Transcriptional vulnerability of brain regions in Alzheimer's disease and dementia☆
Introduction
Significant progress has been made in understanding neuropathological, neuroanatomical, neurochemical and molecular biological abnormalities in the brains of persons with Alzheimer's disease (AD) (Hardy, 2006, Roberson and Mucke, 2006, Terry, 2006). An inherent feature of many neurobiological studies has been the identification of brain regions, cortical laminae and specific cell types that are particularly vulnerable in AD and in dementia (Bussiere et al., 2003, Morrison et al., 2005, Von Gunten et al., 2005). For example, landmark studies by Braak and Braak (Braak et al., 2002, Braak and Braak, 1991, Braak and Braak, 1997) have outlined the progression of neuritic plaque (NP) and neurofibrillary tangle (NFT) pathology; neuroanatomical studies have identified the susceptibility of specific brain regions and neurons in specific cerebral cortical laminae (Braak et al., 2002, Giannakopoulos et al., 2003, Von Gunten et al., 2005), studies of neurochemical abnormalities have pointed to the vulnerability of neurotransmitter and neuropeptide systems (Haroutunian and Davis, 2003), while other studies have attempted to place neuropathological, molecular biological and neurochemical systems within the framework of the progression of the dementia symptoms of AD (Davis et al., 1999b, Davis et al., 1999c, Haroutunian et al., 1998, Haroutunian et al., 1999, Haroutunian et al., 2006, Haroutunian and Davis, 2003, Masliah et al., 1993, Morris et al., 2001, Naslund et al., 2000, Parvathy et al., 2001, Price et al., 2001, Terry, 2006, Uboga and Price, 2000).
The advent of high throughput gene expression technologies has raised our capacities by permitting the study of the expression level of multiple genes simultaneously and defining AD-associated changes in numerous molecular biological systems (Blalock et al., 2004, Blalock et al., 2005, Emilsson et al., 2006, Ginsberg et al., 2000, Ginsberg et al., 2004, Ginsberg et al., 2006, Loring et al., 2001, Parachikova et al., 2006, Pasinetti, 2001, Ricciarelli et al., 2004, Xu et al., 2006, Yao et al., 2003). In addition, microarray techniques have been combined with micro-dissection capabilities to hone in on gene expression abnormalities in discrete neurons and in brain regions known to be affected by AD neuropathology (Ginsberg et al., 2000, Ginsberg et al., 2004, Ginsberg et al., 2006). Despite the breadth of our current technical abilities and understanding of transcriptional abnormalities in AD, most of the studies cited above have approached the question of abnormal gene expression in AD by examining gene expression in a limited number of brain regions and/or at specific neuropathologically or cognitively distinct stages of the disease. Thus, an understanding of the extent and distribution of gene expression abnormalities free from pre-conceived expectations based on the extent and distribution of specific neuropathologic features remains elusive.
The classical neuropathological studies of AD and studies of dementia defined the progression of disease in terms of selected neuropathological lesions in different brain region or the progressive deterioration of different cognitive functions and domains such as memory and executive function (Rapp et al., 2005, Stern et al., 1996). The molecular biological and gene expression counterparts of these progressive changes are obscure, however. It is of interest to learn how the progression of dementia or each of the different hallmark neuropathological lesions of AD such as NPs or NFTs is associated with gene expression within the brain. In addition, it is important to our understanding of the disease process to ascertain how faithfully gene expression changes in different brain regions reflect the different stages of AD, whether disease stage is defined by different neuropathological criteria or by functional and cognitive criteria.
The current study aimed to determine the topography of transcriptional abnormalities in the brain of persons at different stages of AD and dementia. The approach was based on large-scale gene expression profiling in 15 different brain regions of a large and varied enough cohort of cases (N = 53) as to permit case stratification using different schemas for neuropathological and cognitive staging of AD. Transcriptional vulnerability was operationally defined as the number of genes that were abnormally expressed in different brain regions at different stages of AD. The study cohort was specifically selected to represent persons who died at different stages of dementia and with different densities of NFTs and NPs in diagnostically relevant (CERAD-defined; Mirra et al., 1991) brain regions. The gene expression data was then assembled to permit stratification of cases along (a) the dementia dimension as defined by clinical dementia rating (CDR) (Dooneief et al., 1996, Morris, 1993) scores at the time of death; (b) by emphasis on the distribution of NFT pathology using Braak neuropathology staging (Braak and Braak, 1991); and (c) by grouping of cases based on mean density of neuritic plaques in the cerebral cortex. Confounds associated with comorbid neuropathology such as significant cerebrovascular disease or Lewy body lesions were avoided by the selection of cases who had either no significant neuropathology or only those neuropathological lesions that are associated with AD. Additionally, close control was exercised over key variables such as age at death and brain tissue pH by maintaining them within a narrow range so that they were not statistically different from each other irrespective of the three group stratification strategies employed in the data analyses.
Section snippets
General
Brain tissue specimens were derived from the Mount Sinai School of Medicine Alzheimer's disease and Dementia Brain Bank. The precise tissue handling procedures have been described in detail (Davis et al., 1999a, Haroutunian et al., 1998, Haroutunian et al., 1999, Haroutunian et al., 2006). Tissue donors were subjects who had been residents of the Jewish Home and Hospital in Manhattan and the Bronx, NY and were participants in a longitudinal study of aging and dementia. All neuropsychological,
Results
Comparison of the MAS 5.0 normalization with GX™-based differential gene expression discovery versus RMA normalization with Benjamini and Hochberg corrected-CGEM-based differential gene expression discovery showed that although the two procedures differed with respect to the absolute number of differentially expressed genes identified (e.g., the total number of genes that were found to be up or down regulated in the CDR 0.5 group was 127 and 175 using MAS 5.0 and RMA normalization,
Discussion
Microarray analyses of gene expression in the human brain generate enormous data sets even when the analyses are limited to a single brain region and to comparisons between two groups. The wealth of information generated by multi-regional comparisons of multiple groups varying across multiple classification dimensions becomes extraordinarily complex and requires analysis of discreet questions and tests of well-defined hypotheses. The results reported here are of course subject to all the
Conflict of interest
The authors have no actual or potential conflicts of interest.
Acknowledgement
Supported by AG02219 (VH).
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Although we are unable at this time to publish the entire array data set, we are committed to sharing the gene expression data broadly with our academic colleagues. We will be happy to collaborate with interested investigators and to interrogate the data set for the expression levels of genes of interest.