Immune response gene expression increases in the aging murine hippocampus
Introduction
A frequent correlate of human aging is a decline in learning, cognition and memory. Age-related functional decreases in short-term and spatial memory and declines in memory performance have been confirmed in rodent and primate models Moss et al., 1997, Herndon et al., 1997, Gage et al., 1984, Ward et al., 1999. These changes can be attributed to alterations in functions of hippocampal pathways (Lanahan et al., 1997). In humans, the extreme is Alzheimer's disease (AD), a progressive and irreversible loss of memory and cognition, as a result of amyloid plaques in the neurons of the hippocampus and cerebral cortex. Immune response genes are expressed in the hippocampus and have been demonstrated to affect long-term potentiation (LTP) and to be associated with the inflammatory response to amyloid beta in AD. An investigation of age-related changes in expression of hippocampal genes is the first step in determining whether immune response gene expression plays a role in the alterations in learning and memory that occur in old age.
Although immunological function in the periphery has been demonstrated to decline with age (Miller, 1996), cells with immunological capability in the brain become more activated with age. Age-related increases in activation of astrocytes, characterized by increased glial fibrillary acidic protein (GFAP) expression Goss et al., 1991, Morgan et al., 1997, Nichols et al., 1993, O'Callaghan and Miller, 1991, and microglia have been reported in various species Mattiace et al., 1990, Sheng et al., 1998, Peters et al., 1991, Sheffield and Berman, 1998, Ogura et al., 1994, Rozovsky et al., 1998. Microglial activation is manifested by increased phagocytic activity (Dickson et al., 1990), increased expression of major histocompatibility complex (MHC) class II genes Mattiace et al., 1990, Sheffield and Berman, 1998 and increased secretion of proinflammatory cytokines Sheng et al., 1998, Nanamiya et al., 2000, Takao et al., 1996. Immune response genes, in particular those coding cytokines and their receptors, are expressed in high density in the hippocampus Besedovsky and del Rey, 1996, Haas and Schauenstein, 1997, Murray et al., 1999, Rothwell and Hopkins, 1995 and interleukin (IL)-1, as well as IL-6 and tumor necrosis factor (TNF)-α, affect the induction of hippocampal LTP. IL-1β, IL-6 and TNF-α have all been reported to be involved in the formation of neuritic plaques in AD Griffin et al., 1995, Patterson, 1995, Strauss et al., 1992 and anti-inflammatory agents have been shown to slow the progression of AD (Breitner et al., 1995).
In this study, we have examined changes in gene expression that occur in the hippocampus during the aging process using the GeneChip® technology. Previous gene chip studies on aging have examined gene expression in the cortex and cerebellum (Lee et al., 2000). Microarray studies of the rodent hippocampus have focused on subregional expression within this structure (Zhao et al., 2001) and the effect of exercise on gene expression (Tong et al., 2001). A recent study has compared a small number of genes in the hippocampus of young (2 months) and old (20 months) rats (Cho et al., 2002). In the present study, we examined hippocampal mRNA from young (3 months), middle-aged (12 and 18 months) and old (24 months) male C57BL/6 mice. A range of ages was included to determine whether changes in gene expression that were observed occurred gradually or appeared abruptly at a specific time during the aging process. The results obtained in the basal aging experiments were further validated by intraperitoneal (i.p.) LPS administration at each of the four ages, a procedure known to increase expression of cytokines, including IL-1β in the hippocampus Dantzer et al., 1998, Laye et al., 1994.
Section snippets
Animals
Male C57BL/6 mice of ages 3, 12, 18 and 24 months were obtained from the National Institute on Aging rodent colonies. Mouse weights ranged between 27.4 and 42.2 g. Animals were maintained for 1 week before sacrifice in individual polycarbonate cages with Sani-Chip hardwood bedding. All mice had access to filtered, deionized and UV-treated water and food (Purina Certified Rodent Chow #5002) ad libitum. The cages were maintained at ambient temperature (21±2 °C) on a 12-h light/dark cycle with
Peripheral immunological parameters decrease with age
Two components of the peripheral immune response, the ability of splenic T cells to respond to the T cell mitogen, ConA, and splenic ratios of naive to memory T cells, have consistently been demonstrated to decline with age in the mouse (Miller, 1996). To demonstrate that mice used in the present study exhibited these expected decreases in peripheral immune responses, T cell proliferation and splenic ratios of naive to memory T cells were measured. Data are reported from one of two replicate
Discussion
In this study, gene expression was examined using the GeneChip® technology in the hippocampus of young (3 months), middle-aged (12 and 18 months) and old (24 months) mice, at basal levels and after stimulation with LPS, an immunological activator. Of the 12,488 gene elements on the GeneChip®, 128 elements or 1% of the gene elements showed age-related changes in all basal samples tested. After mice were stimulated with LPS, 78 gene elements (0.6%) showed age-related changes in all samples tested.
Acknowledgements
Research supported by NIH grants AG018188 to YRF and HL/MH59658 to TSK.
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