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Alzheimer's Disease Is Associated With Alzheimer’s disease is associated with reduced expression of energy metabolism genes in posterior cingulate neurons Winnie S. Liang*†, Eric M. Reiman*†‡§, Jon Valla†¶, Travis Dunckley*†, Thomas G. Beach†ʈ, Andrew Grover†ʈ, Tracey L. Niedzielko†¶, Lonnie E. Schneider†¶, Diego Mastroeni†ʈ, Richard Caselli†**, Walter Kukull††, John C. Morris‡‡, Christine M. Hulette§§, Donald Schmechel§§, Joseph Rogers†ʈ, and Dietrich A. Stephan*†¶¶ *Neurogenomics Division, Translational Genomics Research Institute, 445 North Fifth Street, Phoenix, AZ 85004; †Arizona Alzheimer’s Consortium, 901 East Willetta Street, Phoenix, AZ 85006; ‡Banner Alzheimer’s Institute, 901 East Willetta Street Phoenix, AZ 85006; §Department of Psychiatry and Evelyn F. McKnight Brain Institute, University of Arizona, 1501 North Campbell Avenue, Tucson, AZ 85724; ¶Barrow Neurological Institute, 350 West Thomas Road, Phoenix, AZ 85013; ʈSun Health Research Institute, 10515 West Santa Fe Drive, Sun City, AZ 85351; **Department of Neurology, Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, AZ 85259; ††National Alzheimer’s Coordinating Center, 4311 11th Avenue NE, No. 300, Seattle, WA 98105; ‡‡Washington University Alzheimer’s Disease Research Center, Washington University School of Medicine, 4488 Forest Park Avenue, Suite 101, St. Louis, MO 63108; and §§Bryan Alzheimer’s Disease Research Center, Duke University Medical Center, 2200 West Main Street, Suite A200, Durham, NC 27705 Edited by Marcus E. Raichle, Washington University School of Medicine, St. Louis, MO, and approved January 15, 2008 (received for review September 28, 2007) Alzheimer’s disease (AD) is associated with regional reductions in of genetic risk for AD) and were progressive in late-middle-aged fluorodeoxyglucose positron emission tomography (FDG PET) mea- persons (19). These reductions were also apparent in young adult surements of the cerebral metabolic rate for glucose, which may APOE ␧4 heterozygotes (13), more than four decades before the begin long before the onset of histopathological or clinical fea- anticipated median onset of dementia, years before the expected tures, especially in carriers of a common AD susceptibility gene. onset of the major histopathological features of AD (neurofi- Molecular evaluation of cells from metabolically affected brain brillary tangles and amyloid plaques), and, indeed, in anticipat- regions could provide new information about the pathogenesis of ing the initial regional appearance of fibrillar amyloid deposi- AD and new targets at which to aim disease-slowing and preven- tion. (20, 21). tion therapies. Data from a genome-wide transcriptomic study AD-related CMRgl reductions could reflect reductions in the were used to compare the expression of 80 metabolically relevant density or activity of terminal neuronal fields or peri-synaptic nuclear genes from laser-capture microdissected non-tangle-bear- glial cells (22, 23), a metabolic dysfunction in neurons or glial ing neurons from autopsy brains of AD cases and normal controls cells not related to neuronal activity (24, 25), or a combination in posterior cingulate cortex, which is metabolically affected in the of these factors. These changes do not appear to be solely earliest stages; other brain regions metabolically affected in PET attributable to the combined effects of atrophy and partial- studies of AD or normal aging; and visual cortex, which is relatively volume averaging (26). In a postmortem histochemistry study, spared. Compared with controls, AD cases had significantly lower we previously found that AD cases had lower cytochrome c expression of 70% of the nuclear genes encoding subunits of the oxidase activity than controls in the PCC, and that this reduction mitochondrial electron transport chain in posterior cingulate cor- was significantly greater than that in primary motor cortex (27), tex, 65% of those in the middle temporal gyrus, 61% of those in another region that is relatively spared. Based on this observa- hippocampal CA1, 23% of those in entorhinal cortex, 16% of those tion, we proposed that AD might be related to an impairment in in visual cortex, and 5% of those in the superior frontal gyrus. neuronal metabolism. Western blots confirmed underexpression of those complex I–V Molecular evaluation of the cells from metabolically affected subunits assessed at the protein level. Cerebral metabolic rate for brain regions could provide new information about the patho- glucose abnormalities in FDG PET studies of AD may be associated genesis of AD and new targets at which to aim disease-slowing with reduced neuronal expression of nuclear genes encoding and prevention therapies. Data from a genome-wide transcrip- subunits of the mitochondrial electron transport chain. tomic study were used to compare, in each of our sampled brain regions, the expression of metabolically relevant nuclear genes gene expression ͉ Affymetrix microarrays ͉ laser capture micro-dissection from laser-capture microdissected non-tangle-bearing neurons of expired cases with clinically characterized and histopatholog- lzheimer’s disease (AD) is associated with characteristic ically verified AD and expired controls who did meet clinical NEUROSCIENCE Aand progressive reductions in regional positron emission criteria for dementia and histopathological criteria for AD. tomography (PET) measurements of the cerebral metabolic rate In particular, the data were used to compare cases and for glucose (CMRgl). These CMRgl reductions have been controls in the expression of 80 nuclear genes encoding mito- reported in the posterior cingulate, parietal, and temporal chondrial electron transport chain (ETC) subunits along with cortex, and in the frontal cortex and whole brain in more severely translocases of the inner and outer mitochondrial membranes affected patients (1–5). Other studies have reported CMRgl reductions in anatomically well characterized hippocampal and Author contributions: D.A.S. designed research; W.S.L., J.V., T.D., T.G.B., T.L.N., and L.E.S. entorhinal cortical regions of interest (6–10). The posterior performed research; A.G., D.M., R.C., W.K., J.C.M., C.M.H., D.S., and J.R. contributed new cingulate cortex (PCC) and the neighboring precuneus are reagents/analytic tools; W.S.L. and J.V. analyzed data; and W.S.L., E.M.R., and J.V. wrote the metabolically affected in the earliest clinical and preclinical paper. stages of AD (4, 11), and the primary visual cortex is relatively The authors declare no conflict of interest. spared (4, 11). In an ongoing series of studies, we have detected This article is a PNAS Direct Submission. CMRgl reductions in cognitively normal carriers of the apoli- Data deposition: The data reported in this paper have been deposited in the Gene poprotein E (APOE) ␧4 allele (11–15), a common late-onset AD Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE5281). susceptibility gene (16–18). CMRgl reductions in AD-affected ¶¶To whom correspondence should be addressed at the * address. E-mail: [email protected]. areas were correlated with APOE ␧4 gene dose (i.e., three levels © 2008 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0709259105 PNAS ͉ March 18, 2008 ͉ vol. 105 ͉ no. 11 ͉ 4441–4446 Fig. 1. Altered expression of mitochondrial energy metabolism elements. Energy metabolism-relevant elements showing statistically significant underex- pression in the PCC are shown. These elements include the five complexes of the ETC and TIMMs and TOMMs. OM, outer mitochondrial membrane; IMS, intermembrane space; IM, inner mitochondrial membrane. (TIMMs and TOMMs, respectively), in six brain regions. These orodeoxyglucose positron emission tomography (FDG PET) nuclear genes included 39 complex I genes coding for NADH studies of AD. dehydrogenase, all 4 nuclear-encoded complex II genes coding for succinate dehydrogenase, 9 complex III genes coding for Results ubiquinol-cytochrome c reductase, 13 complex IV genes coding Fold change values and P values for the 80 ETC and translocase for cytochrome c oxidase, and 15 complex V genes coding for genes in each of the sampled regions are posted at www.tgen.org/ ATP synthase, as well as 11 TIMMs and 6 TOMMs, which neurogenomics/pcc, and additional expression results have been regulate the transport of nuclear-encoded electron transport reported in ref. 54. The proportion of significantly underex- subunits into the mitochondria. These ETC complexes and pressed ETC and translocase genes in each of the sampled brain translocases are illustrated in Fig. 1. The six brain regions regions (P Ͻ 0.01 after correction for multiple comparisons) is included the PCC, which is associated with unusually early shown in Table 1. In comparison with controls, AD cases had CMRgl reductions in AD (4, 28); the middle temporal gyrus significantly lower expression of 70% of the nuclear genes (MTG); the hippocampal field CA1 (HIP) and entorhinal cortex encoding mitochondrial ETC subunits in PCC pyramidal neu- (EC), which are also metabolically affected in AD (1, 20); the rons, 65% of those in MTG neurons, 61% in HIP neurons, 23% superior frontal gyrus (SFG), which is associated with prefer- in EC layer II stellate neurons, 16% in VC neurons, and 5% in ential CMRgl reductions in normal aging (29–33); and the SFG neurons. By comparison, AD cases had significantly higher primary visual cortex (VC), which is relatively spared from expression of only 4% of the nuclear genes encoding mitochon- CMRgl reductions in both aging and AD (4, 11). drial ETC subunits in PCC pyramidal neurons, 13% of those in We initially tested the hypothesis that AD would be associated MTG neurons, 8% of HIP neurons, 1% of EC neurons, 4% of with reduced neuronal expression of metabolically relevant VC neurons, and 0% of SFG neurons (data for these genes are nuclear genes in the PCC and that these AD-related reductions listed on the supplementary data site). Additional factors that would be significantly greater than those in VC. (Findings from displayed statistically significant underexpression in the PCC, our survey of 55,000 neuronal transcripts have been published in and which may influence mitochondrial energy metabolism, ref.
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