Altered neuronal gene expression in brain regions differentially affected by Alzheimer's disease: a reference data set

Liang, Winnie S.; Dunckley, Travis; Beach, Thomas G.; Grover, Andrew; Mastroeni, Diego; Ramsey, Keri; Caselli, Richard J.; Kukull, Walter A.; McKeel, Daniel W.; Morris, John C.; Hulette, Christine M.; Schmechel, Donald E.; Reiman, Eric M.; Rogers, Joseph; Stephan, Dietrich A.

doi:10.1152/physiolgenomics.00242.2007

Cited by 256 publications

(272 citation statements)

References 139 publications

(137 reference statements)

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“…54. The proportion of significantly underexpressed ETC and translocase genes in each of the sampled brain regions (P Ͻ 0.01 after correction for multiple comparisons) is shown in Table 1.…”

Section: Resultsmentioning

confidence: 99%

“…(Findings from our survey of 55,000 neuronal transcripts have been published in ref. 54.) AD-related reductions in the posterior cingulate neuronal expression of several of the implicated complexes I-IV and ATP synthase (complex V) subunits were subsequently validated at the protein level, suggesting that the reductions in the neuronal expression of metabolically relevant nuclear genes might be associated with the CMRgl reductions found in fluorodeoxyglucose positron emission tomography (FDG PET) studies of AD.…”

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confidence: 95%

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

Liang

Reiman

Valla

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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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.gene expression ͉ Affymetrix microarrays ͉ laser capture micro-dissection A lzheimer's disease (AD) is associated with characteristic and progressive reductions in regional positron emission tomography (PET) measurements of the cerebral metabolic rate for glucose (CMRgl). These CMRgl reductions have been reported in the posterior cingulate, parietal, and temporal cortex, and in the frontal cortex and whole brain in more severely affected patients (1-5). Other studies have reported CMRgl reductions in anatomically well characterized hippocampal and entorhinal cortical regions of interest (6-10). The posterior cingulate cortex (PCC) and the neighboring precuneus are metabolically affected in the earliest clinical and preclinical stages of AD (4, 11), and the primary visual cortex is relatively spared (4, 11). In an ongoing series of studies, we have detected CMRgl reductions in cognitively normal carriers of the apolipoprotein E (APOE) 4 allele (11-15), a common late-onset AD susceptibility gene (16)(17)(18). CMRgl reductions in AD-affected areas were correlated with APOE 4 gene dose (i.e., three levels of genetic risk for AD) and were progressive in late-middle-aged persons (19). These reductions were also apparent in young adult APOE 4 heterozygotes (13), more than four decades before the anticipated median onset of dementia, years before the expected onset of the major histopa...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 95%

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

Liang

Reiman

Valla

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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493

405

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“…Gene set enrichment analysis. Associations of autophagy gene sets with AD were evaluated using GSEA (26) and gene expression data from laser-capture microdissected non-tangle-bearing neurons of 34 late-onset AD-afflicted individuals with a mean age at death of 79.9 ± 6.9 y and 14 neurologically normal healthy elderly controls (27) (GEO accession number GSE5281). Analysis of hit gene expression in aging.…”

Section: Methodsmentioning

confidence: 99%

Genome-wide analysis reveals mechanisms modulating autophagy in normal brain aging and in Alzheimer's disease

Lipinski

Zheng

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Dysregulation of autophagy, a cellular catabolic mechanism essential for degradation of misfolded proteins, has been implicated in multiple neurodegenerative diseases. However, the mechanisms that lead to the autophagy dysfunction are still not clear. Based on the results of a genome-wide screen, we show that reactive oxygen species (ROS) serve as common mediators upstream of the activation of the type III PI3 kinase, which is critical for the initiation of autophagy. Furthermore, ROS play an essential function in the induction of the type III PI3 kinase and autophagy in response to amyloid β peptide, the main pathogenic mediator of Alzheimer's disease (AD). However, lysosomal blockage also caused by Aβ is independent of ROS. In addition, we demonstrate that autophagy is transcriptionally down-regulated during normal aging in the human brain. Strikingly, in contrast to normal aging, we observe transcriptional upregulation of autophagy in the brains of AD patients, suggesting that there might be a compensatory regulation of autophagy. Interestingly, we show that an AD drug and an AD drug candidate have inhibitory effects on autophagy, raising the possibility that decreasing input into the lysosomal system may help to reduce cellular stress in AD. Finally, we provide a list of candidate drug targets that can be used to safely modulate levels of autophagy without causing cell death.reactive oxygen species | type III PI3 kinase | neurodegeneration | signaling | transcriptional regulation A utophagy, a lysosome-dependent catabolic process mediating turnover of cellular components, plays an important role in regulating cellular homeostasis in the nervous system (1). Even in the absence of any other risk factors, autophagy deficiency in the CNS has been shown to lead to the accumulation of protein aggregates and progressive neurodegeneration (2). Thus, autophagy has been established as an important mechanism mediating degradation of misfolded proteins in the CNS. Because accumulation of misfolded proteins is a common feature in multiple human neurodegenerative diseases, activation of autophagy has been proposed as a strategy for combating neurodegeneration (3). However, little is currently known about how defects in autophagy might be involved in specific neurodegenerative diseases. Furthermore, as induction of autophagy is frequently associated with cell death, it remains a challenge to identify molecular targets whose inhibition can specifically activate autophagy without compromising cell viability.Pathological evidence supports the involvement of autophagy dysfunction in neurodegenerative diseases in humans. In Alzheimer's disease (AD), one of the earliest pathological changes include accumulation of autophagic vesicles (AVs) specifically within damaged neuritic processes and synaptic terminals (4). This phenotype is also observed in AD animal models and in cellbased models upon exposure to amyloid β peptide (Aβ). However, the mechanisms leading to the accumulation of AVs and the causal relationship to neurodegener...

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“…This can be accomplished by interrogating a human neuron-specific interactome, using the MARINa algorithm as discussed in the previous section, with signatures of disease progression using gene expression profiles from normal and demented AD patients. We have tested this approach for its feasibility by generating a human neuronal interactome using transcriptional data generated from laser-dissected control, nondemented and AD human neurons from multiple regions of postmortem brains (GSE5281 and GSE9770) [50][51][52]. This interactome was then queried using gene expression profiles from AD and control tissues.…”

Section: Development Of a Quantitative Systems Pharmacology Approach mentioning

confidence: 99%

A Systems Approach to Drug Discovery in Alzheimer's Disease

et al. 2015

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In the articles included in this volume, one feels a strong frustration among the writers with the slow course of therapeutics development for Alzheimer's disease and with the clinical failure of targeted therapeutic agents despite substantial progress in our understanding of the biology and biochemistry of the disease. Keywords Master regulator . Interactome . Human neuronsTo date, approaches to Alzheimer disease (AD) therapeutics have followed 2 main avenues. The first addresses neurotransmitter deficits in the early phases of the disease. This approach has led to the handful of AD drugs currently on the market that provide short-term symptomatic improvement but do not alter the course of the disease. The second approach has been directed at decreasing the burden of beta-amyloid (Aβ) in the brain by active or passive immunization or by inhibiting activity of β-or γ-secretases. To date, none of the approaches in this second class has been successful, although trials on β-or γ-secretase (BACE) inhibitors are ongoing.The lack of overt success has been even more frustrating because, in transgenic (Aβ-overproducing) mouse models of AD, Aβ-lowering approaches, as well as treatments with small molecules and biologics, have been successful in blocking memory loss, restoring memory function, reversing dendritic spine alterations, and reversing inhibition of longterm potentiation [1][2][3]. Indeed, as animal models only partially recapitulate the human AD phenotype and because human brain tissue is available only postmortem, translation of preclinical findings to the clinics has been fraught with difficulties.For instance, the characteristic intraneuronal neurofibrillary tangles and extensive neuronal loss observed in human AD are absent in mouse models of the disease. This dichotomy suggests that mouse models replicate only presymptomatic AD stages, while clinical manifestations appear only after neuronal loss becomes irreversible. This hypothesis is directly addressed by ongoing trials, where individuals with genetic mutations that predispose to early AD onset are being treated with Aβ-targeted therapies to assess whether presymptomatic treatment may block an otherwise certain disease progression. Beyond Aβ-targeted therapies, novel approaches are being developed based on inhibition of tau phosphorylation and aggregation, and on blockade of synaptic loss, leveraging "candidate" target approaches derived from human and animal data. Unfortunately, it has so far been impossible to discern whether "candidate genes" represent causal determinants of the disease process or are the downstream result of them.In this review, we will discuss the potential of adapting integrative systems biology approaches that have already proven extremely valuable in understanding multiple cancer related phenotypes to human neurodegenerative diseases.

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Altered neuronal gene expression in brain regions differentially affected by Alzheimer's disease: a reference data set

Cited by 256 publications

References 139 publications

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

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

Genome-wide analysis reveals mechanisms modulating autophagy in normal brain aging and in Alzheimer's disease

A Systems Approach to Drug Discovery in Alzheimer's Disease

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