Genome‐wide methylomic regulation of multiscale gene networks in Alzheimer's disease

Wang, Erming; Wang, Minghui; Guo, Lei; Fullard, John F.; Micallef, Courtney; Bendl, Jaroslav; Song, Won‐Min; Ming, Chi; Huang, Yong; Li, Yuxin; Yu, Kaiwen; Peng, Junmin; Bennett, David A.; Jager, Philip L. De; Roussos, Panos; Haroutunian, Vahram; Zhang, Bin

doi:10.1002/alz.12969

Cited by 14 publications

(19 citation statements)

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“…Detailed clinical data, postmortem neuropathological data, and demographics of the cohort are described in. 29 We constructed gene co-expression and detected multiscale gene modules using MEGENA 30 on the differentially abundant excitatory neurons, which were identified as those neurons in control subjects most susceptible to neuronal loss in AD. Differential expression of genes between AD vs control was identified by the FinderMarkers function of the Seurat (v4.0) workflow 31 , using the MAST algorithm 32 .…”

Section: Double Label Immunohistochemistrymentioning

confidence: 99%

Upregulation of the Proto-Oncogene Src Kinase in Alzheimer’s Disease: From Molecular Interactions to Therapeutic Potential

Mastroeni,

Chan,

Morshed

et al. 2024

Preprint

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Alzheimer’s disease (AD) is a progressive neurodegenerative disease, resulting in an irreversible deterioration of multiple brain regions associated with cognitive dysfunction. Phosphorylation of the microtubule-associated protein, Tau, is known to occur decades before symptomatic AD. The Src family of tyrosine kinases are known to phosphorylate select tyrosine sites on Tau and promote microtubule disassembly and subsequent neurofibrillary tangle (NFT) formation. Our data show that the proto-oncogene, non-receptor tyrosine kinase Src colocalizes with a range of late (PHF1) to early (MC1) AD-associated phosphorylated Tau epitopes. The strongest co-occurrence is seen with MC1 (probability of MC1 given Src =100%), an early AD-specific conformational dependent epitope. Single-cell RNA sequencing data of 101 subjects show thatSrcis upregulated in both AD inhibitory and excitatory neurons. The most significantly affected, by orders of magnitude, were excitatory neurons which are the most prone to pathological Tau accumulation. We measured Src phosphorylation by mass spectrometry across a cohort of 48 patient neocortical tissues and found that Src has increased phosphorylation on Ser75, Tyr187, and Tyr440 in AD, showing that Src kinase undergoes distinct phosphorylation alterations in AD. Through Brownian dynamics simulations of Src and Tau, we show that as Tau undergoes the transition into disease-associated paired helical filaments, there is a notable seven-fold increase in Src contact with Tau. These results collectively emphasize Src kinase’s central role in Tau phosphorylation and its close association with Tau epitopes, presenting a promising target for potential therapeutic intervention.

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Section: Double Label Immunohistochemistrymentioning

confidence: 99%

Upregulation of the Proto-Oncogene Src Kinase in Alzheimer’s Disease: From Molecular Interactions to Therapeutic Potential

Mastroeni,

Chan,

Morshed

et al. 2024

Preprint

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“…We performed DEP analysis in AD vs NL over the proteomics profile in two human AD cohorts using the postmortem tissue from two different brain region: the parahippocampal gyrus (PHG) for the Mount Sinai Brain Bank (MSBB) 32 and the prefrontal cortex (PFC) for the Religious Orders Study and Memory and Rush Aging (ROSMAP) 52,53 cohort, respectively. The processing, normalization and co-variable adjustment for the human proteomics are as previously described 31 . In the present study, we stratified the subjects by sex and then identified the sex-specific DEPs in AD in comparison with NL (Supplementary Data 4).…”

Section: Sex-specific Dep Analysis In Human Cohortsmentioning

confidence: 99%

“…Gene co-expression networks on the proteomes in the human cohorts were identified by using Multiscale Embedded GEne co-expression Network Analysis (MEGENA) as described in 31,54 .…”

Section: Co-expression Network Analysismentioning

confidence: 99%

“…We first compared the mouse DEP signatures in the present study with the human DEPs in AD that were derived from the proteomics profiling in the parahippocampal gyrus (PHG) of the MSBB cohort 31,32 . We stratified the human subjects over sex and thus obtained the sex-specific DEPs in AD vs normal healthy individual (NL) (Supplementary Data 4, and Methods).…”

Section: The Dusp4 Dep and Deptm Signatures Are Enriched In Human Ad ...mentioning

confidence: 99%

“…We projected the mouse DEP signatures onto the MEGENA co-expression networks from the human proteomics 31 to gain further understanding of their functional relevance to human AD. In the MSBB protein co-expression network, more than half (> 15) of the top 30 AD-associated modules were enriched for the mouse DEPs from 5×FADvsWT of both sexes (Figure 5C).…”

Section: The Dusp4 Dep and Deptm Signatures Are Enriched In Human Ad ...mentioning

confidence: 99%

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Proteomic signaling of dual specificity phosphatase 4 (DUSP4) in Alzheimer’s disease

Wang,

Pan,

Bagchi

et al. 2023

Preprint

Self Cite

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DUSP4 is a member of the DUSP (Dual-Specificity Phosphatase) subfamily that is selective to the mitogen-activated protein kinases (MAPK) and has been implicated in a range of biological processes and functions in Alzheimer′s disease (AD). In this study, we utilized stereotactic delivery of adeno-associated virus (AAV)-DUSP4 to overexpress DUSP4 in the dorsal hippocampus of 5xFAD and wildtype (WT) mice, then used mass spectrometry (MS)-based proteomics along with label-free quantification to profile the proteome and phosphoproteome in the hippocampus. We identified patterns of protein expression and phosphorylation that are modulated in 5xFAD mice and examined the sex-specific impact of DUSP4 overexpression on the 5xFAD proteome/phosphoproteome. In 5xFAD mice, a substantial number of proteins were up- or down-regulated in both male and female mice in comparison to age and sex-matched WT mice, many of which are involved in AD-related biological processes, such as the activated immune response or suppression of synaptic activities. Upon DUSP4 overexpression, significantly regulated proteins were found in pathways that were suppressed, such as the immune response, in male 5xFAD mice. In contrast, such a shift was absent in female mice. For the phosphoproteome, we detected an array of phosphorylation sites that are regulated in 5xFAD compared to WT, and are modulated by DUSP4 overexpression in each sex. Interestingly, the changes in 5xFAD- and DUSP4-associated phosphorylation occurred in opposite directions. Strikingly, both the 5xFAD- and DUSP4-associated phosphorylation changes were found for the most part in neurons, and play key roles in neuronal processes and synaptic function. Site-centric pathway analysis revealed that both the 5xFAD- and DUSP4-associated phosphorylation sites were enriched for a number of kinase sets in female, but only a limited number of sets of kinases in male mice. Taken together, our results suggest that male and female 5xFAD mice respond to DUSP4 overexpression via shared and sex-specific molecular mechanisms, which might underly similar reductions in amyloid pathology in both sexes, while learning deficits were reduced in only females with DUSP4 overexpression. Finally, we validated our findings with the sex-specific AD-associated proteomes in human cohorts and further developed DUSP4-centric proteomic network models and signaling maps for each sex.

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Whole genome methylation sequencing in blood identifies extensive differential DNA methylation in late‐onset dementia due to Alzheimer's disease

Breen,

Papale,

Clark

et al. 2023

Alzheimer's & Dementia

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INTRODUCTIONDNA microarray‐based studies report differentially methylated positions (DMPs) in blood between late‐onset dementia due to Alzheimer's disease (AD) and cognitively unimpaired individuals, but interrogate < 4% of the genome.METHODSWe used whole genome methylation sequencing (WGMS) to quantify DNA methylation levels at 25,409,826 CpG loci in 281 blood samples from 108 AD and 173 cognitively unimpaired individuals.RESULTSWGMS identified 28,038 DMPs throughout the human methylome, including 2707 differentially methylated genes (e.g., SORCS3, GABA, and PICALM) encoding proteins in biological pathways relevant to AD such as synaptic membrane, cation channel complex, and glutamatergic synapse. One hundred seventy‐three differentially methylated blood‐specific enhancers interact with the promoters of 95 genes that are differentially expressed in blood from persons with and without AD.DISCUSSIONWGMS identifies differentially methylated CpGs in known and newly detected genes and enhancers in blood from persons with and without AD.Highlights Whole genome DNA methylation levels were quantified in blood from persons with and without Alzheimer's disease (AD). Twenty‐eight thousand thirty‐eight differentially methylated positions (DMPs) were identified. Two thousand seven hundred seven genes comprise DMPs. Forty‐eight of 75 independent genetic risk loci for AD have DMPs. One thousand five hundred sixty‐eight blood‐specific enhancers comprise DMPs, 173 of which interact with the promoters of 95 genes that are differentially expressed in blood from persons with and without AD.

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Genome‐wide methylomic regulation of multiscale gene networks in Alzheimer's disease

Cited by 14 publications

References 136 publications

Upregulation of the Proto-Oncogene Src Kinase in Alzheimer’s Disease: From Molecular Interactions to Therapeutic Potential

Upregulation of the Proto-Oncogene Src Kinase in Alzheimer’s Disease: From Molecular Interactions to Therapeutic Potential

Proteomic signaling of dual specificity phosphatase 4 (DUSP4) in Alzheimer’s disease

Whole genome methylation sequencing in blood identifies extensive differential DNA methylation in late‐onset dementia due to Alzheimer's disease

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