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. 2008 Mar 18;105(11):4441-6.
doi: 10.1073/pnas.0709259105. Epub 2008 Mar 10.

Alzheimer's disease is associated with reduced expression of energy metabolism genes in posterior cingulate neurons

Winnie S Liang  1 , Eric M Reiman, Jon Valla, Travis Dunckley, Thomas G Beach, Andrew Grover, Tracey L Niedzielko, Lonnie E Schneider, Diego Mastroeni, Richard Caselli, Walter Kukull, John C Morris, Christine M Hulette, Donald Schmechel, Joseph Rogers, Dietrich A Stephan
Affiliations

Alzheimer's disease is associated with reduced expression of energy metabolism genes in posterior cingulate neurons

Winnie S Liang et al. Proc Natl Acad Sci U S A. .

Abstract

Alzheimer's disease (AD) is associated with regional reductions in fluorodeoxyglucose positron emission tomography (FDG PET) measurements of the cerebral metabolic rate for glucose, which may begin long before the onset of histopathological or clinical features, especially in carriers of a common AD susceptibility gene. Molecular evaluation of cells from metabolically affected brain regions could provide new information about the pathogenesis of AD and new targets at which to aim disease-slowing and prevention therapies. Data from a genome-wide transcriptomic study were used to compare the expression of 80 metabolically relevant nuclear genes from laser-capture microdissected non-tangle-bearing neurons from autopsy brains of AD cases and normal controls in posterior cingulate cortex, which is metabolically affected in the earliest stages; other brain regions metabolically affected in PET studies of AD or normal aging; and visual cortex, which is relatively spared. Compared with controls, AD cases had significantly lower expression of 70% of the nuclear genes encoding subunits of the mitochondrial electron transport chain in posterior cingulate cortex, 65% of those in the middle temporal gyrus, 61% of those in hippocampal CA1, 23% of those in entorhinal cortex, 16% of those in visual cortex, and 5% of those in the superior frontal gyrus. Western blots confirmed underexpression of those complex I-V subunits assessed at the protein level. Cerebral metabolic rate for glucose abnormalities in FDG PET studies of AD may be associated with reduced neuronal expression of nuclear genes encoding subunits of the mitochondrial electron transport chain.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Altered expression of mitochondrial energy metabolism elements. Energy metabolism-relevant elements showing statistically significant underexpression 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.
Fig. 2.
Fig. 2.
Western blot validation. (A) Western blots using a five-antibody mixture labeling a subunit of each mitochondrial enzyme complex from PCC whole-brain extract. H, human heart for positive control; AD, Alzheimer's patient; NC, normal control. Apparent molecular mass scale is indicated on the right. From highest to lowest are complex V alpha subunit, complex III core 2 subunit, complex II 30-kDa subunit, complex IV subunit II, and complex I 20-kDA subunit. Results are representative of duplicate blots. (B) Western blot-band optical density, expressed as percentage of normal-aged control. Subunit protein expression was significantly lower (two-tailed t test, P < 0.01) for each subunit tested. n = 10 AD; n = 5 NC.
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