that these filaments were intermingled with ribosomes (D, arrow). (E) The ultrastructure of Pick-like inclusions in another case of CBD (case 4) also revealed randomly assembled tau filaments with occasional formation of paired helical filaments (a periodicity of 130 nm, arrow). Scale bars in A to C = 3 μm; D = 50 nm; E = 100 nm. A to D, case 3; E, case 4.
Mentions: Densely packed round inclusions (Pick-like inclusions) were found mainly in the small neurons in the superficial layer of the cerebral cortex of CBD cases; their tau immunoreactivity was more compact and denser than that of CBD-pretangles. On confocal observation, we found that these inclusions often contained small cavities (Figure 6A-B). The correlation of LM and EM images revealed bundles of tau filaments around the cavities (Figure 6B-D). Tau-positive filaments were composed of straight filaments and PHFs with a periodicity of approximately 130 nm (Figure 6D-E). These filaments were loosely assembled and usually intermingled with cellular organellae, especially ribosomes (Figure 6D, arrow). Strictly speaking, the straight filaments were not oriented parallel to each other. The diameters of straight filaments in these inclusions ranged from 13 to 15 nm in case 3 and 15 to 16 nm in case 4. Similarities and differences among AD-pretangles, NFTs in AD, CBD-pretangles, and Pick-like inclusions in CBD are listed in Table 2.Figure 6

Bottom Line: With these methods, we were successful for the first time in demonstrating accurately that LM-defined pretangles are tau-positive straight filaments sparsely distributed throughout neuronal cytoplasm and neurites in both AD and CBD at the EM level.Notably, AD-pretangles showed a strong tendency to form fibrillary tangles even at an early stage, whereas pretangles or Pick-like inclusions in tissue from patients with CBD did not even at an advanced stage.In conclusion, AD-pretangles and CBD-pretangles showed essential differences at the EM level.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Structural Neuropathology, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya 156-8506, Tokyo, Japan. uchihara-ts@igakuken.or.jp.

ABSTRACT
Pretangles are defined under the light microscope as diffuse and granular tau immunoreactivity in neurons in tissue from patients with Alzheimer disease (AD) or corticobasal degeneration (CBD) and are considered to be a premature stage before neurofibrillary tangle formation. However, the ultrastructure of pretangles remains to be described. To clarify the similarities and differences between pretangles from patients with AD and CBD (AD-pretangles and CBD-pretangles, respectively), we examined cortical pretangles in tissue from patients with each of diseases. For direct light and electron microscopic (LM/EM) correlation of the pretangles, we used quantum dot nanocrystals (QDs) with dual fluorescent and electron-dense properties. We first identified tau-labeled pretangles on fluorescence LM and subsequently examined the same neurons on EM. Energy dispersive X-ray spectrometry (EDX) color mapping identified selenium (Se) and cadmium (Cd) as elementary components of QDs and highlighted each QD particle clearly against gray-scale EM images. With these methods, we were successful for the first time in demonstrating accurately that LM-defined pretangles are tau-positive straight filaments sparsely distributed throughout neuronal cytoplasm and neurites in both AD and CBD at the EM level. Notably, AD-pretangles showed a strong tendency to form fibrillary tangles even at an early stage, whereas pretangles or Pick-like inclusions in tissue from patients with CBD did not even at an advanced stage. In conclusion, AD-pretangles and CBD-pretangles showed essential differences at the EM level.

Show MeSH
Related in: MedlinePlus