Brain Research 890 (2001) 137–146 www.elsevier.com / locate / bres Research report Increased chemokine gene expression during aging in the murine brain a,b, a b a * Lisa K. Felzien , Joe T. McDonald , Sheena M. Gleason , Nancy E.J. Berman , a Robert M. Klein a Department of Anatomy and Cell Biology, University of Kansas Medical Center, 3901 Rainbow Boulevard, KansasCity, KS 66160, USA b Department of Biology, Rockhurst University, 1100 Rockhurst Road, KansasCity, MO 64110, USA Accepted 25 October 2000 Abstract Normal aging results in changes in the brain that contribute to the decline of various functions, including learning and memory. Mechanisms causing this decline have not been clearly established. Activation of microglia is associated with the normal aging process in rodents and primates. Microglial activation is regulated by chemokine gene expression, and activated microglia produce substances that can be detrimental to surrounding cells. In this study we determined whether changes in chemokine expression occur during normal aging in the mouse brain. RNA samples taken from the cortex, midbrain, hippocampus, and cerebellum of 4-, 10-, 21- and 30-month-old C57BL6 / DBA2 mice were analyzed for changes in gene expression. RNase protection assays were used to examine a panel of chemokines. Increased expression of macrophage inflammatory protein (MIP)-1a, MIP-1b, and RANTES occurred in all four regions of the brains in the oldest mice. These increases were first detectable at 21 months of age. Increases in MIP-1a, MIP-1b, and RANTES protein levels were also detected in the brains of old mice, as measured by ELISA. Increased microglial activation in the brains of 30-month-old mice, as detected by immunohistochemistry using F4 / 80 antibodies, correlated with increases in chemokine expression. The observed increases in chemokine gene expression that occur in conjunction with increased microglial activation suggest that chemokines may contribute to the decreased brain function that occurs during normal aging.  2001 Elsevier Science B.V. All rights reserved. Theme: Development and regeneration Topic: Aging process Keywords: Chemokine; Microglia; Aging; Neuroimmune modulation 1. Introduction in Ref. [46]). Studies examining the functional changes in the brain during aging have also produced equivocal Alterations in brain function during normal aging result results. Some changes that have been reported include in a variety of measurable changes. These changes include diminished size of cortical neurons [14,15,59], reduced an overall decline in cognition and more specific effects, synaptic function [27,28], decreased glucocorticoid recep- including the reduction of short-term [35] and spatial tor expression [3], and decreased expression of NMDA memory [18]. The underlying mechanisms for decreased receptors in the cerebral cortex [26]. brain function have not been clearly elucidated. Studies More significant age-related changes have been demon- examining whether the number of neurons is altered during strated in the white matter of the brain. For example, both the aging process have produced equivocal results. Initial the volume of the white matter [12,14,46] and the amount observations suggested a significant loss of neurons; of myelin decrease during normal aging [19,22,46]. These however, more recent studies using unbiased stereological changes and associated responses may result from altered methods have shown fewer detectable changes (reviewed glial function [44,45]. Glia play an important role in the functional and morphological changes associated with normal aging. Glia *Corresponding author. Biology Department, Rockhurst University, mediate neuroimmune interactions, which are altered in 1100 Rockhurst Road, Kansas City, MO 64110, USA. Tel.: 11-816-501- older animals. Changes in glial function involved in 4046; fax: 11-816-501-4802. E-mail address: lisa.felzien@rockhurst.edu (L.K. Felzien). immune and inflammatory responses include alterations in 0006-8993 / 01 / $ – see front matter  2001 Elsevier Science B.V. All rights reserved. PII: S0006-8993(00)03090-0