QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, February 11, 2009, 29(6):1805-1816; doi:10.1523/JNEUROSCI.4599-08.2009

This Article Full Text Full Text (PDF) Supplemental Data Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Related articles in J. Neurosci. Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Kadish, I. Articles by Landfield, P. W. Search for Related Content PubMed PubMed Citation Articles by Kadish, I. Articles by Landfield, P. W. Pubmed/NCBI databases GEO DataSet Compound via MeSH Substance via MeSH Hazardous Substances DB CHOLESTEROL Medline Plus Health Information Memory Seniors' Health

 Previous Article  |  Next Article 

Behavioral/Systems/Cognitive
Hippocampal and Cognitive Aging across the Lifespan: A Bioenergetic Shift Precedes and Increased Cholesterol Trafficking Parallels Memory Impairment

Inga Kadish,^1 * Olivier Thibault,^2 * Eric M. Blalock,^2 * Kuey-C. Chen,² John C. Gant,² Nada M. Porter,² and Philip W. Landfield²

¹Department of Cell Biology, University of Alabama, Birmingham, Alabama 35294, and ²Department of Molecular and Biomedical Pharmacology, University of Kentucky College of Medicine, Lexington, Kentucky 40536

Correspondence should be addressed to Dr. Philip W. Landfield, Department of Molecular and Biomedical Pharmacology, University of Kentucky College of Medicine, 800 Rose Street, MS 310, Lexington, KY 40536. Email: pwland{at}uky.edu

Multiple hippocampal processes and cognitive functions change with aging or Alzheimer's disease, but the potential triggers of these aging cascades are not well understood. Here, we quantified hippocampal expression profiles and behavior across the adult lifespan to identify early aging changes and changes that coincide with subsequent onset of cognitive impairment. Well powered microarray analyses (N = 49 arrays), immunohistochemistry, and Morris spatial maze learning were used to study male F344 rats at five age points. Genes that changed with aging (by ANOVA) were assigned to one of four onset age ranges based on template pattern matching; functional pathways represented by these genes were identified statistically (Gene Ontology). In the earliest onset age range (3–6 months old), upregulation began for genes in lipid/protein catabolic and lysosomal pathways, indicating a shift in metabolic substrates, whereas downregulation began for lipid synthesis, GTP/ATP-dependent signaling, and neural development genes. By 6–9 months of age, upregulation of immune/inflammatory cytokines was pronounced. Cognitive impairment first appeared in the midlife range (9–12 months) and coincided and correlated primarily with midlife upregulation of genes associated with cholesterol trafficking (apolipoprotein E), myelinogenic, and proteolytic/major histocompatibility complex antigen-presenting pathways. Immunolabeling revealed that cholesterol trafficking proteins were substantially increased in astrocytes and that myelination increased with aging. Together, our data suggest a novel sequential model in which an early-adult metabolic shift, favoring lipid/ketone body oxidation, triggers inflammatory degradation of myelin and resultant excess cholesterol that, by midlife, activates cholesterol transport from astrocytes to remyelinating oligodendrocytes. These processes may damage structure and compete with neuronal pathways for bioenergetic resources, thereby impairing cognitive function.

Key words: spatial learning; brain aging; Alzheimer's; cholesterol; inflammation; myelination

---

Received Sept. 17, 2008; revised Jan. 7, 2009; accepted Jan. 8, 2009.

Correspondence should be addressed to Dr. Philip W. Landfield, Department of Molecular and Biomedical Pharmacology, University of Kentucky College of Medicine, 800 Rose Street, MS 310, Lexington, KY 40536. Email: pwland{at}uky.edu

Related articles in J. Neurosci.:

This Week in The Journal

J. Neurosci. 2009 29: i. [Full Text]  

This article has been cited by other articles:

				C. C. Kaczorowski and J. F. Disterhoft Memory deficits are associated with impaired ability to modulate neuronal excitability in middle-aged mice Learn. Mem., May 23, 2009; 16(6): 362 - 366. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help