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Age-related changes of the hippocampal estrogen receptor gene expression in senescence-accelerated mouse
International Congress Series 1260 (2004) 237 – 242
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Age-related changes of the hippocampal estrogen receptor gene expression in senescence-accelerated mouse Wenxia Zhou *, Shengjun An, Yanrong Fu, Yongxiang Zhang Department of Neuroimmunopharmacology of Traditional Chinese Medicine, Beijing Institute of Pharmacology and Toxicology, 27, Tai-Ping Road, Beijing 100850, China Received 21 July 2003; received in revised form 29 July 2003; accepted 10 September 2003
Abstract. Estrogen receptor (ER) has two subtypes, ERa and ERh. In this study, age-related changes of hippocampal gene expressions of ERa and ERh were examined in senescence-accelerated mouse (SAM) with real-time reverse transcription-polymerase chain reaction (RT-PCR) technique, in an attempt to explore the relationship between estrogen receptor expression and age-related deficit of learning and memory in SAM. The results showed that the hippocampal ERa gene expressed constantly at the ages from 3 to 15 months in both SAMR1 and SAMP8. But the change of hippocampal ERh gene expression was different from ERa gene during the aging process. In SAMR1, the expression of ERh gene kept at a relatively high level at the ages from 3 to 12 months, and decreased significantly at the age of 15 months. In SAMP8, the expression of ERh gene kept at a higher level at the ages of 3 and 6 months, and gradually decreased with advancing age, and reached the lowest level at the age of 15 months in both genders. The expression of ERh gene decreased earlier in SAMP8 compared with SAMR1 during the aging process. These results suggested that the early decline of the expression of ERh gene, but not ERa gene in the hippocampus of SAMP8 contribute to their age-related deterioration of learning and memory function. D 2003 Published by Elsevier B.V. Keywords: Estrogen receptor a; Estrogen receptor h; Senescence-accelerated mouse; Gene expression; Real-time RT-PCR
1. Introduction It has been well documented that estrogen plays an important role in keeping the normal function of the central learning and memory. Epidemiological investigation Abbreviations: ERa, estrogen receptor a; ERh, estrogen receptor h; Real-time RT-PCR, real-time quantitative reverse transcription-polymerase chain reaction; mRNA, messenger RNA; SAM, senescence-accelerated mouse; SAMP8, Senescence accelerated mouse-prone/8; SAMR1, Senescence accelerated mouse-resistance/1. * Corresponding author. Tel.: +86-10-6693-1625; fax: +86-10-6821-1656. E-mail address: [email protected] (W. Zhou). 0531-5131/ D 2003 Published by Elsevier B.V. doi:10.1016/S0531-5131(03)01685-6
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revealed that the incidence of Alzheimer’s disease (AD) is higher in postmenopausal women than that in age-matched men. Studies demonstrated that lack of estrogen is one of the important factors related to the onset of AD and the cognitive deficits in women were abated with estrogen replacement therapy [1,2]. Estrogen has also been shown to improve the performance of rats in cognitive tests when compared with ovariectomized animals [3]. It is now recognized that the estrogen action is mediated by two types of estrogen receptor (ERs), ERa and ERh. The two subtype ERs were all detected in brain regions associated with learning and memory, including cerebral cortex, hippocampus and the nuclei of the basal forebrain [4], indicated that ERa and ERh might play an important role in learning and memory. Senescence accelerated mouse-prone/8 (SAMP8) shows early-onset decline of learning and memory abilities as assessed by learning behavioral tests compared with SAMresistance/1 (SAMR1) [5,6]. Meanwhile, the cortical and hippocampal changes of gene expressions in SAMP8 were found at the age when learning and memory was impaired [7]. An overproduction of h-amyloid protein (Ah) in the brain was reported in SAMP8 [8]. Our previous study showed that the genes of GR, MR, apoE, PS-2, tau and APP expressed abnormally in the hippocampus of 11-month-old SAMP8 [9]. In this study, age-related changes of hippocampal gene expressions of both ERa and ERh were determined in senescence-accelerated mouse (SAM), in an attempt to explore the relationship between estrogen receptor expression and age-related deficit of central learning and memory in SAM. 2. Material and methods Senescence-accelerated mouse were generously provided by Dr. T. Takeda of Kyoto University, Japan and bred in the experimental center of our institute under conventional conditions. In this experiment, 3-, 6-, 9-, 12- or 15-month-old male and female SAMP8 and age-matched SAMR1 were used. The hippocampus of SAM was dissected and the total hippocampal RNA was extracted by using the TRIzol Reagent (Gibco BRL, USA) according to the manufacturer’s instructions. The levels of hippocampal ERa and ERh mRNA were examined with
Fig. 1. The age-related changes of hippocampal ERh gene expressions in SAMP8 and SAMR1. = SAMP8.
= SAMR1,
W. Zhou et al. / International Congress Series 1260 (2004) 237–242
239
the technique of real-time quantitative reverse transcription-polymerase chain reaction (real-time RT-PCR). The levels of mRNA in each cDNA library were normalized relative to the PCR products of h-actin derived from the same cDNA library. The following primers are used: ERa: upstream primer 5V-TAC AGT CGG TTC CGC ATG ATG-3V, downstream primer: 5V-CAG GTC ATA GAG GGG CAC AAC-3V; ERh: upstream primer: 5V-ACG GTT CCG TGA GTT AAA ACT-3V, downstream primer: 5V-CCT TGT TAC TGA TGT GCC TGA-3V. The thermal cycling conditions comprised an initial denaturation step at 94 jC for 2 min, then 40 cycles at 94 jC for 30 s and annealing step at 60 jC for 1 min, and extension step at 68 jC for 2 min. The expression levels of ERa and ERh mRNA were quantified by measuring Ct (threshold cycle) and by using DDCt method as previously described by Lambertini et al. [10]. Comparisons between SAMP8 and age-matched SAMR1 were made by Student’s t-test. Data are expressed as mean F S.D., n = 3. 3. Results As shown in Fig. 1, the hippocampal ERa gene expressed constantly at the ages of 3, 6, 9, 12 and 15 months in both male and female SAMR1 and SAMP8, and there were no gender differences in the both strains. However, as shown in Fig. 2, the change of hippocampal ERh gene expression was different from ERa gene during the aging process. In both male and female SAMR1, the hippocampal gene expression of ERh kept at a relatively high level at the ages from 3 to 12 months, and decreased significantly at the age of 15 months. The levels of ERh mRNAs in male SAMR1 observed at different ages were all significantly lower than those in female ones. In SAMP8, the expression of hippocampal ERh gene kept at a constant higher level at the ages of 3 and 6 months, and then, gradually decreased with advancing age, and reached the lowest level at the age of 15 months in both genders. Similar to those of SAMR1, the levels of ERh mRNA in male SAMP8 was significantly lower than those of age-matched female ones.
Fig. 2. The age-related changes of hippocampal ERh gene expressions in SAMP8 and SAMR1. = SAMR1, = SAMP8, *P < 0.05, **P < 0.01 vs. age-matched SAMR1; #P < 0.05, ##P < 0.01 vs. 2-month-old SAMR1 or SAMP8, respectively. mean F S.D., n = 3.
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When comparing the expression of ERs genes between SAMP8 and age-matched SAMR1, we found that the level of hippocampal ERa mRNA showed no significant differences between the two strains of SAM. While for ERh mRNA, it is found that the expression of ERh gene in hippocampus of both male and female SAMP8 decreased earlier compared with that in SAMR1 during the aging process. 4. Discussion Evidences have demonstrated that estrogen acts as a potent neuroprotective and neurotrophic factor in CNS. It influences memory and cognition function, decreases the risk and delays the onset of some neurological diseases, and attenuates the extent of cell death caused by brain injuries. In recent years, studies have also found that estrogen exerts its effects on the structure and function of the learning and memory associated brain regions, such as hippocampus and cortex [4]. The localization of ER-a and ER-h mRNAs in the pyramidal cells of the rat hippocampus and ER-h mRNA in rat cortex have also been observed [4,11]. Moreover, recent in vivo 125I-estrogen binding studies have shown that nuclear estrogen binding sites are widely distributed in the pyramidal cells throughout CA1 – 3 of the hippocampus and laminae II – VI of the isocortex, demonstrating that ER mRNAs are translated into biologically active protein [12]. The functional impact of estrogen receptor localization in the cortex and hippocampus may prove relevant to the emerging role for estrogen as a protective factor in neurodegenerative injury. This potential role is further highlighted by the recent findings that the expression of ER-a and ER-h changes following ischemic brain injury and that these changes correlate with the hormonal modulation of protective factors [13]. The localization of ER-h mRNA in brain regions associated with learning and memory suggested that estrogen may directly modulate the function of cortical and hippocampal neurons via nuclear receptor-mediated events [14]. However, the age-related changes of ERs gene expression in the brain, especially in hippocampus, as well as their relationships with learning and memory deficit are not well understood yet. Senescence accelerated mouse (SAM) is a murine model of accelerated aging, consisting of senescence-prone strains (SAMP) and senescence-resistant strains (SAMR). SAM-prone/8 (SAMP8), a substrain of SAMP, shows an early-onset decline of learning and memory ability as assessed by the passive avoidance performances, active avoidance performances and spatial memory task [15]. Our recent experiments demonstrated that the serum estrogen in SAMP8 showed quite different levels from that in age-matched SAMR1 (data not shown), indicated that impairments of learning and memory in SAMP8 might associate with the changes of the estrogen level in the serum, and so we hypothesized that ERs in the brain, especially in the hippocampus, might also play important roles in the age-related decline of learning and memory in SAMP8. In this study, we used real-time RT-PCR technique to determine the age-related changes of hippocampal gene expressions of both ERa and ERh in senescence-accelerated mouse (SAM), in an attempt to explore the relationship between estrogen receptor expression and
W. Zhou et al. / International Congress Series 1260 (2004) 237–242
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age-related deficit of central learning and memory in SAM. The results showed that the expressions of ERa mRNA had little changes in the hippocampus of both SAMP8 and SAMR1 with the advancing of age, and no gender differences in the both strains. However, the expression of ERh mRNA in hippocampus of 9-, 12- and 15-month-old SAMP8 was significantly lower than that in 3-month-old SAMP8, and the expression of hippocampal ERh mRNA in SAMR1 were significantly lowered as later as 15-months old. When comparing the expression of ERs genes between the two strains of SAM, it is found that hippocampal ERa mRNA were at the same levels in SAMP8 and SAMR1, while ERh mRNA decreased earlier in SAMP8 compared with SAMR1 during the aging process. These results suggested that the hippocampal ERa gene expression has little influence on age-related learning and memory deficit in SAMP8. However, the early decline of hippocampal ERh gene expression in SAMP8 may contribute to their agerelated deterioration of central learning and memory function. Further study is being conducted in our laboratory. Acknowledgements This project was supported by The Chinese National Key Project of Basic Research (G1999054401). References [1] A. Paganini-Hill, V.W. Henderson, Estrogen deficiency and risk of Alzheimer’s disease in women, Am. J. Epidemiol. 140 (1994) 256 – 261. [2] M.X. Tang, D. Jacobs, Y. Stern, K. Marder, P. Schofield, B. Gurland, H. Andrews, R. Mayeux, Effect of oestrogen during menopause on risk and age at onset of Alzheimer’s disease, Lancet 348 (1996) 429 – 432. [3] A.J. Fader, A.W. Hendricson, G.P. Dohanich, Estrogen improves performance of reinforced T-maze alternation and prevents the amnestic effects of scopolamine administered systemically or intrahippocampally, Neurobiol. Learn. Mem. 69 (1998) 225 – 240. [4] P.J. Shughrue, M.V. Lane, I. Merchenthaler, The comparative distribution of estrogen receptor-a and h mRNA in the rat central nervous system, J. Comp. Neurol. 388 (1997) 507 – 525. [5] S. Ikegami, S. Shumiya, H. Kawamura, Age-related changes in radial-arm maze learning and basal forebrain cholinergic systems in senescence accelerated mice (SAM), Behav. Brain Res. 51 (1992) 15 – 22. [6] M. Miyamoto, Y. Kiyota, N. Yamazaki, A. Nagaoka, T. Matsuo, Y. Nagawa, T. Takeda, Age-related changes in learning and memory in the senescence-accelerated mouse (SAM), Physoil. Behav. 38 (1986) 399 – 406. [7] Y. Nomura, B.X. Wang, S.B. Qi, T. Namba, S. Kaneko, Biochemical changes related to aging in the senescence-accelerated mouse, Exp. Gerontol. 24 (1989) 49 – 55. [8] W.A. Banks, S.A. Farr, W. Butt, V.B. Kumar, M.W. Franko, J.E. Morley, Delivery across the blood – brain barrier of antisense directed against amyloid beta: reversal of learning and memory deficits in mice overexpressing amyloid precursor protein, J. Pharmacol. Exp. Ther. 297 (2001) 1113 – 1121. [9] X. Wei, Y. Zhang, J. Zhou, Alzheimer’s disease-related gene expression in the brain of senescence accelerated mouse, Neurosci. Lett. 268 (1999) 139 – 142. [10] E. Lambertini, P. Letizia, A. Gianluca, L. del Senno, F. Pezzetti, V. Sollazzo, R. Piva, Osteoblastic differentiation induced by transcription factor decoy against estrogen receptor a, Biochem. Biophys. Res. Commun. 292 (2002) 761 – 770. [11] R.B. Simerly, C. Chang, M. Muramatsu, L.W. Swanson, Distribution of androgen and estrogen receptor mRNA-containing cells in the rat brain: an in situ hybridization study, J. Comp. Neurol. 294 (1990) 76 – 95. [12] P.J. Shughrue, M.V. Lane, I. Merchenthaler, Localization of 125I-estrogen binding sites in the rat cerebral cortex and hippocampus: an in vivo autoradiographic study, Abstr.-Soc. Neurosci. (1999) 25 (abstract 167.1).
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[13] D.B. Dubal, P.J. Shughrue, M.E. Wilson, I. Merchenthaler, P.M. Wise, Estradiol modulates bcl-2 in cerebral ischemia: a potential role for estrogen receptors, J. Neurosci. 19 (1999) 6385 – 6393. [14] P.J. Shughrue, I. Merchenthaler, Estrogen is more than just a ‘‘Sex Hormone’’—novel sites for estrogen action in the hippocampus and cerebral cortex, Front. Neuroendocrinol. 21 (2000) 95 – 101. [15] M. Miyamoto, Characteristics of age-related behavioral changes in senescence-accelerated mouse SAMP8 and SAMP10, Exp. Gerontol. 32 (1997) 139 – 148.
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Age-related changes of the hippocampal estrogen receptor gene expression in senescence-accelerated mouse Wenxia Zhou *, Shengjun An, Yanrong Fu, Yongxiang Zhang Department of Neuroimmunopharmacology of Traditional Chinese Medicine, Beijing Institute of Pharmacology and Toxicology, 27, Tai-Ping Road, Beijing 100850, China Received 21 July 2003; received in revised form 29 July 2003; accepted 10 September 2003
Abstract. Estrogen receptor (ER) has two subtypes, ERa and ERh. In this study, age-related changes of hippocampal gene expressions of ERa and ERh were examined in senescence-accelerated mouse (SAM) with real-time reverse transcription-polymerase chain reaction (RT-PCR) technique, in an attempt to explore the relationship between estrogen receptor expression and age-related deficit of learning and memory in SAM. The results showed that the hippocampal ERa gene expressed constantly at the ages from 3 to 15 months in both SAMR1 and SAMP8. But the change of hippocampal ERh gene expression was different from ERa gene during the aging process. In SAMR1, the expression of ERh gene kept at a relatively high level at the ages from 3 to 12 months, and decreased significantly at the age of 15 months. In SAMP8, the expression of ERh gene kept at a higher level at the ages of 3 and 6 months, and gradually decreased with advancing age, and reached the lowest level at the age of 15 months in both genders. The expression of ERh gene decreased earlier in SAMP8 compared with SAMR1 during the aging process. These results suggested that the early decline of the expression of ERh gene, but not ERa gene in the hippocampus of SAMP8 contribute to their age-related deterioration of learning and memory function. D 2003 Published by Elsevier B.V. Keywords: Estrogen receptor a; Estrogen receptor h; Senescence-accelerated mouse; Gene expression; Real-time RT-PCR
1. Introduction It has been well documented that estrogen plays an important role in keeping the normal function of the central learning and memory. Epidemiological investigation Abbreviations: ERa, estrogen receptor a; ERh, estrogen receptor h; Real-time RT-PCR, real-time quantitative reverse transcription-polymerase chain reaction; mRNA, messenger RNA; SAM, senescence-accelerated mouse; SAMP8, Senescence accelerated mouse-prone/8; SAMR1, Senescence accelerated mouse-resistance/1. * Corresponding author. Tel.: +86-10-6693-1625; fax: +86-10-6821-1656. E-mail address: [email protected] (W. Zhou). 0531-5131/ D 2003 Published by Elsevier B.V. doi:10.1016/S0531-5131(03)01685-6
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W. Zhou et al. / International Congress Series 1260 (2004) 237–242
revealed that the incidence of Alzheimer’s disease (AD) is higher in postmenopausal women than that in age-matched men. Studies demonstrated that lack of estrogen is one of the important factors related to the onset of AD and the cognitive deficits in women were abated with estrogen replacement therapy [1,2]. Estrogen has also been shown to improve the performance of rats in cognitive tests when compared with ovariectomized animals [3]. It is now recognized that the estrogen action is mediated by two types of estrogen receptor (ERs), ERa and ERh. The two subtype ERs were all detected in brain regions associated with learning and memory, including cerebral cortex, hippocampus and the nuclei of the basal forebrain [4], indicated that ERa and ERh might play an important role in learning and memory. Senescence accelerated mouse-prone/8 (SAMP8) shows early-onset decline of learning and memory abilities as assessed by learning behavioral tests compared with SAMresistance/1 (SAMR1) [5,6]. Meanwhile, the cortical and hippocampal changes of gene expressions in SAMP8 were found at the age when learning and memory was impaired [7]. An overproduction of h-amyloid protein (Ah) in the brain was reported in SAMP8 [8]. Our previous study showed that the genes of GR, MR, apoE, PS-2, tau and APP expressed abnormally in the hippocampus of 11-month-old SAMP8 [9]. In this study, age-related changes of hippocampal gene expressions of both ERa and ERh were determined in senescence-accelerated mouse (SAM), in an attempt to explore the relationship between estrogen receptor expression and age-related deficit of central learning and memory in SAM. 2. Material and methods Senescence-accelerated mouse were generously provided by Dr. T. Takeda of Kyoto University, Japan and bred in the experimental center of our institute under conventional conditions. In this experiment, 3-, 6-, 9-, 12- or 15-month-old male and female SAMP8 and age-matched SAMR1 were used. The hippocampus of SAM was dissected and the total hippocampal RNA was extracted by using the TRIzol Reagent (Gibco BRL, USA) according to the manufacturer’s instructions. The levels of hippocampal ERa and ERh mRNA were examined with
Fig. 1. The age-related changes of hippocampal ERh gene expressions in SAMP8 and SAMR1. = SAMP8.
= SAMR1,
W. Zhou et al. / International Congress Series 1260 (2004) 237–242
239
the technique of real-time quantitative reverse transcription-polymerase chain reaction (real-time RT-PCR). The levels of mRNA in each cDNA library were normalized relative to the PCR products of h-actin derived from the same cDNA library. The following primers are used: ERa: upstream primer 5V-TAC AGT CGG TTC CGC ATG ATG-3V, downstream primer: 5V-CAG GTC ATA GAG GGG CAC AAC-3V; ERh: upstream primer: 5V-ACG GTT CCG TGA GTT AAA ACT-3V, downstream primer: 5V-CCT TGT TAC TGA TGT GCC TGA-3V. The thermal cycling conditions comprised an initial denaturation step at 94 jC for 2 min, then 40 cycles at 94 jC for 30 s and annealing step at 60 jC for 1 min, and extension step at 68 jC for 2 min. The expression levels of ERa and ERh mRNA were quantified by measuring Ct (threshold cycle) and by using DDCt method as previously described by Lambertini et al. [10]. Comparisons between SAMP8 and age-matched SAMR1 were made by Student’s t-test. Data are expressed as mean F S.D., n = 3. 3. Results As shown in Fig. 1, the hippocampal ERa gene expressed constantly at the ages of 3, 6, 9, 12 and 15 months in both male and female SAMR1 and SAMP8, and there were no gender differences in the both strains. However, as shown in Fig. 2, the change of hippocampal ERh gene expression was different from ERa gene during the aging process. In both male and female SAMR1, the hippocampal gene expression of ERh kept at a relatively high level at the ages from 3 to 12 months, and decreased significantly at the age of 15 months. The levels of ERh mRNAs in male SAMR1 observed at different ages were all significantly lower than those in female ones. In SAMP8, the expression of hippocampal ERh gene kept at a constant higher level at the ages of 3 and 6 months, and then, gradually decreased with advancing age, and reached the lowest level at the age of 15 months in both genders. Similar to those of SAMR1, the levels of ERh mRNA in male SAMP8 was significantly lower than those of age-matched female ones.
Fig. 2. The age-related changes of hippocampal ERh gene expressions in SAMP8 and SAMR1. = SAMR1, = SAMP8, *P < 0.05, **P < 0.01 vs. age-matched SAMR1; #P < 0.05, ##P < 0.01 vs. 2-month-old SAMR1 or SAMP8, respectively. mean F S.D., n = 3.
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When comparing the expression of ERs genes between SAMP8 and age-matched SAMR1, we found that the level of hippocampal ERa mRNA showed no significant differences between the two strains of SAM. While for ERh mRNA, it is found that the expression of ERh gene in hippocampus of both male and female SAMP8 decreased earlier compared with that in SAMR1 during the aging process. 4. Discussion Evidences have demonstrated that estrogen acts as a potent neuroprotective and neurotrophic factor in CNS. It influences memory and cognition function, decreases the risk and delays the onset of some neurological diseases, and attenuates the extent of cell death caused by brain injuries. In recent years, studies have also found that estrogen exerts its effects on the structure and function of the learning and memory associated brain regions, such as hippocampus and cortex [4]. The localization of ER-a and ER-h mRNAs in the pyramidal cells of the rat hippocampus and ER-h mRNA in rat cortex have also been observed [4,11]. Moreover, recent in vivo 125I-estrogen binding studies have shown that nuclear estrogen binding sites are widely distributed in the pyramidal cells throughout CA1 – 3 of the hippocampus and laminae II – VI of the isocortex, demonstrating that ER mRNAs are translated into biologically active protein [12]. The functional impact of estrogen receptor localization in the cortex and hippocampus may prove relevant to the emerging role for estrogen as a protective factor in neurodegenerative injury. This potential role is further highlighted by the recent findings that the expression of ER-a and ER-h changes following ischemic brain injury and that these changes correlate with the hormonal modulation of protective factors [13]. The localization of ER-h mRNA in brain regions associated with learning and memory suggested that estrogen may directly modulate the function of cortical and hippocampal neurons via nuclear receptor-mediated events [14]. However, the age-related changes of ERs gene expression in the brain, especially in hippocampus, as well as their relationships with learning and memory deficit are not well understood yet. Senescence accelerated mouse (SAM) is a murine model of accelerated aging, consisting of senescence-prone strains (SAMP) and senescence-resistant strains (SAMR). SAM-prone/8 (SAMP8), a substrain of SAMP, shows an early-onset decline of learning and memory ability as assessed by the passive avoidance performances, active avoidance performances and spatial memory task [15]. Our recent experiments demonstrated that the serum estrogen in SAMP8 showed quite different levels from that in age-matched SAMR1 (data not shown), indicated that impairments of learning and memory in SAMP8 might associate with the changes of the estrogen level in the serum, and so we hypothesized that ERs in the brain, especially in the hippocampus, might also play important roles in the age-related decline of learning and memory in SAMP8. In this study, we used real-time RT-PCR technique to determine the age-related changes of hippocampal gene expressions of both ERa and ERh in senescence-accelerated mouse (SAM), in an attempt to explore the relationship between estrogen receptor expression and
W. Zhou et al. / International Congress Series 1260 (2004) 237–242
241
age-related deficit of central learning and memory in SAM. The results showed that the expressions of ERa mRNA had little changes in the hippocampus of both SAMP8 and SAMR1 with the advancing of age, and no gender differences in the both strains. However, the expression of ERh mRNA in hippocampus of 9-, 12- and 15-month-old SAMP8 was significantly lower than that in 3-month-old SAMP8, and the expression of hippocampal ERh mRNA in SAMR1 were significantly lowered as later as 15-months old. When comparing the expression of ERs genes between the two strains of SAM, it is found that hippocampal ERa mRNA were at the same levels in SAMP8 and SAMR1, while ERh mRNA decreased earlier in SAMP8 compared with SAMR1 during the aging process. These results suggested that the hippocampal ERa gene expression has little influence on age-related learning and memory deficit in SAMP8. However, the early decline of hippocampal ERh gene expression in SAMP8 may contribute to their agerelated deterioration of central learning and memory function. Further study is being conducted in our laboratory. Acknowledgements This project was supported by The Chinese National Key Project of Basic Research (G1999054401). References [1] A. Paganini-Hill, V.W. Henderson, Estrogen deficiency and risk of Alzheimer’s disease in women, Am. J. Epidemiol. 140 (1994) 256 – 261. [2] M.X. Tang, D. Jacobs, Y. Stern, K. Marder, P. Schofield, B. Gurland, H. Andrews, R. Mayeux, Effect of oestrogen during menopause on risk and age at onset of Alzheimer’s disease, Lancet 348 (1996) 429 – 432. [3] A.J. Fader, A.W. Hendricson, G.P. Dohanich, Estrogen improves performance of reinforced T-maze alternation and prevents the amnestic effects of scopolamine administered systemically or intrahippocampally, Neurobiol. Learn. Mem. 69 (1998) 225 – 240. [4] P.J. Shughrue, M.V. Lane, I. Merchenthaler, The comparative distribution of estrogen receptor-a and h mRNA in the rat central nervous system, J. Comp. Neurol. 388 (1997) 507 – 525. [5] S. Ikegami, S. Shumiya, H. Kawamura, Age-related changes in radial-arm maze learning and basal forebrain cholinergic systems in senescence accelerated mice (SAM), Behav. Brain Res. 51 (1992) 15 – 22. [6] M. Miyamoto, Y. Kiyota, N. Yamazaki, A. Nagaoka, T. Matsuo, Y. Nagawa, T. Takeda, Age-related changes in learning and memory in the senescence-accelerated mouse (SAM), Physoil. Behav. 38 (1986) 399 – 406. [7] Y. Nomura, B.X. Wang, S.B. Qi, T. Namba, S. Kaneko, Biochemical changes related to aging in the senescence-accelerated mouse, Exp. Gerontol. 24 (1989) 49 – 55. [8] W.A. Banks, S.A. Farr, W. Butt, V.B. Kumar, M.W. Franko, J.E. Morley, Delivery across the blood – brain barrier of antisense directed against amyloid beta: reversal of learning and memory deficits in mice overexpressing amyloid precursor protein, J. Pharmacol. Exp. Ther. 297 (2001) 1113 – 1121. [9] X. Wei, Y. Zhang, J. Zhou, Alzheimer’s disease-related gene expression in the brain of senescence accelerated mouse, Neurosci. Lett. 268 (1999) 139 – 142. [10] E. Lambertini, P. Letizia, A. Gianluca, L. del Senno, F. Pezzetti, V. Sollazzo, R. Piva, Osteoblastic differentiation induced by transcription factor decoy against estrogen receptor a, Biochem. Biophys. Res. Commun. 292 (2002) 761 – 770. [11] R.B. Simerly, C. Chang, M. Muramatsu, L.W. Swanson, Distribution of androgen and estrogen receptor mRNA-containing cells in the rat brain: an in situ hybridization study, J. Comp. Neurol. 294 (1990) 76 – 95. [12] P.J. Shughrue, M.V. Lane, I. Merchenthaler, Localization of 125I-estrogen binding sites in the rat cerebral cortex and hippocampus: an in vivo autoradiographic study, Abstr.-Soc. Neurosci. (1999) 25 (abstract 167.1).
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[13] D.B. Dubal, P.J. Shughrue, M.E. Wilson, I. Merchenthaler, P.M. Wise, Estradiol modulates bcl-2 in cerebral ischemia: a potential role for estrogen receptors, J. Neurosci. 19 (1999) 6385 – 6393. [14] P.J. Shughrue, I. Merchenthaler, Estrogen is more than just a ‘‘Sex Hormone’’—novel sites for estrogen action in the hippocampus and cerebral cortex, Front. Neuroendocrinol. 21 (2000) 95 – 101. [15] M. Miyamoto, Characteristics of age-related behavioral changes in senescence-accelerated mouse SAMP8 and SAMP10, Exp. Gerontol. 32 (1997) 139 – 148.