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

Neurogenomics Division, Translational Genomics Research Institute, 445 North Fifth Street, Phoenix, AZ 85004, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 04/2008; 105(11):4441-6. DOI: 10.1073/pnas.0709259105
Source: PubMed


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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Available from: Walter A Kukull
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    • "For the latter , it would be necessary to find an approach that would preserve RNA quality while allowing detection of neurofibrillary tangles. Potentially, fluorescent staining with Thioflavin-S could allow such an analysis , as was done by Liang et al. [26] [28] [29]. "
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    ABSTRACT: Causes of initiation and progression of sporadic Alzheimer's disease (sAD) are likely multiple and include impairment of mitochondrial bioenergetics. We analyzed RNA expression levels of multiple mitochondrial oxidative phosphorylation (OXPHOS) and biogenesis (mitobiogenesis) genes in unfixed hippocampal (WH) frozen sections (10 sAD; 9 CTL) and laser-captured hippocampal pyramidal neurons (PyNs, ~1000 neurons from each case) from 8 sAD and 7 CTL cases. Nuclear-encoded OXPHOS genes in WH were significantly increased in sAD, whereas in isolated sAD PyNs, these same genes were significantly decreased. Mitochondrial DNA-encoded genes were increased in sAD PyNs but showed a non-significant downward trend in sAD WH. Relationships among WH and PyN gene expression levels in sAD distributed in a different population compared to CTL. Principal component analysis (PCA) revealed clustering of CTL but widespread heterogeneity of sAD samples. In sAD, mitochondrial bioenergetics at the gene expression level are depressed in vulnerable PyNs. PCA revealed that CTL samples clustered together, whereas sAD samples varied widely. From the perspective of OXPHOS bioenergetics, sAD is a heterogeneous syndrome and not likely due to a single abnormality. Increased stimulation of nuclear-encoded OXPHOS gene expression in PyNs is a rational therapeutic approach for most but not all cases of sAD.
    Full-text · Article · Feb 2015 · Journal of Alzheimer's disease: JAD
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    • "Left medial prefrontal cortex showed partial dosedependent correlation to 4 alleles (Fig. 3-B), although the regionally averaged values did not show significance (Table 3). Left posterior cingulate cortex is previously reported to be most afflicted by AD pathologies and the more rapid structural decline caused by ApoE-4 alleles [3] [11] [41]. "
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    Full-text · Article · Jan 2014 · Current Alzheimer research
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    • "Interestingly, evidence outlining metabolic brain abnormalities in young and old ApoEe4 carriers alike suggests that metabolic decline, mitochondrial dysfunction, and eventual hypometabolism are critical risk factors in the development of ApoEe4 associated LOAD [81] [82] [83] [84] [85] [86] [87] [88]. Less robust cognitive test performance in individuals harboring the allele can be observed in middle adulthood [89]. "
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