Microarray analyses of laser-captured hippocampus reveal distinct gray and white matter signatures associated with incipient Alzheimer's disease

Eric M. Blalock, Heather M. Buechel, Jelena Popovic, James W. Geddes, Philip W. Landfield

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158 Scopus citations


Alzheimer's disease (AD) is a devastating neurodegenerative disorder that threatens to reach epidemic proportions as our population ages. Although much research has examined molecular pathways associated with AD, relatively few such studies have focused on the disease's critical early stages. In a prior microarray study we correlated gene expression in hippocampus with degree of Alzheimer's disease and found close associations between upregulation of apparent glial transcription factor/epigenetic/tumor suppressor genes and incipient AD. The results suggested a new model in which AD pathology spreads along myelinated axons (Blalock et al., 2004). However, the microarray analyses were performed on RNA extracted from frozen hand-dissected hippocampal CA1 tissue blocks containing both gray and white matter, limiting the confidence with which transcriptional changes in gray matter could be distinguished from those in white matter. Here, we used laser capture microdissection (LCM) to exclude major white matter tracts while selectively collecting CA1 hippocampal gray matter from formalin-fixed, paraffin-embedded (FFPE) hippocampal sections of the same subjects assessed in our prior study. Microarray analyses of this gray matter-enriched tissue revealed many transcriptional changes similar to those seen in our past study and in studies by others, particularly for downregulated neuron-related genes. Additionally, the present analyses identified several previously undetected pathway alterations, including downregulation of molecules that stabilize ryanodine receptor Ca2+ release and upregulation of vasculature development. Conversely, we found a striking paucity of the upregulated changes in the putative glial and growth-related genes that had been strongly overrepresented in the prior mixed-tissue study. We conclude that FFPE tissue can be a reliable resource for microarray studies of brain tissue, that upregulation of growth-related epigenetic/transcription factors during incipient AD is predominantly localized in and around white matter (supporting our prior findings and model), and that novel alterations in vascular and ryanodine receptor-related pathways in gray matter are closely associated with incipient AD.

Original languageEnglish
Pages (from-to)118-126
Number of pages9
JournalJournal of Chemical Neuroanatomy
Issue number2
StatePublished - Oct 2011

Bibliographical note

Funding Information:
We thank Sonya Anderson and Ela Patel from the Sanders-Brown Center on Aging for sectioning and mounting hippocampal specimens, Jeff Gilbert and Zeiss Microscopy, as well as Woods Hole Research Center for generously allowing us to use their Zeiss PALM Microbeam system, Anjali Chhabra for performing RNA isolation and amplification protocols, and Dr. Kuey Chu Chen and Donna Wall of the University of Kentucky Microarray Core Facility for microarray hybridization and scanning. This work was supported in part by Grants from the University of Kentucky Alzheimer's Disease Center ( AG028383 ) and the NIH Research Resources Center ( S10RR024704 ) (to E.M.B.), and by Grants AG034605 , AG004542 and P01AG010836 from the National Institute on Aging (to P.W.L.).


  • Aging
  • Cognitive impairment
  • Glia
  • Myelin
  • Neurodegeneration
  • Neurofibrillary tangles

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience


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