Integrating Gene and Protein Expression Reveals Perturbed Functional Networks in Alzheimer’s Disease

Canchi, Saranya; Raao, Balaji; Masliah, Deborah; Rosenthal, Sara Brin; Šášik, Roman; Fisch, Kathleen M.; Jager, Philip L. De; Bennett, David A.; Rissman, Robert A.

doi:10.1016/j.celrep.2019.06.073

Cited by 73 publications

(76 citation statements)

References 97 publications

(177 reference statements)

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“…Further investigation on the interaction among GSK3beta\tau\OCIAD1, and its other regulators (e.g., b-catenin, p53) in cell models, or postmortem brain of AD patients at different disease stages would help determine whether Ab-GSK3-OCIAD1 axis exists in vivo and its relationship to tauopathy under pathological context of AD. The lower OCIAD1 level in the frontal lobe of AD patients is not a surprise as it is consistent with other reports [76]. Although the mechanism of lower OCIAD1 in the frontal lobe is unknown, poor correlation between mRNA level and protein product of a gene has been well reported [77].…”

Section: Discussionsupporting

confidence: 88%

OCIAD1 contributes to neurodegeneration in Alzheimer's disease by inducing mitochondria dysfunction, neuronal vulnerability and synaptic damages

Wang

Cykowski

et al. 2020

EBioMedicine

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A B S T R A C TBackground: Hyperamyloidosis in the brain is known as the earliest neuropathological change and a unique etiological factor in Alzheimer's disease (AD), while progressive neurodegeneration in certain vulnerable brain regions forms the basis of clinical syndromes. It is not clear how early hyperamyloidosis is implicated in progressive neurodegeneration and what factors contribute to the selective brain vulnerability in AD. Methods: Bioinformatics and experimental neurobiology methods were integrated to identify novel factors involved in the hyperamyloidosis-induced brain vulnerability in AD. We first examined neurodegenerationspecific gene signatures from sporadic AD patients and synaptic protein changes in young transgenic AD mice. Then, we systematically assessed the association of a top candidate gene with AD and investigated its mechanistic role in neurodegeneration. Findings: We identified the ovary-orientated protein OCIAD1 (Ovarian-Carcinoma-Immunoreactive-Antigen-Domain-Containing-1) as a neurodegeneration-associated factor for AD. Higher levels of OCIAD1, found in vulnerable brain areas and dystrophic neurites, were correlated with disease severity. Multiple early AD pathological events, particularly Ab/GSK-3b signaling, elevate OCIAD1, which in turn interacts with BCL-2 to impair mitochondrial function and facilitates mitochondria-associated neuronal injury. Notably, elevated OCIAD1 by Ab increases cell susceptibility to other AD pathological challenges. Interpretation: Our findings suggest that OCIAD1 contributes to neurodegeneration in AD by impairing mitochondria function, and subsequently leading to neuronal vulnerability, and synaptic damages. Funding: Ting Tsung & Wei Fong Chao Foundation, John S Dunn Research Foundation, Cure Alzheimer's Fund, and NIH R01AG057635 to STCW.

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Section: Discussionsupporting

confidence: 88%

OCIAD1 contributes to neurodegeneration in Alzheimer's disease by inducing mitochondria dysfunction, neuronal vulnerability and synaptic damages

Wang

Cykowski

et al. 2020

EBioMedicine

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“…10b. Processes affected by the disease in APP/PS1 mice overlap with pathways well-established in AD patients including ATP metabolism, ion transport, nervous system development, synaptic transmission, and inflammation [49][50][51][52][53][54] (Extended Data Fig. 10b).…”

Section: Cp2 Treatment Activates Translational Neuroprotective Mechanmentioning

confidence: 99%

Partial inhibition of mitochondrial complex I attenuates neurodegeneration and restores energy homeostasis and synaptic function in a symptomatic Alzheimer’s mouse model

Stojakovic

Trushin

Sheu

et al. 2020

Preprint

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AbstractWe demonstrate that mitochondrial respiratory chain complex I is an important small molecule druggable target in Alzheimer’s Disease (AD). Partial inhibition of complex I triggers the AMP-activated protein kinase-dependent signaling network leading to neuroprotection in symptomatic APP/PS1 mice, a translational model of AD. Treatment of APP/PS1 mice with complex I inhibitor after the onset of AD-like neuropathology improved energy homeostasis, synaptic activity, long-term potentiation, dendritic spine maturation, cognitive function and proteostasis, and reduced oxidative stress and inflammation in brain and periphery, ultimately blocking the ongoing neurodegeneration. Therapeutic efficacy in vivo was monitored using translational biomarkers FDG-PET, 31P NMR, and metabolomics. Cross-validation of the mouse and the human AMP-AD transcriptomic data demonstrated that pathways improved by the treatment in APP/PS1 mice, including the immune system response and neurotransmission, represent mechanisms essential for therapeutic efficacy in AD patients.

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“…At the same time, region-specific coexpression networks and gene modules were constructed, which were correlated with disease characteristics and showed that changes to oligodendrocytes mainly occurred in the early stages of AD progression (15). Combining the brain-specific protein interaction group with the gene network demonstrated that there were extensive changes in the expression levels of different complex gene clusters in AD, among which overall expression was downregulated for gene associated with synaptic transmission, metabolism, cell cycle, survival, and immune response (16). Three new candidate genes screened by differential gene expression, gene ontology (GO) enrichment analysis, pathway analysis, and PPI analysis, were identified as potential candidates for AD pathology (17).…”

Section: Introductionmentioning

confidence: 99%

The Predicted Key Molecules, Functions, and Pathways That Bridge Mild Cognitive Impairment (MCI) and Alzheimer's Disease (AD)

Han

et al. 2020

Front. Neurol.

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To elucidate the key molecules, functions, and pathways that bridge mild cognitive impairment (MCI) and Alzheimer's disease (AD), we investigated open gene expression data sets. Differential gene expression profiles were analyzed and combined with potential MCI-and AD-related gene expression profiles in public databases. Then, weighted gene co-expression network analysis was performed to identify the gene co-expression modules. One module was significantly negatively associated with MCI samples, in which gene ontology function and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis showed that these genes were related to cytosolic ribosome, ribosomal structure, oxidative phosphorylation, AD, and metabolic pathway. The other two modules correlated significantly with AD samples, in which functional and pathway enrichment analysis revealed strong relationships of these genes with cytoplasmic ribosome, protein binding, AD, cancer, and apoptosis. In addition, we regarded the core genes in the module network closely related to MCI and AD as bridge genes and submitted them to protein interaction network analysis to screen for major pathogenic genes according to the connectivity information. Among them, small nuclear ribonucleoprotein D2 polypeptide (SNRPD2), ribosomal protein S3a (RPS3A), S100 calcium binding protein A8 (S100A8), small nuclear ribonucleoprotein polypeptide G (SNRPG), U6 snRNA-associated Sm-like protein LSm3 (LSM3), ribosomal protein S27a (RPS27A), and ATP synthase F1 subunit gamma (ATP5C1) were not only major pathogenic genes of MCI, but also bridge genes. In addition, SNRPD2, RPS3A, S100A8, SNRPG, LSM3, thioredoxin (TXN), proteasome 20S subunit alpha 4 (PSMA4), annexin A1 (ANXA1), DnaJ heat shock protein family member A1 (DNAJA1), and prefoldin subunit 5 (PFDN5) were not only major pathogenic genes of AD, but also bridge genes. Next, we screened for differentially expressed microRNAs (miRNAs) to predict the miRNAs and transcription factors related the MCI and AD modules, respectively. The significance score of miRNAs in each module was calculated using a hypergeometric test to obtain the miRNApivot-Module interaction pair. Thirty-four bridge regulators were analyzed, among Tao et al. Pathogenic Mechanism of MCI and AD which hsa-miR-519d-3p was recognized as the bridge regulator between MCI and AD. Our study contributed to a better understanding of the pathogenic mechanisms of MCI and AD, and might lead to the development of a new strategy for clinical diagnosis and treatment.

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Integrating Gene and Protein Expression Reveals Perturbed Functional Networks in Alzheimer’s Disease

Cited by 73 publications

References 97 publications

OCIAD1 contributes to neurodegeneration in Alzheimer's disease by inducing mitochondria dysfunction, neuronal vulnerability and synaptic damages

OCIAD1 contributes to neurodegeneration in Alzheimer's disease by inducing mitochondria dysfunction, neuronal vulnerability and synaptic damages

Partial inhibition of mitochondrial complex I attenuates neurodegeneration and restores energy homeostasis and synaptic function in a symptomatic Alzheimer’s mouse model

The Predicted Key Molecules, Functions, and Pathways That Bridge Mild Cognitive Impairment (MCI) and Alzheimer's Disease (AD)

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