Life-long overexpression of S100beta in Down's syndrome: implications for Alzheimer pathogenesis

Abstract

Chronic overexpression of the neurite growth-promoting factor S100beta has been implicated in the pathogenesis of neuritic plaques in Alzheimer's disease. Such plaques are virtually universal in middle-aged Down's syndrome, making Down's a natural model of Alzheimer's disease. We determined numbers of astrocytes overexpressing S100beta, and of neurons overexpressing beta-amyloid precursor protein (beta-APP), and assayed for neurofibrillary tangles in neocortex of 20 Down's syndrome patients (17 weeks gestation to 68 years). Compared to controls, there were twice as many S100beta-immunoreactive (S100beta+) astrocytes in Down's patients at all ages: fetal, young, and adult (p = 0.01, or better, in each age group). These were activated (i.e., enlarged), and intensely immunoreactive, even in the fetal group. There were no neurofibrillary changes in fetal or young Down's patients. The numbers of S100beta+ astrocytes in young and adult Down's patients correlated with the numbers of neurons overexpressing beta-APP (p < 0.05). Our findings are consistent with the idea that conditions--including Down's syndrome--that promote chronic overexpression of S100beta may confer increased risk for later development of Alzheimer's disease.

FIG. 1

Photomicrographs showing S100β⁺ astrocytes in neocortex of fetal (F) young (Y), and adult (A) Down’s (DS) and control (C) patients. Bars = 15 µm.

FIG. 2

Numerical density of S100β⁺ astrocytes in neocortex of Down’s (●) and control (○) patients. The mean values were significantly different for fetal (17–35 weeks gestation, p < 0.001), for young (8 months to 9 years, p < 0.05), and for adult (22 years to 68 years, p < 0.005) age ranges.

FIG. 3

Whole-mount photomicrographs of hippocampus and adjacent neocortical regions from control (A, 24 weeks gestation) and Down’s (B, 18 weeks gestation) fetuses showing the distributions of S100β⁺ astrocytes. Magnification: 6X.

FIG. 4

Photomicrographs showing β-APP⁺ neurons in neocortex of young (Y) and adult (A) Down’s (DS) and control (C) patients (top four panels). Lower two panels show Tau2⁺ neurons in adult Down’s (A-DS) but not control (A-C) patients. Bars = 15 µm.

FIG. 5

Numerical density of β-APP⁺ neurons (A) and of Tau2⁺ neurons (B) in neocortex of Down’s and control patients. For β-APP⁺ neurons, the mean values were significantly different for young (* p < 0.02), and for adult (** p < 0.0001), but not for fetal age ranges. For Tau2⁺ neurons the mean values were significantly different for adults (** p < 0.0001).

FIG. 6

Dual plots of the numerical density of β-APP⁺ neurons vs. numerical density of S100β⁺ astrocytes for young and adult Down’s (●) and control (○) patients show a separation of the two patient populations. A regression line is shown for the Down’s syndrome values only. Values were significantly correlated for Down’s (r = 0.75, p < 0.05) but not for control patients.