Corticosterone and related receptor expression are associated with increased beta-amyloid plaques in isolated Tg2576 mice

Abstract

Previously, we reported that the stress associated with chronic isolation was associated with increased beta-amyloid (Abeta) plaque deposition and memory deficits in the Tg2576 transgenic animal model of Alzheimer's disease (AD) [Dong H, Goico B, Martin M, Csernansky CA, Bertchume A, Csernansky JG (2004) Effects of isolation stress on hippocampal neurogenesis, memory, and amyloid plaque deposition in APP (Tg2576) mutant mice. Neuroscience 127:601-609]. In this study, we investigated the potential mechanisms of stress-accelerated Abeta plaque deposition in this Tg2576 mice by examining the relationship between plasma corticosterone levels, expression of glucocorticoid receptor (GR) and corticotropin-releasing factor receptor-1 (CRFR1) in the brain, brain tissue Abeta levels and Abeta plaque deposition during isolation or group housing from weaning (i.e. 3 weeks of age) until 27 weeks of age. We found that isolation housing significantly increased plasma corticosterone levels as compared with group-housing in both Tg+ mice (which contain and overexpress human amyloid precursor protein (hAPP) gene) and Tg- mice (which do not contain hAPP gene as control). Also, isolated, but not group-housed animals showed increases in the expression of GR in the cortex. Furthermore, the expression of CRFR1 was increased in isolated Tg+ mice, but decreased in isolated Tg- mice in both cortex and hippocampus. Changes in the components of hypothalamic-pituitary-adrenal (HPA) axis were accompanied by increases in brain tissue Abeta levels and Abeta plaque deposition in the hippocampus and overlying cortex in isolated Tg+ mice. These results suggest that isolation stress increases corticosterone levels and GR and CRFR1 expression in conjunction with increases in brain tissue Abeta levels and Abeta plaque deposition in the Tg2576 mouse model of AD.

Fig. 1

Plasma corticosterone levels in Tg+ and Tg− mice. Regardless of housing condition, plasma corticosterone levels were significantly higher in Tg+ mice than Tg− mice. Plasma corticosterone levels were dramatically increased in both Tg+ and Tg− mice after 24 weeks of isolation stress.

Fig. 2

GR and CRFR1 expression in the hippocampus in Tg+ mice. Immunocytochemical staining of GR (A, B) and CRFR1 (C, D) in the hippocampus of isolated Tg+ mice (B, D) and group-housed Tg+ mice (A, C). Scale bar=40 μm (B); applies to A. Scale bar=40 μm (D); applies to C.

Fig. 3

Quantitative analysis of GR and CRFR1 expression in Tg+ and Tg− mice. GR-immunoreactive cell density was significantly increased in isolated Tg+ mice as compared with group-housed Tg+ mice in the cortex and the hippocampus (A, B). CRFR1-immunoreactive cell density was significantly increased in the cortex of isolated Tg+ mice as compared with group-housed Tg+ mice and isolated Tg− mice. CRFR1-immunoreactive cell density was significantly decreased in the cortex of isolated Tg− mice as compared with group-housed Tg− mice (C). CRFR1 immunoreactive cell density was significantly increased in the hippocampus of isolated Tg+ mice as compared with group-housed Tg+ mice and isolated Tg− mice, but no significant change between group housed Tg− mice and isolated Tg− mice (D).

Fig. 4

Aβ_1–40 and Aβ_1–42 levels in brain tissue of Tg+ mice. There was a significant increase in Aβ_1–40 (A) and Aβ_1–42 (B) in isolated Tg+ mice as compared with group-housed Tg+ mice at same age.

Fig. 5

Aβ plaque deposition in Tg+ mice. Aβ immunocytochemical and Thioflavine S fluorescence stains were used to identify and count Aβ plaques in Tg+ mice at 27 weeks of age (isolated for 24 weeks from weaning). Aβ plaques were easily found in isolated Tg+ mice in the cortex (A, Aβ-immunocytochemical staining) and hippocampus (B, Thioflavine S staining), but Aβ plaques were rare in Tg+ mice in age-matched group-housed controls. Scale bar=50 μm (A, B).

Fig. 6

Quantitative analysis of Aβ plaque deposition in Tg+ mice. Both Aβ immunocytochemically positive plaques (A–C) and Thioflavine S stained plaques (D), as well as percentage of plaque loading (E) were significantly increased at 27 weeks of age after 24 weeks of isolation stress in Tg+ mice as compared with group-housed Tg+ mice. The plaques distributed mainly in the cortex. After stress, the ratio of increased plaque was evenly distributed in the cortex (B) and hippocampus (C) as compared group-housed animals.

Fig. 7

Hippocampus volume in Tg+ and Tg− mice. A significant decrease in volume of the hippocampus in both Tg+ and Tg− mice after 24 weeks of isolation stress, however, there was no significant stress by genotype interaction.