Biochemical analysis of tau proteins in argyrophilic grain disease, Alzheimer's disease, and Pick's disease : a comparative study - PubMed (original) (raw)

Comparative Study

Biochemical analysis of tau proteins in argyrophilic grain disease, Alzheimer's disease, and Pick's disease : a comparative study

Victoria Zhukareva et al. Am J Pathol. 2002 Oct.

Abstract

Although argyrophilic grain disease is characterized histopathologically by tau-positive lesions known as argyrophilic grains located predominantly in limbic brain regions in the absence of other diagnostic neuropathologies, the biochemical correlates of argyrophilic grains in gray and white matter have not been reported. Thus, we analyzed insoluble (pathological) tau proteins in five argyrophilic grain disease brains in comparison with those seen in Alzheimer's disease and Pick's disease. Analyses of separately dissected gray and white matter samples from various cortical regions revealed that pathological tau in argyrophilic grain disease was confined primarily to mediotemporal neocortical gray and adjacent white matter, and also to the allocortex, amygdala, and hippocampus. The amounts of sarcosyl-insoluble tau in all five cases were substantially lower than in Alzheimer's disease and Pick's disease, but the amounts of sarcosyl-insoluble tau in white matter were higher or comparable to that detected in gray matter from the same region, which distinguishes argyrophilic grain disease from Alzheimer's disease. The banding patterns of tau isoforms in argyrophilic grain disease varied: in three cases they were similar to Alzheimer's disease, but in two other cases, 4 microtubule binding repeat (4R) tau predominated, which distinguishes argyrophilic grain disease from classical Pick's disease. The differences between these three diseases were re-enforced by the predominance of straight tau filaments from argyrophilic grain disease brains. Thus, we conclude that argyrophilic grain disease is a distinct tauopathy characterized by prominent accumulation of argyrophilic grains in limbic brain regions in association with the characteristic tau biochemical and ultrastructural profile reported here.

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Figures

Figure 1.

Figure 1.

Neuropathology of AGD cases. Sections of hippocampus, amygdala, entorhinal cortex, and temporal cortex of different AGD cases were stained with τ mAb PHF1 (1:3000). AGs are seen in amygdala (A, case 1, arrows show the punctate AGs distribution; B, case 5; C, case 2), hippocampus (D, case 1; F, case 3) and temporal cortex (C, case 4), whereas AD-type pathology and AGs are seen in entorhinal cortex (E, case 3). E: Glial inclusions are seen in temporal cortex (case 2). Original magnifications: ×2300 (A, C–F); ×7750 (B).

Figure 2.

Figure 2.

Biochemical and ultrastructural analysis of sarcosyl-insoluble τ. A: Dephosphorylated samples from different brain regions were resolved onto 7.5% SDS-polyacrylamide gel. Twenty percent of total sarcosyl-insoluble material from each sample was loaded in each lane, and nitrocellulose replicas were probed with a mixture of mAbs Tau14 and Tau46. A: Brain region-specific distribution of pathological τ. F, frontal; T, temporal; P, parietal; O, occipital cortex; C, cerebellum; Hipp, hippocampus; Amy, amygdala; Th, thalamus; E, entorhinal cortex; BG, basal ganglia; g, gray matter; w, white matter. A mixture of six recombinant human τ isoforms is shown on the right for the comparison (Rt). Case numbers are shown on the left and on the right. Asterisks indicate samples with 30% reduction of loaded material to avoid the saturation. B: Dispersed τ filaments were isolated from frozen temporal cortical gray and white matter (case 2) adjacent to tissue used for biochemical analysis. a: Electron microphotographs of τ filament stained with 0.4% uranyl acetate. Microphotographs were taken at a nominal original magnification of ×120,000. b: Immunogold labeling of τ filaments using PHF1 antibodies.

Figure 3.

Figure 3.

Sequential extraction of τ proteins from AGD, AD, and PiD cases: Western blot analysis. Temporal cortex (AD, cases 8 and 9; PiD, cases 6 and 7; AGD, cases 1, 2, and 5) and entorhinal cortex and amygdala (AGD, case 4) with abundant τ pathology were studied after repeated extraction with buffers of increasing stringency as described in Materials and Methods. Lane 1: Buffer A (first extraction is shown); lane 2: 1% Triton X-100 in buffer A; lane 3: RIPA buffer; lane 4: 2% SDS; lane 5: 70% formic acid. A mixture of mAbs Tau14 and Tau46 were used for the Western blot analysis. An equal amount of material from each extraction step was loaded. Highly insoluble aggregated τ species were detected in AGD cases 2, 4, and 5 (arrowheads).

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