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Short-term recognition memory impairment is associated with decreased expression of FK506 binding protein 51 in the aged mouse brain.

Soontornniyomkij V, Risbrough VB, Young JW, Wallace CK, Soontornniyomkij B, Jeste DV, Achim CL - Age (Dordr) (2010)

Bottom Line: Evidence suggests that increased glucocorticoid receptor (GR) signaling may contribute to cognitive decline with age.In aged mice, the frontal cortex FKBP51 IRn correlated directly with DR (r (s) = 0.68, p = 0.002, Spearman rank correlation).These observations suggest that recognition memory impairment in aged mice is associated with decreased FKBP51 expression that may promote GR-mediated glucocorticoid signaling to a greater extent than in unimpaired aged mice.

View Article: PubMed Central - PubMed

Affiliation: Sam and Rose Stein Institute for Research on Aging, University of California, San Diego, La Jolla, CA 92093-0603, USA. vsoontor@ucsd.edu

ABSTRACT
Evidence suggests that increased glucocorticoid receptor (GR) signaling may contribute to cognitive decline with age. We hypothesized that alterations in GR signaling pathway molecules, FK506 binding protein (FKBP) 51 and FKBP52, were associated with memory impairment in aged mice. We used the single-trial object recognition test to measure short-term memory in 18 aged mice compared to 22 young mice, and employed quantitative immunohistochemistry to assess cellular expression of those three proteins in the frontal cortex, hippocampal CA1, and dentate gyrus. Values of the discrimination ratio (DR, a measure of novelty preference) in aged mice were significantly lower than those in young mice (mean 0.54 vs. 0.67, p = 0.003, t test). Aged mice with DR below 0.54 were considered impaired (n = 9). In the three neuroanatomic regions studied, the immunoreactivity normalized to the area measured (IRn) for GR was significantly increased in aged mice regardless of their task performance compared to young mice (p < 0.005), as was the FKBP52 IRn (p < 0.007, U test). In the frontal cortex and CA1, the FKBP51 IRn was significantly lower in impaired aged mice than in unimpaired aged mice (p < 0.01 and <0.05, respectively) and in young mice (p < 0.05 and <0.01, respectively, Dunn's post hoc test). In aged mice, the frontal cortex FKBP51 IRn correlated directly with DR (r (s) = 0.68, p = 0.002, Spearman rank correlation). These observations suggest that recognition memory impairment in aged mice is associated with decreased FKBP51 expression that may promote GR-mediated glucocorticoid signaling to a greater extent than in unimpaired aged mice.

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a The distribution of glucocorticoid receptor (GR) immunoreactivity on the entire parasagittal right hemi-brain section. b, c Immunoreactive signals for GR are observed in neuronal nuclei (weak to intense; in the dorsal hippocampal CA1 [CA], granule cell layer of the dorsal dentate gyrus [DG], and the thalamus [TH, cinset]) and cytoplasm (weak; in TH [cinset]). d–g Immunoreactive signals for FK506 binding protein (FKBP) 52 are observed in neuronal cytoplasm (weak to intense; in the frontal cortex [FC], dorsal hippocampal formation [HP], CA, DG, and TH [ginset]) and nuclei (weak; in TH [ginset]). h–k Immunoreactive signals for FKBP51 are observed in neuronal cytoplasm (weak to intense; in FC, HP, CA, DG, and TH [kinset]) but not in neuronal nuclei. Note that right hemi-brain sections immunostained for GR and FKBP51 are of one of the young mice, and that for FKBP52 is of one of the unimpaired aged mice (original magnification, ×100 in a, d, e, h, and i and ×400 in b, c, f, g, j, and k)
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Fig3: a The distribution of glucocorticoid receptor (GR) immunoreactivity on the entire parasagittal right hemi-brain section. b, c Immunoreactive signals for GR are observed in neuronal nuclei (weak to intense; in the dorsal hippocampal CA1 [CA], granule cell layer of the dorsal dentate gyrus [DG], and the thalamus [TH, cinset]) and cytoplasm (weak; in TH [cinset]). d–g Immunoreactive signals for FK506 binding protein (FKBP) 52 are observed in neuronal cytoplasm (weak to intense; in the frontal cortex [FC], dorsal hippocampal formation [HP], CA, DG, and TH [ginset]) and nuclei (weak; in TH [ginset]). h–k Immunoreactive signals for FKBP51 are observed in neuronal cytoplasm (weak to intense; in FC, HP, CA, DG, and TH [kinset]) but not in neuronal nuclei. Note that right hemi-brain sections immunostained for GR and FKBP51 are of one of the young mice, and that for FKBP52 is of one of the unimpaired aged mice (original magnification, ×100 in a, d, e, h, and i and ×400 in b, c, f, g, j, and k)

Mentions: Immunoreactive signals for GR (Fig. 3a–c) were observed in neuronal nuclei (weak to intense) and cytoplasm (weak) in the cerebral cortex (Fig. 3a), hippocampal CA1 (intense in nuclei; Fig. 3b) and CA3 (weak in nuclei), granule cell layer of the dentate gyrus (intense in nuclei; Fig. 3c), olfactory bulb, caudate-putamen, thalamus (intense in nuclei and weak in cytoplasm; Fig. 3c, inset), hypothalamus, midbrain, brainstem, and cerebellum (in Purkinje cells, granule cells, and some neurons in the molecular layer). Oligodendroglial nuclei were also moderately to intensely immunoreactive.Fig. 3


Short-term recognition memory impairment is associated with decreased expression of FK506 binding protein 51 in the aged mouse brain.

Soontornniyomkij V, Risbrough VB, Young JW, Wallace CK, Soontornniyomkij B, Jeste DV, Achim CL - Age (Dordr) (2010)

a The distribution of glucocorticoid receptor (GR) immunoreactivity on the entire parasagittal right hemi-brain section. b, c Immunoreactive signals for GR are observed in neuronal nuclei (weak to intense; in the dorsal hippocampal CA1 [CA], granule cell layer of the dorsal dentate gyrus [DG], and the thalamus [TH, cinset]) and cytoplasm (weak; in TH [cinset]). d–g Immunoreactive signals for FK506 binding protein (FKBP) 52 are observed in neuronal cytoplasm (weak to intense; in the frontal cortex [FC], dorsal hippocampal formation [HP], CA, DG, and TH [ginset]) and nuclei (weak; in TH [ginset]). h–k Immunoreactive signals for FKBP51 are observed in neuronal cytoplasm (weak to intense; in FC, HP, CA, DG, and TH [kinset]) but not in neuronal nuclei. Note that right hemi-brain sections immunostained for GR and FKBP51 are of one of the young mice, and that for FKBP52 is of one of the unimpaired aged mice (original magnification, ×100 in a, d, e, h, and i and ×400 in b, c, f, g, j, and k)
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Related In: Results  -  Collection

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Fig3: a The distribution of glucocorticoid receptor (GR) immunoreactivity on the entire parasagittal right hemi-brain section. b, c Immunoreactive signals for GR are observed in neuronal nuclei (weak to intense; in the dorsal hippocampal CA1 [CA], granule cell layer of the dorsal dentate gyrus [DG], and the thalamus [TH, cinset]) and cytoplasm (weak; in TH [cinset]). d–g Immunoreactive signals for FK506 binding protein (FKBP) 52 are observed in neuronal cytoplasm (weak to intense; in the frontal cortex [FC], dorsal hippocampal formation [HP], CA, DG, and TH [ginset]) and nuclei (weak; in TH [ginset]). h–k Immunoreactive signals for FKBP51 are observed in neuronal cytoplasm (weak to intense; in FC, HP, CA, DG, and TH [kinset]) but not in neuronal nuclei. Note that right hemi-brain sections immunostained for GR and FKBP51 are of one of the young mice, and that for FKBP52 is of one of the unimpaired aged mice (original magnification, ×100 in a, d, e, h, and i and ×400 in b, c, f, g, j, and k)
Mentions: Immunoreactive signals for GR (Fig. 3a–c) were observed in neuronal nuclei (weak to intense) and cytoplasm (weak) in the cerebral cortex (Fig. 3a), hippocampal CA1 (intense in nuclei; Fig. 3b) and CA3 (weak in nuclei), granule cell layer of the dentate gyrus (intense in nuclei; Fig. 3c), olfactory bulb, caudate-putamen, thalamus (intense in nuclei and weak in cytoplasm; Fig. 3c, inset), hypothalamus, midbrain, brainstem, and cerebellum (in Purkinje cells, granule cells, and some neurons in the molecular layer). Oligodendroglial nuclei were also moderately to intensely immunoreactive.Fig. 3

Bottom Line: Evidence suggests that increased glucocorticoid receptor (GR) signaling may contribute to cognitive decline with age.In aged mice, the frontal cortex FKBP51 IRn correlated directly with DR (r (s) = 0.68, p = 0.002, Spearman rank correlation).These observations suggest that recognition memory impairment in aged mice is associated with decreased FKBP51 expression that may promote GR-mediated glucocorticoid signaling to a greater extent than in unimpaired aged mice.

View Article: PubMed Central - PubMed

Affiliation: Sam and Rose Stein Institute for Research on Aging, University of California, San Diego, La Jolla, CA 92093-0603, USA. vsoontor@ucsd.edu

ABSTRACT
Evidence suggests that increased glucocorticoid receptor (GR) signaling may contribute to cognitive decline with age. We hypothesized that alterations in GR signaling pathway molecules, FK506 binding protein (FKBP) 51 and FKBP52, were associated with memory impairment in aged mice. We used the single-trial object recognition test to measure short-term memory in 18 aged mice compared to 22 young mice, and employed quantitative immunohistochemistry to assess cellular expression of those three proteins in the frontal cortex, hippocampal CA1, and dentate gyrus. Values of the discrimination ratio (DR, a measure of novelty preference) in aged mice were significantly lower than those in young mice (mean 0.54 vs. 0.67, p = 0.003, t test). Aged mice with DR below 0.54 were considered impaired (n = 9). In the three neuroanatomic regions studied, the immunoreactivity normalized to the area measured (IRn) for GR was significantly increased in aged mice regardless of their task performance compared to young mice (p < 0.005), as was the FKBP52 IRn (p < 0.007, U test). In the frontal cortex and CA1, the FKBP51 IRn was significantly lower in impaired aged mice than in unimpaired aged mice (p < 0.01 and <0.05, respectively) and in young mice (p < 0.05 and <0.01, respectively, Dunn's post hoc test). In aged mice, the frontal cortex FKBP51 IRn correlated directly with DR (r (s) = 0.68, p = 0.002, Spearman rank correlation). These observations suggest that recognition memory impairment in aged mice is associated with decreased FKBP51 expression that may promote GR-mediated glucocorticoid signaling to a greater extent than in unimpaired aged mice.

Show MeSH
Related in: MedlinePlus