Distinct patterns of plaque and microglia glycosylation in Alzheimer’s disease
Caitlyn Fastenau, Madison Bunce, Mallory Keating, Jessica Wickline, Sarah C Hopp, Kevin F Bieniek
Brain Pathol. 2024 Jul;34(4):e13267. doi: 10.1111/bpa.13267. Epub 2024 May 9.
Abstract:
Glycosylation is the most common form of post-translational modification in the brain. Aberrant glycosylation has been observed in cerebrospinal fluid and brain tissue of Alzheimer’s disease (AD) cases, including dysregulation of terminal sialic acid (SA) modifications. While alterations in sialylation have been identified in AD, the localization of SA modifications on cellular or aggregate-associated glycans is largely unknown because of limited spatial resolution of commonly utilized methods. The present study aims to overcome these limitations with novel combinations of histologic techniques to characterize the sialylation landscape of O- and N-linked glycans in autopsy-confirmed AD post-mortem brain tissue. Sialylated glycans facilitate important cellular functions including cell-to-cell interaction, cell migration, cell adhesion, immune regulation, and membrane excitability. Previous studies have not investigated both N- and O-linked sialylated glycans in neurodegeneration. In this study, the location and distribution of sialylated glycans were evaluated in three brain regions (frontal cortex, hippocampus, and cerebellum) from 10 AD cases using quantitative digital pathology techniques. Notably, we found significantly greater N-sialylation of the Aβ plaque microenvironment compared with O-sialylation. Plaque-associated microglia displayed the most intense N-sialylation proximal to plaque pathology. Further analyses revealed distinct differences in the levels of N- and O-sialylation between cored and diffuse Aβ plaque morphologies. Interestingly, phosphorylated tau pathology led to a slight increase in N-sialylation and no influence of O-sialylation in these AD brains. Confirming our previous observations in mice with novel histologic approach, these findings support microglia sialylation appears to have a relationship with AD protein aggregates while providing potential targets for therapeutic strategies.
Keywords: Alzheimer’s disease; digital pathology; glycosylation; microglia; senile plaque; sialylation.
Gender-based heterogeneity of FAHFAs in trained runners
Alisa B Nelson, Lisa S Chow, Donald R Dengel, Meixia Pan, Curtis C Hughey, Xianlin Han, Patrycja Puchalska, Peter A Crawford
PLoS One. 2024 May 6;19(5):e0300037. doi: 10.1371/journal.pone.0300037. eCollection 2024.
Abstract:
Fatty acid esters of hydroxy fatty acid (FAHFA) are anti-diabetic and anti-inflammatory lipokines. Recently FAHFAs were also found to predict cardiorespiratory fitness in a cross-sectional study of recreationally trained runners. Here we report the influences of body composition and gender on static FAHFA abundances in circulation. We compared the association between circulating FAHFA concentrations and body composition, determined by dual x-ray absorptiometry, in female recreational runners who were lean (BMI < 25 kg/m2, n = 6), to those who were overweight (BMI ≥ 25 kg/m2, n = 7). To characterize the effect of gender we also compared circulating FAHFAs in lean male recreational runners (n = 8) to recreationally trained lean female (n = 6) runner group. Circulating FAHFAs were increased in females in a manner that was modulated by specific adipose depot sizes, blood glucose, and lean body mass. As expected, circulating FAHFAs were diminished in the overweight group, but strikingly, within the lean cohort, increases in circulating FAHFAs were promoted by increased fat mass, relative to lean mass, while the overweight group showed a significantly attenuated relationship. These studies suggest multimodal regulation of circulating FAHFAs and raise hypotheses to test endogenous FAHFA dynamic sources and sinks in health and disease, which will be essential for therapeutic target development. Baseline circulating FAHFA concentrations could signal sub-clinical metabolic dysfunction in metabolically healthy obesity.
STAT3 activation of SCAP-SREBP-1 signaling upregulates fatty acid synthesis to promote tumor growth
Yunzhou Fan, Rui Zhang, Chao Wang, Meixia Pan, Feng Geng, Yaogang Zhong, Huali Su, Yongjun Kou, Xiaokui Mo, Etienne Lefai, Xianlin Han, Arnab Chakravarti, Deliang Guo
J Biol Chem. 2024 Jun;300(6):107351. doi: 10.1016/j.jbc.2024.107351. Epub 2024 May 6.
Abstract:
SCAP plays a central role in controlling lipid homeostasis by activating SREBP-1, a master transcription factor in controlling fatty acid (FA) synthesis. However, how SCAP expression is regulated in human cancer cells remains unknown. Here, we revealed that STAT3 binds to the promoter of SCAP to activate its expression across multiple cancer cell types. Moreover, we identified that STAT3 also concurrently interacts with the promoter of SREBF1 gene (encoding SREBP-1), amplifying its expression. This dual action by STAT3 collaboratively heightens FA synthesis. Pharmacological inhibition of STAT3 significantly reduces the levels of unsaturated FAs and phospholipids bearing unsaturated FA chains by reducing the SCAP-SREBP-1 signaling axis and its downstream effector SCD1. Examination of clinical samples from patients with glioblastoma, the most lethal brain tumor, demonstrates a substantial co-expression of STAT3, SCAP, SREBP-1, and SCD1. These findings unveil STAT3 directly regulates the expression of SCAP and SREBP-1 to promote FA synthesis, ultimately fueling tumor progression.
Keywords: FASN; SCAP; SCD1; SREBP-1; STAT3; fatty acid; glioblastoma; lipogenesis; phospholipid.
Perinatal maternal undernutrition in baboons modulates hepatic mitochondrial function but not metabolites in aging offspring
Daniel A Adekunbi, Bowen Yang, Hillary F Huber, Angelica M Riojas, Alexander J Moody, Cun Li, Michael Olivier, Peter W Nathanielsz, Geoffery D Clarke, Laura A Cox, Adam B Salmon
bioRxiv [Preprint]. 2024 May 5:2024.05.02.592246. doi: 10.1101/2024.05.02.592246.
Abstract:
We previously demonstrated in baboons that maternal undernutrition (MUN), achieved by 70 % of control nutrition, impairs fetal liver function, but long-term changes associated with aging in this model remain unexplored. Here, we assessed clinical phenotypes of liver function, mitochondrial bioenergetics, and protein abundance in adult male and female baboons exposed to MUN during pregnancy and lactation and their control counterparts. Plasma liver enzymes were assessed enzymatically. Liver glycogen, choline, and lipid concentrations were quantified by magnetic resonance spectroscopy. Mitochondrial respiration in primary hepatocytes under standard culture conditions and in response to metabolic (1 mM glucose) and oxidative (100 µM H2O2) stress were assessed with Seahorse XFe96. Hepatocyte mitochondrial membrane potential (MMP) and protein abundance were determined by tetramethylrhodamine ethyl ester staining and immunoblotting, respectively. Liver enzymes and metabolite concentrations were largely unaffected by MUN, except for higher aspartate aminotransferase levels in MUN offspring when male and female data were combined. Oxygen consumption rate, extracellular acidification rate, and MMP were significantly higher in male MUN offspring relative to control animals under standard culture. However, in females, cellular respiration was similar in control and MUN offspring. In response to low glucose challenge, only control male hepatocytes were resistant to low glucose-stimulated increase in basal and ATP-linked respiration. H2O2 did not affect hepatocyte mitochondrial respiration. Protein markers of mitochondrial respiratory chain subunits, biogenesis, dynamics, and antioxidant enzymes were unchanged. Male-specific increases in mitochondrial bioenergetics in MUN offspring may be associated with increased energy demand in these animals. The similarity in systemic liver parameters suggests that changes in hepatocyte bioenergetics capacity precede detectable circulatory hepatic defects in MUN offspring and that the mitochondria may be an orchestrator of liver programming outcome.
Keywords: baboons; bioenergetics; developmental programming; hepatocytes; liver.
The Gehan test identifies life-extending compounds overlooked by the log-rank test in the NIA Interventions Testing Program: Metformin, Enalapril, caffeic acid phenethyl ester, green tea extract, and 17-dimethylaminoethylamino-17-demethoxygeldanamycin hydrochloride
Nisi Jiang, Jonathan Gelfond, Qianqian Liu, Randy Strong, James F Nelson
Geroscience. 2024 Oct;46(5):4533-4541. doi: 10.1007/s11357-024-01161-9. Epub 2024 Apr 17.
Abstract:
The National Institute on Aging Interventions Testing Program (ITP) has so far identified 12 compounds that extend the lifespan of genetically heterogeneous mice using the log-rank test. However, the log-rank test is relatively insensitive to any compound that does not uniformly reduce mortality across the lifespan. This test may thus miss compounds that only reduce mortality before midlife, for example, a plausible outcome if a compound only mitigates risk factors before midlife or if its efficacy is reduced at later ages. We therefore reanalyzed all data collected by the ITP from 2004-2022 using the Gehan test, which is more sensitive to mortality differences earlier in the life course and does not assume a uniformly reduced mortality hazard across the lifespan. The Gehan test identified 5 additional compounds, metformin, enalapril, 17-dimethylaminoethylamino-17-demethoxygeldanamycin hydrochloride (17-DMAG), caffeic acid phenethyl ester (CAPE), and green tea extract (GTE), which significantly increased survival but were previously missed by the log-rank test. Three (metformin, enalapril, and 17-DMAG) were only effective in males and two (CAPE and GTE) were only effective in females. In addition, 1,3-butanediol, which by log-rank analysis increased survival in females but not males, increased survival in males by the Gehan test. These results suggest that statistical tests sensitive to non-uniformity of drug efficacy across the lifespan should be included in the standard statistical testing protocol to minimize overlooking geroprotective interventions.
Keywords: Anti-aging interventions; Early mortality rate; Gehan-Breslow-Wilcoxon test; Intervention testing program; Lifespan; UM-HET3 mice.
Long-term benefits of hematopoietic stem cell-based macrophage/microglia delivery of GDNF to the CNS in a mouse model of Parkinson’s disease
Guo Ge, Barath P Sivasubramanian, Bill D Geng, Shujie Zhao, Qing Zhou, Gang Huang, Jason C O’Connor, Robert A Clark, Senlin Li
Gene Ther. 2024 May;31(5-6):324-334. doi: 10.1038/s41434-024-00451-3. Epub 2024 Apr 16.
Abstract:
Glial cell line-derived neurotrophic factor (GDNF) protects dopaminergic neurons in various models of Parkinson’s disease (PD). Cell-based GDNF gene delivery mitigates neurodegeneration and improves both motor and non-motor functions in PD mice. As PD is a chronic condition, this study aims to investigate the long-lasting benefits of hematopoietic stem cell (HSC)-based macrophage/microglia-mediated CNS GDNF (MMC-GDNF) delivery in an MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mouse model. The results indicate that GDNF treatment effectively ameliorated MPTP-induced motor deficits for up to 12 months, which coincided with the protection of nigral dopaminergic neurons and their striatal terminals. Also, the HSC-derived macrophages/microglia were recruited selectively to the neurodegenerative areas of the substantia nigra. The therapeutic benefits appear to involve two mechanisms: (1) macrophage/microglia release of GDNF-containing exosomes, which are transferred to target neurons, and (2) direct release of GDNF by macrophage/microglia, which diffuses to target neurons. Furthermore, the study found that plasma GDNF levels were significantly increased from baseline and remained stable over time, potentially serving as a convenient biomarker for future clinical trials. Notably, no weight loss, altered food intake, cerebellar pathology, or other adverse effects were observed. Overall, this study provides compelling evidence for the long-term therapeutic efficacy and safety of HSC-based MMC-GDNF delivery in the treatment of PD.
Differential mitochondrial bioenergetics and cellular resilience in astrocytes, hepatocytes, and fibroblasts from aging baboons
Daniel A Adekunbi, Hillary F Huber, Cun Li, Peter W Nathanielsz, Laura A Cox, Adam B Salmon
Geroscience. 2024 Oct;46(5):4443-4459. doi: 10.1007/s11357-024-01155-7. Epub 2024 Apr 12.
Abstract:
Biological resilience, broadly defined as the ability to recover from an acute challenge and return to homeostasis, is of growing importance to the biology of aging. At the cellular level, there is variability across tissue types in resilience and these differences are likely to contribute to tissue aging rate disparities. However, there are challenges in addressing these cell-type differences at regional, tissue, and subject level. To address this question, we established primary cells from aged male and female baboons between 13.3 and 17.8 years spanning across different tissues, tissue regions, and cell types including (1) fibroblasts from skin and from the heart separated into the left ventricle (LV), right ventricle (RV), left atrium (LA), and right atrium (RA); (2) astrocytes from the prefrontal cortex and hippocampus; and (3) hepatocytes. Primary cells were characterized by their cell surface markers and their cellular respiration was assessed with Seahorse XFe96. Cellular resilience was assessed by modifying a live-cell imaging approach; we previously reported that monitors proliferation of dividing cells following response and recovery to oxidative (50 µM-H2O2), metabolic (1 mM-glucose), and proteostasis (0.1 µM-thapsigargin) stress. We noted significant differences even among similar cell types that are dependent on tissue source and the diversity in cellular response is stressor-specific. For example, astrocytes had a higher oxygen consumption rate and exhibited greater resilience to oxidative stress (OS) than both fibroblasts and hepatocytes. RV and RA fibroblasts were less resilient to OS compared with LV and LA, respectively. Skin fibroblasts were less impacted by proteostasis stress compared to astrocytes and cardiac fibroblasts. Future studies will test the functional relationship of these outcomes to the age and developmental status of donors as potential predictive markers.
Keywords: Astrocytes; Baboons; Bioenergetics; Fibroblasts; Hepatocytes; Resilience.
Functional regulation of microglia by vitamin B12 alleviates ischemic stroke-induced neuroinflammation in mice
Yong Ge, Changjun Yang, Mojgan Zadeh, Shane M Sprague, Yang-Ding Lin, Heetanshi Sanjay Jain, Brenden Fitzgerald Determann 2nd, William H Roth, Juan Pablo Palavicini, Jonathan Larochelle, Eduardo Candelario-Jalil, Mansour Mohamadzadeh
iScience. 2024 Mar 14;27(4):109480. doi: 10.1016/j.isci.2024.109480. eCollection 2024 Apr 19.
Abstract:
Ischemic stroke is the second leading cause of death and disability worldwide, and efforts to prevent stroke, mitigate secondary neurological damage, and promote neurological recovery remain paramount. Recent findings highlight the critical importance of microbiome-related metabolites, including vitamin B12 (VB12), in alleviating toxic stroke-associated neuroinflammation. Here, we showed that VB12 tonically programmed genes supporting microglial cell division and activation and critically controlled cellular fatty acid metabolism in homeostasis. Intriguingly, VB12 promoted mitochondrial transcriptional and metabolic activities and significantly restricted stroke-associated gene alterations in microglia. Furthermore, VB12 differentially altered the functions of microglial subsets during the acute phase of ischemic stroke, resulting in reduced brain damage and improved neurological function. Pharmacological depletion of microglia before ischemic stroke abolished VB12-mediated neurological improvement. Thus, our preclinical studies highlight the relevance of VB12 in the functional programming of microglia to alleviate neuroinflammation, minimize ischemic injury, and improve host neurological recovery after ischemic stroke.
Keywords: Immunology; Neuroscience; Omics; Transcriptomics.
Therapy-Induced Senescence: Opportunities to Improve Anticancer Therapy
Pataje G Prasanna, Deborah E Citrin, Jeffrey Hildesheim, Mansoor M Ahmed, Sundar Venkatachalam, Gabriela Riscuta, Dan Xi, Guangrong Zheng, Jan van Deursen, Jorg Goronzy, Stephen J Kron, Mitchell S Anscher, Norman E Sharpless, Judith Campisi, Stephen L Brown, Laura J Niedernhofer, Ana O’Loghlen, Alexandros G Georgakilas, Francois Paris, David Gius, David A Gewirtz, Clemens A Schmitt, Mohamed E Abazeed, James L Kirkland, Ann Richmond, Paul B Romesser, Scott W Lowe, Jesus Gil, Marc S Mendonca, Sandeep Burma, Daohong Zhou, C Norman Coleman
J Natl Cancer Inst. 2021 Oct 1;113(10):1285-1298. doi: 10.1093/jnci/djab064.
Abstract:
Cellular senescence is an essential tumor suppressive mechanism that prevents the propagation of oncogenically activated, genetically unstable, and/or damaged cells. Induction of tumor cell senescence is also one of the underlying mechanisms by which cancer therapies exert antitumor activity. However, an increasing body of evidence from preclinical studies demonstrates that radiation and chemotherapy cause accumulation of senescent cells (SnCs) both in tumor and normal tissue. SnCs in tumors can, paradoxically, promote tumor relapse, metastasis, and resistance to therapy, in part, through expression of the senescence-associated secretory phenotype. In addition, SnCs in normal tissue can contribute to certain radiation- and chemotherapy-induced side effects. Because of its multiple roles, cellular senescence could serve as an important target in the fight against cancer. This commentary provides a summary of the discussion at the National Cancer Institute Workshop on Radiation, Senescence, and Cancer (August 10-11, 2020, National Cancer Institute, Bethesda, MD) regarding the current status of senescence research, heterogeneity of therapy-induced senescence, current status of senotherapeutics and molecular biomarkers, a concept of “one-two punch” cancer therapy (consisting of therapeutics to induce tumor cell senescence followed by selective clearance of SnCs), and its integration with personalized adaptive tumor therapy. It also identifies key knowledge gaps and outlines future directions in this emerging field to improve treatment outcomes for cancer patients.
Thioredoxin – a magic bullet or a double-edged sword for mammalian aging?
Yuji Ikeno
Aging Pathobiol Ther. 2021;3(2):17-19. doi: 10.31491/apt.2021.06.056. Epub 2021 Jun 29.
Abstract:
After the discovery of thioredoxin as a reductant for many important enzymes in the early 1960s, biological roles of thioredoxin in pathophysiology have been examined using various species and experimental models, e.g., yeast, invertebrates, rodents, and humans. A large number of studies demonstrated that thioredoxin plays an essential role to maintain a reduced cellular environment and possesses many beneficial effects by maintaining cellular/organ functions and against diseases. However, an important question that remains to be answered is whether thioredoxin could attenuate aging by reducing oxidative damage and changing cellular redox state, which alters redox-sensitive signaling pathways. To address this important question, we have been conducting aging studies with transgenic and knockout mice, and transgenic rats to examine whether the upregulation or downregulation of thioredoxin alters lifespan and age-related pathology. Aging studies conducted by our laboratory and others revealed that the roles of thioredoxin on pathophysiology seem to be more complex than our initial expectations as a potential magic bullet to solve the issues with age. Recent studies indicate that thioredoxin could have both beneficial and potentially deleterious effects on aging and age-related diseases. To critically evaluate the biological effects of thioredoxin on aging and age-related diseases, studies require further consideration to assess additional factors, e.g. levels of thioredoxin in different cellular compartments, different effects in each cell/tissue/organ, physiological aging vs. pathology, and/or at different life stages.
Keywords: Thioredoxin; aging; cancer; knockout mouse; oxidative stress; transgenic mouse.