A public resource of single cell transcriptomes and multiscale networks from persons with and without Alzheimer’s disease

Wang, Qi; Antone, Jerry; Alsop, Eric; Reiman, Rebecca; Funk, Cory; Bendl, Jaroslav; Dudley, Joel T; Liang, Winnie S; Karr, Timothy L; Roussos, Panos; Bennett, David A; De Jager, Philip L; Serrano, Geidy E; Beach, Thomas G; Keuren-Jensen, Kendall Van; Mastroeni, Diego; Reiman, Eric M; Readhead, Benjamin P

doi:10.1101/2023.10.20.563319

Cited by 8 publications

(8 citation statements)

References 96 publications

(145 reference statements)

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“…To examine the effect of APOE2 in the aging human brain, we investigated the single-nucleus RNA sequencing dataset of 52 individuals, which included 25 APOE2/3-carriers and 27 APOE3/3-carriers, randomly chosen from the ROSMAP. Among the 52 individuals, half exhibited high levels of β-amyloid and other pathological hallmarks of Alzheimer’s disease ('AD-pathology', 'AD'), while the remaining half showed either no or low β-amyloid burden ('non-AD-pathology', 'nonAD'), which aligned with the NIA-AA criteria [ 18 , 38 , 39 ]. Both APOE3/3 and APOE2/3 groups maintained a balance in terms of AD pathology, gender (APOE2/3: 11 males and 14 females, APOE3/3: 12 males and 15 females), age (median: 86.78 APOE2/3, 85.76 APOE3/3), years of education (median: 16.20 APOE2/3, 16.04 APOE3/3), and post mortem interval (PMI) (median: 7.245 APOE2/3, 8.026 APOE3/3) (Fig.…”

Section: Resultsmentioning

confidence: 64%

APOE2 protects against Aβ pathology by improving neuronal mitochondrial function through ERRα signaling

Ning,

Liu,

Wan

et al. 2024

Cell Mol Biol Lett

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Background Alzheimer’s disease (AD) is a progressive neurodegenerative disease and apolipoprotein E (APOE) genotypes (APOE2, APOE3, and APOE4) show different AD susceptibility. Previous studies indicated that individuals carrying the APOE2 allele reduce the risk of developing AD, which may be attributed to the potential neuroprotective role of APOE2. However, the mechanisms underlying the protective effects of APOE2 is still unclear. Methods We analyzed single-nucleus RNA sequencing and bulk RNA sequencing data of APOE2 and APOE3 carriers from the Religious Orders Study and Memory and Aging Project (ROSMAP) cohort. We validated the findings in SH-SY5Y cells and AD model mice by evaluating mitochondrial functions and cognitive behaviors respectively. Results The pathway analysis of six major cell types revealed a strong association between APOE2 and cellular stress and energy metabolism, particularly in excitatory and inhibitory neurons, which was found to be more pronounced in the presence of beta-amyloid (Aβ). Moreover, APOE2 overexpression alleviates Aβ1-42-induced mitochondrial dysfunction and reduces the generation of reactive oxygen species in SH-SY5Y cells. These protective effects may be due to ApoE2 interacting with estrogen-related receptor alpha (ERRα). ERRα overexpression by plasmids or activation by agonist was also found to show similar mitochondrial protective effects in Aβ1-42-stimulated SH-SY5Y cells. Additionally, ERRα agonist treatment improve the cognitive performance of Aβ injected mice in both Y maze and novel object recognition tests. ERRα agonist treatment increased PSD95 expression in the cortex of agonist-treated-AD mice. Conclusions APOE2 appears to enhance neural mitochondrial function via the activation of ERRα signaling, which may be the protective effect of APOE2 to treat AD.

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Section: Resultsmentioning

confidence: 64%

APOE2 protects against Aβ pathology by improving neuronal mitochondrial function through ERRα signaling

Ning,

Liu,

Wan

et al. 2024

Cell Mol Biol Lett

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“…The emergence of large-scale single nuclei RNAseq (snRNAseq) data generated from post-mortem brain tissue from subjects affected by AD has offered new approaches for characterizing AD-associated molecular networks in a cell-specific manner. We recently generated snRNAseq superior frontal gyrus (SFG) profiles from 101 exceptionally well characterized subjects 50 , and interrogated this data to examine AD-associated Src mRNA expression in a cell-type specific manner. Consistent with our histochemical and protein quantification analyses, we observed that Src is significantly upregulated in excitatory neurons (Ex).…”

Section: Resultsmentioning

confidence: 99%

“…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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“…It plays a role in the regulation of neurotransmitter release at synapses [66] although there is limited study for its characterization. Its expression has been found to be positively correlated with cognitive function and consistently downregulated in multiple neuron subtypes from AD brains especially in females, in numerous transcriptomic profiles by snRNAseq [53,[67][68][69]. Further characterization of the transcript and protein and their roles in neurological function and disorder is thus warranted.…”

Section: Discussionmentioning

confidence: 99%

Interpretable deep learning framework for understanding molecular changes in human brains with Alzheimer’s disease: implications for microglia activation and sex differences

Trivedi,

Joshi,

Shah

et al. 2023

Preprint

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INTRODUCTIONThe objective of this study is to characterize the molecular changes associated with AD from gene expression data of brain tissues taking an interpretable deep learning approach which has not been fully exploited.METHODSWe trained multi-layer perceptron (MLP) models for the classification of neuropathologically confirmed AD vs. controls using the transcriptomic data of three brain regions from the ROSMAP study. The whole disease spectrum was then modeled as a progressive trajectory. SHAP (SHapley Additive exPlanations) value was derived to explain model predictions and identify significant implicated genes for subsequent network analysis of key gene modules underlying AD progression. The framework was validated using two external datasets: the Mayo RNA-seq study cohort and the Mount Sinai Brain Bank study cohort.RESULTSThe MLP models achieved superior performance in classification and prediction in external datasets. SHAP explainer revealed common and specific transcriptomic signatures from different brain regions.DISCUSSIONWe identified common gene signatures in microglia and sex specific modules in neurons that are implicated in AD. This work paves the way for utilizing artificial intelligence approaches in studying AD at the molecular level.Research-in-ContextSystematic review: Postmortem brain transcriptomes have been analyzed to study the molecular changes associated with Alzheimer’s disease, usually by a direct contrast approach such as differential gene expression analysis. Nuanced gene regulations thus cannot be easily pinpointed from convoluted data such as those from bulk-tissue profiling. We applied a novel interpretable deep learning approach to dissect the RNA-seq data collected from three different brain regions of a large clinical cohort and identified significant genes for network analysis implicated for AD.Interpretation: Our models successfully predicted neuropathological and clinical traits in both internal and external validations. We corroborated known microglial biology in addition to revealing novel sex chromosome-linked gene contributing to sex dimorphism in AD.Future directions: The framework could have broader utility of interpreting multi-omics data such as those from single-cell profiling, to advance our understanding of molecular mechanism of complex human disease such as AD.HighlightsWe applied novel interpretable deep learning methods on the postmortem brain transcriptomes from three different brain regionsWe interpreted the models to identify the most important genes implicated for ADNetwork analysis corroborated known microglial biology and revealed novel sex specific transcriptional factors for neuronal loss in AD

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A public resource of single cell transcriptomes and multiscale networks from persons with and without Alzheimer’s disease

Cited by 8 publications

References 96 publications

APOE2 protects against Aβ pathology by improving neuronal mitochondrial function through ERRα signaling

APOE2 protects against Aβ pathology by improving neuronal mitochondrial function through ERRα signaling

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

Interpretable deep learning framework for understanding molecular changes in human brains with Alzheimer’s disease: implications for microglia activation and sex differences

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