Concise Communication

Abstract

Carrying the ε4 allele of the APOE gene encoding apolipoprotein E (APOE4) markedly increases the risk for late-onset Alzheimer’s disease (AD), in which APOE4 exacerbates the brain accumulation and subsequent deposition of amyloid-β (Aβ) peptides. While the LDL receptor–related protein 1 (LRP1) is a major apoE receptor in the brain, we found that its levels are associated with those of insoluble Aβ depending on APOE genotype status in postmortem AD brains. Thus, to determine the functional interaction of apoE4 and LRP1 in brain Aβ metabolism, we crossed neuronal LRP1-knockout mice with amyloid model APP/PS1 mice and APOE3–targeted replacement (APO3-TR) or APOE4-TR mice. Consistent with previous findings, mice expressing apoE4 had increased Aβ deposition and insoluble amounts of Aβ40 and Aβ42 in the hippocampus of APP/PS1 mice compared with those expressing apoE3. Intriguingly, such effects were reversed in the absence of neuronal LRP1. Neuronal LRP1 deficiency also increased detergent-soluble apoE4 levels, which may contribute to the inhibition of Aβ deposition. Together, our results suggest that apoE4 exacerbates Aβ pathology through a mechanism that depends on neuronal LRP1. A better understanding of apoE isoform–specific interaction with their metabolic receptor LRP1 on Aβ metabolism is crucial for defining APOE4-related risk for AD.

Authors

Masaya Tachibana, Marie-Louise Holm, Chia-Chen Liu, Mitsuru Shinohara, Tomonori Aikawa, Hiroshi Oue, Yu Yamazaki, Yuka A. Martens, Melissa E. Murray, Patrick M. Sullivan, Kathrin Weyer, Simon Glerup, Dennis W. Dickson, Guojun Bu, Takahisa Kanekiyo

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Abstract

Septic patients frequently develop cognitive impairment that persists beyond hospital discharge. The impact of sepsis on electrophysiological and molecular determinants of learning is underexplored. We observed that mouse survivors of sepsis or endotoxemia experienced loss of hippocampal long-term potentiation (LTP), a brain-derived neurotrophic factor (BDNF)-mediated process responsible for spatial memory formation. Memory impairment occurred despite preserved hippocampal BDNF content and could be reversed by stimulation of BDNF signaling, suggesting the presence of a local BDNF inhibitor. Sepsis is associated with degradation of the endothelial glycocalyx, releasing heparan sulfate fragments (of sufficient size and sulfation to bind BDNF) into the circulation. Heparan sulfate fragments penetrated the hippocampal blood-brain barrier during sepsis and inhibited BDNF-mediated LTP. Glycoarray approaches demonstrated that heparan sulfate’s avidity for BDNF increased with sulfation at the 2-O-position of iduronic acid and N-position of glucosamine. Circulating heparan sulfate in endotoxemic mice and septic humans was enriched in 2-O- and N-sulfated disaccharides; furthermore, the presence of these sulfation patterns in the plasma of septic patients at intensive care unit (ICU) admission predicted persistent cognitive impairment 14 days after ICU discharge or at hospital discharge. Our findings indicate that circulating 2-O- and N-sulfated heparan sulfate fragments contribute to septic cognitive impairment.

Authors

Joseph A. Hippensteel, Brian J. Anderson, James E. Orfila, Sarah A. McMurtry, Robert M. Dietz, Guowei Su, Joshay A. Ford, Kaori Oshima, Yimu Yang, Fuming Zhang, Xiaorui Han, Yanlei Yu, Jian Liu, Robert J. Linhardt, Nuala J. Meyer, Paco S. Herson, Eric P. Schmidt

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Abstract

Authors

Parisa Malekzadeh, Anna Pasetto, Paul F. Robbins, Maria R. Parkhurst, Biman C. Paria, Li Jia, Jared J. Gartner, Victoria Hill, Zhiya Yu, Nicholas P. Restifo, Abraham Sachs, Eric Tran, Winifred Lo, Robert P.T. Somerville, Steven A. Rosenberg, Drew C. Deniger

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Abstract

Using an integrated approach to characterize the pancreatic tissue and isolated islets from a 33-year-old with 17 years of type 1 diabetes (T1D), we found that donor islets contained β cells without insulitis and lacked glucose-stimulated insulin secretion despite a normal insulin response to cAMP-evoked stimulation. With these unexpected findings for T1D, we sequenced the donor DNA and found a pathogenic heterozygous variant in the gene encoding hepatocyte nuclear factor-1α (HNF1A). In one of the first studies of human pancreatic islets with a disease-causing HNF1A variant associated with the most common form of monogenic diabetes, we found that HNF1A dysfunction leads to insulin-insufficient diabetes reminiscent of T1D by impacting the regulatory processes critical for glucose-stimulated insulin secretion and suggest a rationale for a therapeutic alternative to current treatment.

Authors

Rachana Haliyur, Xin Tong, May Sanyoura, Shristi Shrestha, Jill Lindner, Diane C. Saunders, Radhika Aramandla, Greg Poffenberger, Sambra D. Redick, Rita Bottino, Nripesh Prasad, Shawn E. Levy, Raymond D. Blind, David M. Harlan, Louis H. Philipson, Roland W. Stein, Marcela Brissova, Alvin C. Powers

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Abstract

Replicative immortality is a hallmark of cancer governed by telomere maintenance. About 90% of human cancers maintain their telomeres by activating telomerase, driven by transcriptional upregulation of telomerase reverse transcriptase (TERT). Although TERT promoter mutations (TPMs) are a major cancer-associated genetic mechanism of TERT upregulation, many cancers exhibit TERT upregulation without TPMs. In this study, we described TERT Hypermethylated Oncological Region (THOR), a 433-bp genomic region encompassing 52 CpG sites located immediately upstream of the TERT core promoter, as a cancer-associated epigenetic mechanism of TERT upregulation. Unmethylated THOR repressed TERT promoter activity regardless of TPMs status, and hypermethylation of THOR counteracted this repressive function. THOR methylation analysis in 1,352 human tumors revealed frequent (>45%) cancer-associated DNA hypermethylation in 9 of 11 (82%) tumor types screened. Additionally, THOR hypermethylation — either independently or along with TPMs — accounted for how approximately 90% of human cancers can aberrantly activate telomerase. Thus, we propose THOR hypermethylation as a prevalent telomerase activating mechanism in cancer that can act independently or in conjunction with TPMs, further supporting the utility of THOR hypermethylation as a prognostic biomarker.

Authors

Donghyun D. Lee, Ricardo Leão, Martin Komosa, Marco Gallo, Cindy H. Zhang, Tatiana Lipman, Marc Remke, Abolfazl Heidari, Nuno Miguel Nunes, Joana D. Apolónio, Ramon Andrade De Mello, João Dias, David Huntsman, Thomas Hermanns, Peter J. Wild, Robert Vanner, Gelareh Zadeh, Jason Karamchandani, Sunit Das, Michael D. Taylor, Cynthia E. Hawkins, Jonathan D. Wasserman, Arnaldo Figueiredo, Robert J. Hamilton, Mark D. Minden, Khalida Wani, Bill Diplas, Hai Yan, Kenneth Aldape, Mohammad R. Akbari, Arnavaz Danesh, Trevor J. Pugh, Peter B. Dirks, Pedro Castelo-Branco, Uri Tabori

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Abstract

Angelman syndrome (AS) is a neurodevelopmental disorder in which epilepsy is common (~90%) and often refractory to antiepileptics. AS is caused by mutation of the maternal allele encoding the ubiquitin protein ligase E3A (UBE3A), but it is unclear how this genetic insult confers vulnerability to seizure development and progression (i.e., epileptogenesis). Here we implemented the flurothyl kindling and retest paradigm in AS model mice to assess epileptogenesis and to gain mechanistic insights owed to loss of maternal Ube3a. AS model mice kindled similarly to wildtype mice, but they displayed a markedly increased sensitivity to flurothyl-, kainic acid-, and hyperthermia-induced seizures measured a month later during retest. Pathological characterization revealed enhanced deposition of perineuronal nets in dentate gyrus of hippocampus of AS mice in the absence of overt neuronal loss or mossy fiber sprouting. This pro-epileptogenic phenotype resulted from Ube3a deletion in GABAergic but not glutamatergic neurons, and it was rescued by pancellular reinstatement of Ube3a at postnatal day 21 (P21), but not during adulthood. Our results suggest that epileptogenic susceptibility in AS patients is a consequence of the dysfunctional development of GABAergic circuits, which may be amenable to therapies leveraging juvenile reinstatement of UBE3A.

Authors

Bin Gu, Kelly E. Carstens, Matthew C. Judson, Katherine A. Dalton, Marie Rougié, Ellen P. Clark, Serena M. Dudek, Benjamin D. Philpot

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Abstract

The loss of insulin-secreting β cells is characteristic among Type I and Type II diabetes. Stimulating proliferation to expand sources of β cells for transplantation remains a challenge because adult β cells do not proliferate readily. The cell cycle inhibitor p57 has been shown to control cell division in human β cells. Expression of p57 is regulated by the DNA methylation status of the Imprinting Control Region 2 (ICR2), which is commonly hypomethylated in Beckwith Wiedemann-Syndrome patients who exhibit massive β cell proliferation. We hypothesized that targeted demethylation of the ICR2 using a transcription activator-like effector protein fused to the catalytic domain of TET1 (ICR2-TET1) would repress p57 expression and promote cell proliferation. We report here that overexpression of ICR2-TET1 in human fibroblasts reduces p57 expression levels and increases proliferation. Furthermore, human islets overexpressing ICR2-TET1 exhibit repression of p57 with concomitant upregulation of Ki-67 while maintaining glucose-sensing functionality. When transplanted into diabetic, immunodeficient mice, the epigenetically edited islets show increased β cell replication compared to control islets. These findings demonstrate that epigenetic editing is a promising tool for inducing β cell proliferation, which may one day alleviate the scarcity of transplantable β cells for the treatment of diabetes.

Authors

Kristy Ou, Ming Yu, Nicholas G. Moss, Yue J. Wang, Amber W. Wang, Son C. Nguyen, Connie Jiang, Eseye Feleke, Vasumathi Kameswaran, Eric F. Joyce, Ali Naji, Benjamin Glaser, Dana Avrahami, Klaus H. Kaestner

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Abstract

In the era of combined antiretroviral therapy (cART), lung diseases such as chronic bronchitis (CB) and COPD are common among persons living with HIV (PLWH), particularly smokers. Although smoking is highly prevalent among PLWH, HIV may be an independent risk factor for lung diseases; however, the role of HIV and cigarette smoke (CS) and their potential interaction in the development of chronic lung diseases among PLWH has not been delineated. To investigate this interaction, cynomolgus macaques were exposed to CS and/or simian-adapted human immunodeficiency virus (SHIV) and treated with cART. The development of CB and the lung functions were evaluated following CS±SHIV treatment. The results showed that in the lung, SHIV was a strong independent risk factor for goblet cell metaplasia/hyperplasia and mucus formation, MUC5AC synthesis, loss of tight junction proteins, and increased expression of Th2 cytokines/transcription factors. In addition, SHIV and CS synergistically reduced the lung function and increased the extrathoracic tracheal ring thickness. Interestingly, SHIV-infection generated significant numbers of HIV-gp120+ epithelial cells (HGECs) in small airways and alveoli and their numbers doubled in CS+SHIV-infected lungs. We conclude that even with cART, SHIV independently induces CB and pro-COPD changes in the lung and the effects are exacerbated by CS.

Authors

Hitendra S. Chand, Rodrigo Vazquez-Guillamet, Christopher M. Royer, Karin Rudolph, Neerad C. Mishra, Shashi P. Singh, Shah S. Hussain, Edward G. Barrett, Shannon Callen, Siddappa N. Byrareddy, Maria Cristina Vazquez Guillamet, Jawad Abukhalaf, Aryaz Sheybani, Vernat Exil, Veena Raizada, Hemant Agarwal, Madhavan Nair, Francois Villinger, Shilpa Buch, Mohan Sopori

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Abstract

Hyperphosphatemic familial tumoral calcinosis (HFTC)/hyperostosis-hyperphosphatemia syndrome (HHS) is an autosomal recessive disorder of ectopic calcification due to deficiency of or resistance to intact fibroblast growth factor 23 (iFGF23). Inactivating mutations in FGF23, N-acetylgalactosaminyltransferase 3 (GALNT3), or KLOTHO have been reported to cause HFTC/HHS. We present the first identified case of autoimmune hyperphosphatemic tumoral calcinosis in an 8-year-old boy. In addition to the classical clinical and biochemical features of hyperphosphatemic tumoral calcinosis, the patient exhibited markedly elevated intact and C-terminal FGF23 levels suggestive of FGF23 resistance. However, no mutations in FGF23, KLOTHO, or fibroblast growth factor receptor 1 (FGFR1) were identified. He subsequently developed type 1 diabetes mellitus, which raised the possibility of an autoimmune cause for hyperphosphatemic tumoral calcinosis. Luciferase immunoprecipitation systems revealed significantly elevated FGF23 autoantibodies without detectable FGFR1 or KLOTHO autoantibodies. Using an in vitro FGF23 functional assay, the FGF23 autoantibodies in the patient’s plasma blocked downstream signaling via the MAPK/ERK signaling pathway in a dose-dependent manner. Thus, this report describes the first case of autoimmune hyperphosphatemic tumoral calcinosis with pathogenic autoantibodies targeting FGF23. Identification of this pathophysiology extends the etiologic spectrum of hyperphosphatemic tumoral calcinosis and suggests that immunomodulatory therapy may be an effective treatment.

Authors

Mary Scott Roberts, Peter D. Burbelo, Daniela Egli-Spichtig, Farzana Perwad, Christopher J. Romero, Shoji Ichikawa, Emily G. Farrow, Michael J. Econs, Lori C. Guthrie, Michael T. Collins, Rachel I. Gafni

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Abstract

Neutrophil extracellular traps (NETs) are involved in the pathogenesis of many infectious diseases, yet their dynamics and impact on HIV/SIV infection were not yet assessed. We hypothesized that SIV infection and the related microbial translocation trigger NET activation and release (NETosis), and investigated the interactions between NETs and immune cell populations and platelets. We compared and contrasted the levels of NETs between SIV-uninfected, SIV-infected, and SIV-infected antiretroviral-treated nonhuman primates. We also cocultured neutrophils from these animals with either peripheral blood mononuclear cells or platelets. Increased NET production was observed throughout SIV infection. In chronically infected animals, NETs were found in the gut, lung, liver, and in the blood vessels of kidney and heart. ART decreased NETosis, albeit above preinfection levels. NETs captured CD4+ and CD8+ T-cells, B-cells, and monocytes, irrespective of their infection status, potentially contributing to the indiscriminate generalized immune cell loss characteristic to HIV/SIV infection, and limiting the CD4+ T-cell recovery under ART. By capturing and facilitating aggregation of platelets, and through expression of increased tissue factor levels, NETs may also enhance HIV/SIV-related coagulopathy and promote cardiovascular comorbidities.

Authors

Ranjit Sivanandham, Egidio Brocca-Cofano, Noah Krampe, Elizabeth Falwell, Sindhuja Murali Kilapandal Venkatraman, Ruy M. Ribeiro, Cristian Apetrei, Ivona Pandrea

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