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

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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Available from: Walter A Kukull, Sep 26, 2015
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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.
    Journal of Alzheimer's disease: JAD 02/2015; 45(4). DOI:10.3233/JAD-142937 · 4.15 Impact Factor
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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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    ABSTRACT: Two major genotypes are known to affect the development and progression of Alzheimer's disease (AD) and its response to cholinesterase inhibitors: the apolipoprotein E (ApoE) and butyrylcholinesterase genes (BChE). This study analyzed the effects of the BChE and ApoE genotypes on the cortical thickness of patients with AD and examined how these genotypes affect the neuropsychiatric symptoms of AD. AD-drug-naïve patients who met the probable AD criteria proposed by the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association were recruited. Of 96 patients with AD, 65 were eligible for cortical thickness analysis. 3D T1-weighted images were acquired, and the cortical regions were segmented using the constrained Laplacian-based automated segmentation with proximities (CLASP) algorithm. Neuropsychiatric symptoms were measured by Neuropsychiatric Inventory (NPI) scores. BChE wild-type carriers (BChE-W) showed more thinning in the left dorsolateral prefrontal cortex, including the lateral premotor regions and anterior cingulate cortex, than did BChE-K variant carriers (BChE-K). ApoE-ε4 carriers had a thinner left medial prefrontal cortex, left superior frontal cortex, and left posterior cingulate cortex than did ApoE-ε4 non-carriers. Statistical analyses revealed that BChE-K carriers showed significantly less severe aberrant motor behavioral symptoms and that ε4 non-carriers showed less severe anxiety and indifference symptoms.The current findings show that, similar to ApoE-ε4 non-carriers, BChE-K carriers are protected from the pathological detriments of AD that affect frontal cortical thickness and neuropsychiatric symptoms. This study visually demonstrated the effects of the BChE-K and ApoE genotypes on the structural degeneration and complex aspects of the symptoms of AD.
    Current Alzheimer research 01/2014; 11(2). DOI:10.2174/1567205011666140130152114 · 3.89 Impact Factor
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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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    ABSTRACT: A popular, if not centric, approach to the study of an event is to first consider that of the simplest cause. When dissecting the underlying mechanisms governing idiopathic diseases, this generally takes the form of an ab initio genetic approach. To date, this genetic 'smoking gun' has remained elusive in diabetes mellitus and for many affected by neurodegenerative diseases. With no single gene, or even subset of genes, conclusively causative in all cases, other approaches to the etiology and treatment of these diseases seem reasonable, including the correlation of a systems' predisposed sensitivity to particular influence. In the cases of diabetes mellitus and neurodegenerative diseases, overlapping themes of mitochondrial influence or dysfunction and iron dyshomeostasis are apparent and relatively consistent. This mini-review discusses the influence of mitochondrial function and iron homeostasis on diabetes mellitus and neurodegenerative disease, namely Alzheimer's disease. Also discussed is the incidence of diabetes accompanied by neuropathy and neurodegeneration along with neurodegenerative disorders prone to development of diabetes. Mouse models containing multiple facets of this overlap are also described alongside current molecular trends attributed to both diseases. As a way of approaching the idiopathic and complex nature of these diseases we are proposing the consideration of a MIND (mitochondria, iron, neurodegeneration, and diabetes) paradigm in which systemic metabolic influence, iron homeostasis, and respective genetic backgrounds play a central role in the development of disease.
    Biochemical pharmacology 12/2013; 88(4). DOI:10.1016/j.bcp.2013.11.022 · 5.01 Impact Factor
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