Elsevier

Brain Research

Volume 1256, 23 February 2009, Pages 101-110
Brain Research

Research Report
Hippocampal gene expression changes during age-related cognitive decline

https://doi.org/10.1016/j.brainres.2008.12.039Get rights and content

Abstract

As humans age, cognitive performance decreases differentially across individuals. This age-related decline in otherwise healthy individuals is likely due to the interaction of multiple factors including genetics and environment. We hypothesized that altered spatial memory performance in genetically similar mice could be in part due to differential gene expression patterns in the hippocampus. To investigate this we utilized Morris water maze (MWM) testing in a group of young (3 months) and aged (24 months) C57BL/J male mice. Two sub-groups were identified in the aged animals; one in which MWM performance was not significantly different when compared to the young animals (aged-unimpaired; “AU”) and one in which performance was significantly different by 1.5 standard deviations from the mean (aged-impaired; “AI”). One week after testing was completed the entire hippocampus was collected from six each of AU, AI and young mice and their gene expression profiles were compared using Affymetrix microarrays. Benjamini and Hochberg FDR correction at p < 0.05 identified 18 genes differentially expressed between the AI and AU mice. The correlation between behavioral deficits and gene expression patterning allows a better understanding of how altered gene expression in the hippocampus contributes to accelerated age-related cognitive decline and delineates between gene expression changes associated with normal aging vs. memory performance.

Introduction

Brain aging leading to cognitive decline is a process that is not well understood. The hippocampus is integral to memory function and is a brain area greatly affected by aging. Some individuals have a greater loss of neuronal plasticity than others, leading to an accelerated deterioration of memory function as they age.

Numerous studies in rats (Blalock et al., 2003, Burger et al., 2007, Rowe et al., 2007, Burger et al., 2008) and mice (Verbitsky et al. 2004) have documented age-related memory impairment using the Morris water maze (MWM). Using microarrays, these studies have found significant changes in genes related to cholesterol synthesis, inflammation, transcription factors, neurogenesis and synaptic plasticity. A decline in memory performance utilizing the MWM from young to middle-aged to aged rats was observed by Blalock et al. with only changes between the young and aged rats reaching statistical significance. The gene expression profiling of the CA1 region of the hippocampus of these animals found genes involved in cell signaling, metabolism, transcription factors and neurite plasticity to be down-regulated in aged rats. Up-regulated in the aging animals were inflammation, growth, glial, signal transduction and protein vesicle genes. A similar study (Verbitsky et al. 2004) comparing young and middle-aged mice found a decline of memory function associated with aging based on MWM performance. The hippocampal gene expression results of this study found genes associated with inflammation, iron homeostasis, calcium dependent phospholipid binding and acetyl-CoA biosynthesis to be up-regulated in the middle aged animals.

Other studies have observed that some aged rats have a decline in spatial memory as measured by the MWM, while others perform as well as young animals. Microarray analysis of the hippocampal gene expression revealed significant differences between young, AU and AI animals that represent a variety of functions (Burger et al., 2007, Rowe et al., 2007, Burger et al., 2008). The study by Rowe found more genes associated with aging were differentially expressed than genes just associated with impairment. Both Burger and Rowe found that genes associated with neuron growth and cell morphology were down-regulated in aging animals.

Terao et al. (2002) examined the changes in hippocampal gene expression in 3, 12, 18 and 24 month old mice, both with and without immune system stimulation with lipopolysaccharide (LPS). They discovered that 128 genes were significantly differentially expressed with aging and 14 with immune system stimulation and aging. Eight of these genes overlapped, and all had immune system or antioxidant functions. This study found that most hippocampal gene expression age-related changes were increases in expression and a great number of these transcripts were associated with immune response.

In this study we have also observed gene expression changes in the hippocampus of animals who demonstrated memory impairment on the MWM when compared to their age-matched peers. This comparison was made by observing that some aged (24 months) animals performed as well as young (3 months) animals, while another group of aged animals were memory impaired compared to young animals. Microarray analysis revealed very few changes between young and aged-unimpaired (AU) animals, but found significant differences between memory unimpaired animals and aged-impaired animals (AI). We have the advantage of utilizing the most recent mouse expression arrays (Affymetrix 430) with more than 30,000 transcripts to allow us to further investigate subtle gene expression changes that may influence memory impairment. By using a robust statistical test, we were able to concentrate on a narrow list of 19 differentially expressed genes. This focused list allowed us to do a detailed pathway analysis that uncovered the role of heat shock 70 kDa protein 5 (Hspa5, also known as BiP or GRP78) and calreticulin (Calr) in the regulation of apolipoprotein B (Apob) and also the up-regulation of myelin oligodendrocyte glycoprotein (Mog). Mog has been observed to have demyelinating and inflammatory effects. We hypothesize that this combination of higher Apob, allowed by the down-regulation of Hspa5 and Calr, and higher expression of Mog causes inflammation and lipid changes that cause a subtle degradation in the hippocampus leading to memory impairment.

Section snippets

Maze learning

Mean swim times for the 10 spatial learning blocks are shown in Fig. 1. All groups showed improvement over the blocks. However, two-way ANOVA indicated a significant interaction between group and training block (F = 1.72, p = 0.03, as well as significant main effects of Group (F = 8.45, p = 0.0009) and training block (F = 2.94, p = 0.0001). Follow-up ANOVAs compared each of the aged groups to the young group individually. When AU were compared with the young group, there was not a significant interaction (F

Discussion

This study adds to previous works that have discussed age-related spatial memory deficits in rats and mice (Blalock et al., 2003, Verbitsky et al., 2004, Burger et al., 2007, Burger et al., 2008). Unique to our study is the utilization of a 39,000 probe chip and an age-matched group consisting of 24 month animals who demonstrated spatial memory performance on par with young mice versus 24 month mice with a clearly impaired spatial memory performance. The memory performance of AU animals

Animals

Male C57BL/6J Nia mice aged 23 and 2 months old were obtained from Charles River Laboratories. Behavioral assessments were begun 1 month after the arrival of the mice. They were housed individually in clear polypropylene cages in a temperature- and humidity-controlled room with an artificial 12 h:12 h light:dark cycle, lights on at 0700 h. Standard pelleted chow and water were freely available at all times.

Behavioral testing

Learning was conducted in a water maze, which consisted of a galvanized tank 122 cm in

Acknowledgments

The authors wish to recognize the support of the State of Arizona, Science Foundation Arizona, and the Arizona Alzheimer's Consortium.

References (44)

  • YamamotoN. et al.

    Role of Deltex-1 as a transcriptional regulator downstream of the Notch receptor

    J. Biol. Chem.

    (2001)
  • YangY. et al.

    The chaperone BiP/GRP78 binds to amyloid precursor protein and decreases Abeta40 and Abeta42 secretion

    J. Biol. Chem.

    (1998)
  • YangG.H. et al.

    Down-regulation of the endoplasmic reticulum chaperone GRP78/BiP by vomitoxin (Deoxynivalenol)

    Toxicol. Appl. Pharmacol.

    (2000)
  • YoshidaI. et al.

    Depletion of intracellular Ca2+ store itself may be a major factor in thapsigargin-induced ER stress and apoptosis in PC12 cells

    Neurochem. Int.

    (2006)
  • ZangX. et al.

    Homologues of human macrophage migration inhibitory factor from a parasitic nematode. Gene cloning, protein activity, and crystal structure

    J. Biol. Chem.

    (2002)
  • AuldG.C. et al.

    Identification of calcium-regulated heat-stable protein of 24 kDa (CRHSP24) as a physiological substrate for PKB and RSK using KESTREL

    Biochem. J.

    (2005)
  • Bereczki, E., Bernat, G., Csont, T., Ferdinandy, P., Scheich, H., Santha, M., 2008. Overexpression of human...
  • BlalockE.M. et al.

    Gene microarrays in hippocampal aging: statistical profiling identifies novel processes correlated with cognitive impairment

    J. Neurosci.

    (2003)
  • CaramelliP. et al.

    Increased apolipoprotein B serum concentration in Alzheimer's disease

    Acta Neurol. Scand.

    (1999)
  • DayM.L. et al.

    Phorbol ester-induced apoptosis is accompanied by NGFI-A and c-fos activation in androgen-sensitive prostate cancer cells

    Cell Growth Differ.

    (1994)
  • HoshinoT. et al.

    Endoplasmic reticulum chaperones inhibit the production of amyloid-beta peptides

    Biochem. J.

    (2007)
  • JinK. et al.

    Increased hippocampal neurogenesis in Alzheimer's disease

    Proc. Natl. Acad. Sci. U. S. A.

    (2004)
  • Cited by (0)

    View full text