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Comparative analysis of transcriptome remodeling in plaque-associated and plaque-distant microglia during amyloid-β pathology progression in mice

Hemonnot-Girard, Anne-Laure; Meersseman, Cédric; Pastore, Manuela; Garcia, Valentin; Linck, Nathalie; Rey, Catherine; Chebbi, Amine; Jeanneteau, Freddy; Ginsberg, Stephen D; Lachuer, Joël; Reynes, Christelle; Rassendren, François; Hirbec, Hélène
BACKGROUND:Research in recent years firmly established that microglial cells play an important role in the pathogenesis of Alzheimer's disease (AD). In parallel, a series of studies showed that, under both homeostatic and pathological conditions, microglia are a heterogeneous cell population. In AD, amyloid-β (Aβ) plaque-associated microglia (PAM) display a clearly distinct phenotype compared to plaque-distant microglia (PCM), suggesting that these two microglia subtypes likely differently contribute to disease progression. So far, molecular characterization of PAM was performed indirectly using single cell RNA sequencing (scRNA-seq) approaches or based on markers that are supposedly up-regulated in this microglia subpopulation. METHODS:In this study based on a well-characterized AD mouse model, we combined cell-specific laser capture microdissection and RNA-seq analysis to i) identify, without preconceived notions of the molecular and/or functional changes that would affect these cells, the genes and gene networks that are dysregulated in PAM or PCM at three critical stages of the disease, and ii) to investigate the potential contribution of both plaque-associated and plaque-distant microglia. RESULTS:First, we established that our approach allows selective isolation of microglia, while preserving spatial information and preventing transcriptome changes induced by classical purification approaches. Then, we identified, in PAM and PCM subpopulations, networks of co-deregulated genes and analyzed their potential functional roles in AD. Finally, we investigated the dynamics of microglia transcriptomic remodeling at early, intermediate and late stages of the disease and validated select findings in postmortem human AD brain. CONCLUSIONS:Our comprehensive study provides useful transcriptomic information regarding the respective contribution of PAM and PCM across the Aβ pathology progression. It highlights specific pathways that would require further study to decipher their roles across disease progression. It demonstrates that the proximity of microglia to Aβ-plaques dramatically alters the microglial transcriptome and reveals that these changes can have both positive and negative impacts on the surrounding cells. These opposing effects may be driven by local microglia heterogeneity also demonstrated by this study. Our approach leads to molecularly define the less well studied plaque-distant microglia. We show that plaque-distant microglia are not bystanders of the disease, although the transcriptomic changes are far less striking compared to what is observed in plaque-associated microglia. In particular, our results suggest they may be involved in Aβ oligomer detection and in Aβ-plaque initiation, with increased contribution as the disease progresses.
PMID: 36153535
ISSN: 1742-2094
CID: 5333902

Loss of glucocorticoid receptor phosphorylation contributes to cognitive and neurocentric damages of the amyloid-β pathway

Dromard, Yann; Arango-Lievano, Margarita; Borie, Amelie; Dedin, Maheva; Fontanaud, Pierre; Torrent, Joan; Garabedian, Michael J; Ginsberg, Stephen D; Jeanneteau, Freddy
Aberrant cortisol and activation of the glucocorticoid receptor (GR) play an essential role in age-related progression of Alzheimer's disease (AD). However, the GR pathways required for influencing the pathobiology of AD dementia remain unknown. To address this, we studied an early phase of AD-like progression in the well-established APP/PS1 mouse model combined with targeted mutations in the BDNF-dependent GR phosphorylation sites (serines 134/267) using molecular, behavioral and neuroimaging approaches. We found that disrupting GR phosphorylation (S134A/S267A) in mice exacerbated the deleterious effects of the APP/PS1 genotype on mortality, neuroplasticity and cognition, without affecting either amyloid-β deposition or vascular pathology. The dynamics, maturation and retention of task-induced new dendritic spines of cortical excitatory neurons required GR phosphorylation at the BDNF-dependent sites that amyloid-β compromised. Parallel studies in postmortem human prefrontal cortex revealed AD subjects had downregulated BDNF signaling and concomitant upregulated cortisol pathway activation, which correlated with cognitive decline. These results provide key evidence that the loss of neurotrophin-mediated GR phosphorylation pathway promotes the detrimental effects of the brain cortisol response that contributes to the onset and/or progression of AD dementia. These findings have important translational implications as they provide a novel approach to treating AD dementia by identifying drugs that increase GR phosphorylation selectively at the neurotrophic sites to improve memory and cognition.
PMID: 35733193
ISSN: 2051-5960
CID: 5278042

Disease-specific interactome alterations via epichaperomics: the case for Alzheimer's disease

Ginsberg, Stephen D; Neubert, Thomas A; Sharma, Sahil; Digwal, Chander S; Yan, Pengrong; Timbus, Calin; Wang, Tai; Chiosis, Gabriela
The increasingly appreciated prevalence of complicated stressor-to-phenotype associations in human disease requires a greater understanding of how specific stressors affect systems or interactome properties. Many currently untreatable diseases arise due to variations in, and through a combination of, multiple stressors of genetic, epigenetic, and environmental nature. Unfortunately, how such stressors lead to a specific disease phenotype or inflict a vulnerability to some cells and tissues but not others remains largely unknown and unsatisfactorily addressed. Analysis of cell- and tissue-specific interactome networks may shed light on organization of biological systems and subsequently to disease vulnerabilities. However, deriving human interactomes across different cell and disease contexts remains a challenge. To this end, this opinion article links stressor-induced protein interactome network perturbations to the formation of pathologic scaffolds termed epichaperomes, revealing a viable and reproducible experimental solution to obtaining rigorous context-dependent interactomes. This article presents our views on how a specialized 'omics platform called epichaperomics may complement and enhance the currently available conventional approaches and aid the scientific community in defining, understanding, and ultimately controlling interactome networks of complex diseases such as Alzheimer's disease. Ultimately, this approach may aid the transition from a limited single-alteration perspective in disease to a comprehensive network-based mindset, which we posit will result in precision medicine paradigms for disease diagnosis and treatment.
PMID: 34028172
ISSN: 1742-4658
CID: 4905732

Correction to: Profiling Basal Forebrain Cholinergic Neurons Reveals a Molecular Basis for Vulnerability Within the Ts65Dn Model of Down Syndrome and Alzheimer's Disease

Alldred, Melissa J; Penikalapati, Sai C; Lee, Sang Han; Heguy, Adriana; Roussos, Panos; Ginsberg, Stephen D
PMID: 34837629
ISSN: 1559-1182
CID: 5063972

Associations Between DNA Methylation Age Acceleration, Depressive Symptoms, and Cardiometabolic Traits in African American Mothers From the InterGEN Study

Perez, Nicole Beaulieu; Vorderstrasse, Allison A; Yu, Gary; Melkus, Gail D'Eramo; Wright, Fay; Ginsberg, Stephen D; Crusto, Cindy A; Sun, Yan V; Taylor, Jacquelyn Y
Background/UNASSIGNED:African American women (AAW) have a high risk of both cardiometabolic (CM) illness and depressive symptoms. Depressive symptoms co-occur in individuals with CM illness at higher rates than the general population, and accelerated aging may explain this. In this secondary analysis, we examined associations between age acceleration; depressive symptoms; and CM traits (hypertension, diabetes mellitus [DM], and obesity) in a cohort of AAW. Methods/UNASSIGNED:Genomic and clinical data from the InterGEN cohort (n = 227) were used. Age acceleration was based on the Horvath method of DNA methylation (DNAm) age estimation. Accordingly, DNAm age acceleration (DNAm AA) was defined as the residuals from a linear regression of DNAm age on chronological age. Spearman's correlations, linear and logistic regression examined associations between DNAm AA, depressive symptoms, and CM traits. Results/UNASSIGNED:DNAm AA did not associate with total depressive symptom scores. DNAm AA correlated with specific symptoms including self-disgust/self-hate (-0.13, 95% CI -0.26, -0.01); difficulty with making decisions (-0.15, 95% CI -0.28, -0.02); and worry over physical health (0.15, 95% CI 0.02, 0.28), but were not statistically significant after multiple comparison correction. DNAm AA associated with obesity (0.08, 95% CI 1.02, 1.16), hypertension (0.08, 95% CI 1.01, 1.17), and DM (0.20, 95% CI 1.09, 1.40), after adjustment for potential confounders. Conclusions/UNASSIGNED:Associations between age acceleration and depressive symptoms may be highly nuanced and dependent on study design contexts. Factors other than age acceleration may explain the connection between depressive symptoms and CM traits. AAW with CM traits may be at increased risk of accelerated aging.
PMID: 35784386
ISSN: 2516-8657
CID: 5280162

The penalty of stress - Epichaperomes negatively reshaping the brain in neurodegenerative disorders

Ginsberg, Stephen D; Joshi, Suhasini; Sharma, Sahil; Guzman, Gianny; Wang, Tai; Arancio, Ottavio; Chiosis, Gabriela
Adaptation to acute and chronic stress and/or persistent stressors is a subject of wide interest in central nervous system disorders. In this context, stress is an effector of change in organismal homeostasis and the response is generated when the brain perceives a potential threat. Herein, we discuss a nuanced and granular view whereby a wide variety of genotoxic and environmental stressors, including aging, genetic risk factors, environmental exposures, and age- and lifestyle-related changes, act as direct insults to cellular, as opposed to organismal, homeostasis. These two concepts of how stressors impact the central nervous system are not mutually exclusive. We discuss how maladaptive stressor-induced changes in protein connectivity through epichaperomes, disease-associated pathologic scaffolds composed of tightly bound chaperones, co-chaperones, and other factors, impact intracellular protein functionality altering phenotypes, that in turn disrupt and remodel brain networks ranging from intercellular to brain connectome levels. We provide an evidence-based view on how these maladaptive changes ranging from stressor to phenotype provide unique precision medicine opportunities for diagnostic and therapeutic development, especially in the context of neurodegenerative disorders including Alzheimer's disease where treatment options are currently limited.
PMID: 34657288
ISSN: 1471-4159
CID: 5043062

Pharmacologically controlling protein-protein interactions through epichaperomes for therapeutic vulnerability in cancer

Joshi, Suhasini; Gomes, Erica DaGama; Wang, Tai; Corben, Adriana; Taldone, Tony; Gandu, Srinivasa; Xu, Chao; Sharma, Sahil; Buddaseth, Salma; Yan, Pengrong; Chan, Lon Yin L; Gokce, Askan; Rajasekhar, Vinagolu K; Shrestha, Lisa; Panchal, Palak; Almodovar, Justina; Digwal, Chander S; Rodina, Anna; Merugu, Swathi; Pillarsetty, NagaVaraKishore; Miclea, Vlad; Peter, Radu I; Wang, Wanyan; Ginsberg, Stephen D; Tang, Laura; Mattar, Marissa; de Stanchina, Elisa; Yu, Kenneth H; Lowery, Maeve; Grbovic-Huezo, Olivera; O'Reilly, Eileen M; Janjigian, Yelena; Healey, John H; Jarnagin, William R; Allen, Peter J; Sander, Chris; Erdjument-Bromage, Hediye; Neubert, Thomas A; Leach, Steven D; Chiosis, Gabriela
Cancer cell plasticity due to the dynamic architecture of interactome networks provides a vexing outlet for therapy evasion. Here, through chemical biology approaches for systems level exploration of protein connectivity changes applied to pancreatic cancer cell lines, patient biospecimens, and cell- and patient-derived xenografts in mice, we demonstrate interactomes can be re-engineered for vulnerability. By manipulating epichaperomes pharmacologically, we control and anticipate how thousands of proteins interact in real-time within tumours. Further, we can essentially force tumours into interactome hyperconnectivity and maximal protein-protein interaction capacity, a state whereby no rebound pathways can be deployed and where alternative signalling is supressed. This approach therefore primes interactomes to enhance vulnerability and improve treatment efficacy, enabling therapeutics with traditionally poor performance to become highly efficacious. These findings provide proof-of-principle for a paradigm to overcome drug resistance through pharmacologic manipulation of proteome-wide protein-protein interaction networks.
PMID: 34824367
ISSN: 2399-3642
CID: 5063822

Expression and proteolytic processing of the amyloid precursor protein is unaffected by the expression of the three human apolipoprotein E alleles in the brains of mice

Novy, Mariah J; Newbury, Samantha F; Liemisa, Braison; Morales-Corraliza, Jose; Alldred, Melissa J; Ginsberg, Stephen D; Mathews, Paul M
The 3 human apolipoprotein E (APOE) gene alleles modify an individual's risk of developing Alzheimer's disease (AD): compared to the risk-neutral APOE ε3 allele, the ε4 allele (APOE4) is strongly associated with increased AD risk while the ε2 allele is protective. Multiple mechanisms have been shown to link APOE4 expression and AD risk, including the possibility that APOE4 increases the expression of the amyloid precursor protein (APP) (Y-W.A. Huang, B. Zhou, A.M. Nabet, M. Wernig, T.C. Südhof, 2019). In this study, we investigated the impact of APOE genotype on the expression, and proteolytic processing of endogenously expressed APP in the brains of mice humanized for the 3 APOE alleles. In contrast to prior studies using neuronal cultures, we found in the brain that both App gene expression, and the levels of APP holoprotein were not affected by APOE genotype. Additionally, our analysis of APP fragments showed that APOE genotype does not impact APP processing in the brain: the levels of both α- and β-cleaved soluble APP fragments (sAPPs) were similar across genotypes, as were the levels of the membrane-associated α- and β-cleaved C-terminal fragments (CTFs) of APP. Lastly, APOE genotype did not impact the level of soluble amyloid beta (Aβ). These findings argue that the APOE-allele-dependent AD risk is independent of the brain expression and processing of APP.
PMID: 34875506
ISSN: 1558-1497
CID: 5099572

Profiling Basal Forebrain Cholinergic Neurons Reveals a Molecular Basis for Vulnerability Within the Ts65Dn Model of Down Syndrome and Alzheimer's Disease

Alldred, Melissa J; Penikalapati, Sai C; Lee, Sang Han; Heguy, Adriana; Roussos, Panos; Ginsberg, Stephen D
Basal forebrain cholinergic neuron (BFCN) degeneration is a hallmark of Down syndrome (DS) and Alzheimer's disease (AD). Current therapeutics have been unsuccessful in slowing disease progression, likely due to complex pathological interactions and dysregulated pathways that are poorly understood. The Ts65Dn trisomic mouse model recapitulates both cognitive and morphological deficits of DS and AD, including BFCN degeneration. We utilized Ts65Dn mice to understand mechanisms underlying BFCN degeneration to identify novel targets for therapeutic intervention. We performed high-throughput, single population RNA sequencing (RNA-seq) to interrogate transcriptomic changes within medial septal nucleus (MSN) BFCNs, using laser capture microdissection to individually isolate ~500 choline acetyltransferase-immunopositive neurons in Ts65Dn and normal disomic (2N) mice at 6 months of age (MO). Ts65Dn mice had unique MSN BFCN transcriptomic profiles at ~6 MO clearly differentiating them from 2N mice. Leveraging Ingenuity Pathway Analysis and KEGG analysis, we linked differentially expressed gene (DEG) changes within MSN BFCNs to several canonical pathways and aberrant physiological functions. The dysregulated transcriptomic profile of trisomic BFCNs provides key information underscoring selective vulnerability within the septohippocampal circuit. We propose both expected and novel therapeutic targets for DS and AD, including specific DEGs within cholinergic, glutamatergic, GABAergic, and neurotrophin pathways, as well as select targets for repairing oxidative phosphorylation status in neurons. We demonstrate and validate this interrogative quantitative bioinformatic analysis of a key dysregulated neuronal population linking single population transcript changes to an established pathological hallmark associated with cognitive decline for therapeutic development in human DS and AD.
PMID: 34263425
ISSN: 1559-1182
CID: 4937542

Chemical tools for epichaperome-mediated interactome dysfunctions of the central nervous system

Bolaender, Alexander; Zatorska, Danuta; He, Huazhong; Joshi, Suhasini; Sharma, Sahil; Digwal, Chander S; Patel, Hardik J; Sun, Weilin; Imber, Brandon S; Ochiana, Stefan O; Patel, Maulik R; Shrestha, Liza; Shah, Smit K; Wang, Shuo; Karimov, Rashad; Tao, Hui; Patel, Pallav D; Martin, Ananda Rodilla; Yan, Pengrong; Panchal, Palak; Almodovar, Justina; Corben, Adriana; Rimner, Andreas; Ginsberg, Stephen D; Lyashchenko, Serge; Burnazi, Eva; Ku, Anson; Kalidindi, Teja; Lee, Sang Gyu; Grkovski, Milan; Beattie, Bradley J; Zanzonico, Pat; Lewis, Jason S; Larson, Steve; Rodina, Anna; Pillarsetty, Nagavarakishore; Tabar, Viviane; Dunphy, Mark P; Taldone, Tony; Shimizu, Fumiko; Chiosis, Gabriela
Diseases are a manifestation of how thousands of proteins interact. In several diseases, such as cancer and Alzheimer's disease, proteome-wide disturbances in protein-protein interactions are caused by alterations to chaperome scaffolds termed epichaperomes. Epichaperome-directed chemical probes may be useful for detecting and reversing defective chaperomes. Here we provide structural, biochemical, and functional insights into the discovery of epichaperome probes, with a focus on their use in central nervous system diseases. We demonstrate on-target activity and kinetic selectivity of a radiolabeled epichaperome probe in both cells and mice, together with a proof-of-principle in human patients in an exploratory single group assignment diagnostic study ( Identifier: NCT03371420). The clinical study is designed to determine the pharmacokinetic parameters and the incidence of adverse events in patients receiving a single microdose of the radiolabeled probe administered by intravenous injection. In sum, we introduce a discovery platform for brain-directed chemical probes that specifically modulate epichaperomes and provide proof-of-principle applications in their use in the detection, quantification, and modulation of the target in complex biological systems.
PMID: 34344873
ISSN: 2041-1723
CID: 5004212