Tau and alpha-synuclein pathology in amygdala of Parkinsonism-dementia complex patients of Guam - PubMed (original) (raw)

Tau and alpha-synuclein pathology in amygdala of Parkinsonism-dementia complex patients of Guam

Mark S Forman et al. Am J Pathol. 2002 May.

Abstract

Amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) is a progressive neurodegenerative disorder of Chamorro residents of Guam and the Mariana Islands, characterized by abundant neuron loss and tau neurofibrillary pathology similar to that observed in Alzheimer's disease (AD). A variety of neurodegenerative diseases with tau pathology including ALS/PDC also have alpha-synuclein positive pathology, primarily in the amygdala. We further characterized the tau and alpha-synuclein pathology in the amygdala of a large series of 30 Chamorros using immunohistochemical and biochemical techniques. Tau pathology was readily detected in both affected and unaffected Chamorros. In contrast, alpha-synuclein pathology was detected in 37% of patients with PDC but not detected in Chamorros without PDC or AD. The alpha-synuclein aggregates often co-localized within neurons harboring neurofibrillary tangles suggesting a possible interaction between the two proteins. Tau and alpha-synuclein pathology within the amygdala is biochemically similar to that observed in AD and synucleinopathies, respectively. Thus, the amygdala may be selectively vulnerable to developing both tau and alpha-synuclein pathology or tau pathology may predispose it to synuclein aggregation. Furthermore, in PDC, tau and alpha-synuclein pathology occurs independent of beta-amyloid deposition in amygdala thereby implicating the aggregation of these molecules in the severe neurodegeneration frequently observed in this location.

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Figures

Figure 1.

Figure 1.

Tau and GFAP positive pathology in the amygdala of Guam PDC patients. A and B: NFTs in the amygdala of PDC patients 21 (A) and 3 (B), immunostained with the phosphorylation-dependent tau mAb AT8. C and D: Numerous tau-positive astrocytes in the amygdala of PDC patients 10 (C) and 6 (D), immunostained with the mAb AT8. Inset shows high power magnification of tau-positive astrocytes with morphology resembling the hazy, granular astrocytes described by Oyanagi et al. E and F: Moderate to severe astrocytosis in the same amygdala of the patients illustrated in C and D, (patient 10, E; patient 6, F), immunostained with GFAP polyclonal antisera. G–I: Tau-positive hazy, granular astrocytes co-express GFAP. Double-labeling immunofluorescence of the amygdala of patient 5 stained with the mAb PHF1 (G, green) and GFAP polyclonal antisera (H, red). I represents an overlay of G and H. A–F: Scale bar, 40 μm. G–I: Scale bar, 20 μm.

Figure 2.

Figure 2.

α-Synuclein-positive pathology in the amygdala of Guam PDC patients. A–G: Variable density of Lewy bodies and neuritic pathology in the amygdala of PDC patients immunostained with mAb Syn202. Patient 26 (A), diagnosed with AD, was assessed as having mild (1+) α-synuclein pathology; patients 3 (B) and 20 (C) were assessed as moderate; (2+) patient 10 (D) was assessed as having a marked (3+) density of α-synuclein pathology. E–G: Variable morphology of α-synuclein pathology including LBs that appear fragmented within the neuron (F, G). A–D: Scale bar, 40 μm. E–G: Scale bar, 20 μm.

Figure 3.

Figure 3.

Colocalization of LBs and NFTs in neurons of the amygdala of Guam PDC patients. Double-stained preparations for LBs and NFTs are as follows: A–F: Bright-field images of LBs immunostained with Syn202 using the ABC procedure and DAB as chromogen. A′-F′: Fluorescent images of Congo red stained NFTs in the same sections as shown in A–F. A″-F″: Fluorescent images after conversion to black and white superimposed onto the bright-field images. In A (patient 10), B (patient 3), and F (patient 6, upper right), three neurons are depicted in which the LB and NFT are located side by side. In C (patient 3), D and E (patient 21) and F (bottom left) the neurons show NFTs intermingled with LBs. The arrows in D′ and D″ point to extracellular NFTs which were not associated with LBs. Scale bar, 20 μm.

Figure 4.

Figure 4.

Western blot analysis of soluble and insoluble tau and α-synuclein in the amygdala of Guam PDC patient. A: RIPA and insoluble (FA extractable) fractions were resolved by SDS-PAGE and immunoblotted with both phosphorylation-dependent (PHF1 and 12E8) and phosphorylation-independent (T14) tau antibodies as indicated. The insoluble tau from the Chamorro patients was composed of four major bands ranging from 60- to 72-kd similar to that observed in the non-Chamorro LBVAD control patient. In the formic acid extracts, the tau was also extensively aggregated. Molecular weight standards are indicated to the left of A. B: Aliquots of both soluble and insoluble (RIPA and formic acid extracts) were dephosphorylated with E. coli alkaline phosphatase, resolved by SDS-PAGE, and immunoblotted with T14. The soluble extracts were composed of all six tau isoforms that are normally expressed in adult brain. The RIPA and formic acid extracts from the Chamorro patients were also composed of all six tau isoforms similar to that observed in the non-Chamorro LBVAD patient. Recombinant tau isoforms (rTau) are indicated to the left of B. C: Soluble and formic acid fractions were resolved by SDS-PAGE and immunoblotted with Syn303. High molecular weight aggregates of insoluble synuclein was detected in two of three Chamorro patients with α-synuclein pathology detected by immunohistochemistry similar to that observed in the non-Chamorro LBVAD control. Non-aggregated α-synuclein is indicated by the arrowheads. The asterisks indicate proteins that are variably detected in both affected and normal control patients. Molecular weight standards are indicated to the right of C.

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