Correlation of astrocytic S100 beta expression with dystrophic neurites in amyloid plaques of Alzheimer's disease

Abstract

The neurite extension factor S100 beta is overexpressed by activated astrocytes associated with amyloid-containing plaques in Alzheimer's disease, and has been implicated in dystrophic neurite formation in these plaques. This predicts (a) that the appearance of S100beta- immunoreactive (S100beta+) astrocytes precedes that of dystrophic neurites in diffuse amyloid deposits and (b) that the number of these astrocytes correlates with the degree of dystrophic neurite proliferation in neuritic plaques. As a test of the first prediction, we determined the number of S100beta+ astrocytes associated with different plaque types: diffuse non-neuritic, diffuse neuritic, dense-core neuritic, and dense-core non-neuritic. Diffuse non-neuritic plaques had small numbers of associated S100beta+ astrocytes (1.3 +/- 0.1 S100beta astrocytes per plaque [mean +/- SEM]; 80% of plaques had one or more). These astrocytes were most abundant in diffuse neuritic plaques (4.2 +/- 0.2; 100%), were somewhat less numerous in dense-core neuritic plaques (1.6 +/- 0.2; 90%), and were only rarely associated with dense-core non-neuritic plaques (0.15 +/- 0.05; 12%). As a test of the second prediction, we correlated the number of S100beta+ astrocytes per plaque with the area of beta-amyloid precursor protein (beta-APP) immunoreactivity per plaque (an index of the size of the plaques' dystrophic neurite shells) and found a significant positive correlation (r = 0.74, p < 0.001). This correlation was also evident at the tissue level: the numbers of S100beta+ astrocytes per plaque-rich field correlated with the total area beta-APP immunoreactivity in these fields (r = 0.66, p < 0.05). These correlations support the idea that astrocytic activation and S100 beta overexpression are involved in the induction and maintenance of dystrophic neurites in amyloid deposits, and support the concept of a glial cytokine-mediated cascade underlying the progression of neuropathological changes in Alzheimer's disease.

Fig. 1

Examples of plaque types dual-immunolabeled for β-amyloid (β-AP, brown) and β-amyloid precursor protein (β-APP, red) (left column, a–d) or for S100β (S100β, brown) and β-amyloid (β-AP, red) (right column, e–h). (a, e) Diffuse non-neuritic plaques devoid of condensed amyloid and β-APP⁺ neurites, and with several associated S100β⁺ activated astrocytes, (b, f) Diffuse neuritic plaques with both diffuse and condensed amyloid as well as dystrophic β-APP⁺ neurites, but without a dense β-amyloid core, and with an abundance of associated activated S100β⁺ astrocytes, (c, g) Dense-core neuritic plaques with compact round core deposits, halos of diffuse amyloid, β-APP⁺ neurites, and several associated S100β⁺ activated astrocytes, (d, h) Dense-core, non-neuritic plaques devoid of diffuse amyloid, β-APP⁺ neurites, and S100β⁺ astrocytes. Arrowheads denote examples of S100β⁺ astrocytes. Bars = 15 μm.

Fig. 2

Number of S100β⁺ astrocytes associated with each of the 4 defined plaque types. DnNP = diffuse non-neuritic plaques; DNP = diffuse neuritic plaques; DCNP = dense-core neuritic plaques; DCnNP = dense-core, non-neuritic plaques. Data expressed as mean ± SEM for 60 plaques of each type (5 in each of 12 patients). In each case, the number of S100β⁺ astrocytes associated with plaque types was significantly different from that of the postulated predecessor plaque type (i.e. the plaque type to the left in the figure); p < 0.001 in each case.

Fig. 3

Photomicrograph of S100β/β-APP dual-immunolabeled tissue sections showing β-amyloid precursor protein-immunoreactive dystrophic neurites (red) and associated S100β immunoreactive astrocytes (brown; arrowheads denote examples of S100β⁺ astrocytes) in neuritic plaques of 3 sizes. Note the greater number of S100β⁺ astrocytes associated with the larger plaques (b and c compared with a). Bars = 15 μm.

Fig. 4

Positive correlation between β-APP⁺ dystrophic neurite cross-sectional area and the number of associated S100β⁺ astrocytes for 50 neuritic plaques from 7 Alzheimer patients (r = 0.74; p = 0.001).

Fig. 5

Positive correlation between β-APP⁺ dystrophic neurite cross sectional area and the number of S100β⁺ astrocytes within plaque-rich fields in adjacent sections of parahippocampal cortex from each of 9 Alzheimer patients (r = 0.86; p < 0.05).