Abstract:
:Neurovascular dysfunction substantially contributes to Alzheimer disease. Here, we show that transcriptional profiling of human brain endothelial cells (BECs) defines a subset of genes whose expression is age-independent but is considerably altered in Alzheimer disease, including the homeobox gene MEOX2 (also known as GAX), a regulator of vascular differentiation, whose expression is low in Alzheimer disease. By using viral-mediated MEOX2 gene silencing and transfer, we show that restoring expression of the protein it encodes, GAX, in BECs from individuals with Alzheimer disease stimulates angiogenesis, transcriptionally suppresses AFX1 forkhead transcription factor-mediated apoptosis and increases the levels of a major amyloid-beta peptide (Abeta) clearance receptor, the low-density lipoprotein receptor-related protein 1 (LRP), at the blood-brain barrier. In mice, deletion of Meox2 (also known as Gax) results in reductions in brain capillary density and resting cerebral blood flow, loss of the angiogenic response to hypoxia in the brain and an impaired Abeta efflux from brain caused by reduced LRP levels. The link of MEOX2 to neurovascular dysfunction in Alzheimer disease provides new mechanistic and therapeutic insights into this illness.
journal_name
Nat Medjournal_title
Nature medicineauthors
Wu Z,Guo H,Chow N,Sallstrom J,Bell RD,Deane R,Brooks AI,Kanagala S,Rubio A,Sagare A,Liu D,Li F,Armstrong D,Gasiewicz T,Zidovetzki R,Song X,Hofman F,Zlokovic BVdoi
10.1038/nm1287keywords:
subject
Has Abstractpub_date
2005-09-01 00:00:00pages
959-65issue
9eissn
1078-8956issn
1546-170Xpii
nm1287journal_volume
11pub_type
杂志文章相关文献
NATURE MEDICINE文献大全abstract::Foxp3(+) regulatory T (T(reg)) cells suppress different types of immune responses to help maintain homeostasis in the body. How T(reg) cells regulate humoral immunity, including germinal center reactions, is unclear. Here we identify a subset of T(reg) cells expressing CXCR5 and Bcl-6 that localize to the germinal cen...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm.2426
更新日期:2011-07-24 00:00:00
abstract::Neurofibrillary tangles (NFTs), composed of truncated and hyperphosphorylated tau, are a common feature of numerous aging-related neurodegenerative diseases, including Alzheimer's disease (AD). However, the molecular mechanisms mediating tau truncation and aggregation during aging remain elusive. Here we show that asp...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm.3700
更新日期:2014-11-01 00:00:00
abstract::The impact of single-agent antibodies against programmed death-ligand 1 (PD-L1) as maintenance therapy is unknown in patients with metastatic breast cancer. The SAFIR02-BREAST IMMUNO substudy included patients with human epidermal growth factor receptor type 2 (Her2)-negative metastatic breast cancer whose disease did...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/s41591-020-01189-2
更新日期:2021-01-18 00:00:00
abstract::We and others have postulated that a constant number of T lymphocytes is normally maintained without regard to CD4+ or CD8+ phenotype ('blind' T-cell homeostasis). Here we confirm essentially constant T-cell levels (despite marked decline in CD4+ T cells and increase in CD8+ T cells) in homosexual men with incident hu...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm0795-674
更新日期:1995-07-01 00:00:00
abstract::Treatment of cocaine addiction is hampered by high rates of relapse even after prolonged drug abstinence. This relapse to compulsive cocaine use can be triggered by re-exposure to cocaine, by re-exposure to stimuli previously associated with cocaine or by exposure to stress. In laboratory rats, similar events reinstat...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm1001-1151
更新日期:2001-10-01 00:00:00
abstract::HIV infection can cause extensive neuronal loss and clinically a severe dementia. The cause of the neurotoxicity remains unclear as neurons are not infected, but disturbance of glutamate-linked calcium entry has been implicated. In this study, we have shown a decrease in HIV-infected brain of the expression of mRNA an...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm1195-1174
更新日期:1995-11-01 00:00:00
abstract::Copy number variants are a recently discovered source of large-scale genomic diversity present in all individuals. We capitalize on these inherent genomic differences, focusing on deletion polymorphisms, to develop informative fluorescence in situ hybridization probes with the ability to unequivocally distinguish betw...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm.1862
更新日期:2009-02-01 00:00:00
abstract::Immune sensing of a microbe occurs via multiple receptors. How signals from different receptors are coordinated to yield a specific immune response is poorly understood. We show that two pathogen recognition receptors, Toll-like receptor 2 (TLR2) and dectin-1, recognizing the same microbial stimulus, stimulate distinc...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm.1925
更新日期:2009-04-01 00:00:00
abstract::While investigating the novel anticancer drug ecteinascidin 743 (Et743), a natural marine product isolated from the Caribbean sea squirt, we discovered a new cell-killing mechanism mediated by DNA nucleotide excision repair (NER). A cancer cell line selected for resistance to Et743 had chromosome alterations in a regi...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/91008
更新日期:2001-08-01 00:00:00
abstract::Treatment with glatiramer acetate (GA, copolymer-1, Copaxone), a drug approved for multiple sclerosis (MS), in a mouse model promoted development of anti-inflammatory type II monocytes, characterized by increased secretion of interleukin (IL)-10 and transforming growth factor (TGF)-beta, and decreased production of IL...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm1620
更新日期:2007-08-01 00:00:00
abstract::While searching for alternative reading-frame peptides encoded by influenza A virus that are recognized by CD8+ T cells, we found an abundant immunogenic peptide encoded by the +1 reading frame of PB1. This peptide derives from a novel conserved 87-residue protein, PB1-F2, which has several unusual features compared w...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm1201-1306
更新日期:2001-12-01 00:00:00
abstract::The N-terminal fragment of prolactin (16K PRL) inhibits tumor growth by impairing angiogenesis, but the underlying mechanisms are unknown. Here, we found that 16K PRL binds the fibrinolytic inhibitor plasminogen activator inhibitor-1 (PAI-1), which is known to contextually promote tumor angiogenesis and growth. Loss o...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm.3552
更新日期:2014-07-01 00:00:00
abstract::The ability to patent human genes has been costly to researchers and patients, and has restricted competition in the biotech marketplace. The recent US Supreme Court decision making isolated human genes unpatentable will bring freedom of choice to the patient, and level the playing field for research and development. ...
journal_title:Nature medicine
pub_type: 社论
doi:10.1038/nm.3279
更新日期:2013-07-01 00:00:00
abstract::Immunodeficiency is a barrier to successful vaccination in individuals with cancer and chronic infection. We performed a randomized phase 1/2 study in lymphopenic individuals after high-dose chemotherapy and autologous hematopoietic stem cell transplantation for myeloma. Combination immunotherapy consisting of a singl...
journal_title:Nature medicine
pub_type: 杂志文章,随机对照试验
doi:10.1038/nm1310
更新日期:2005-11-01 00:00:00
abstract::Restriction factors are host cell proteins that inhibit retroviral infection. A new study using mutants of human HIV-1 restriction factor SAMHD1 suggests that it inhibits infection through degradation of viral RNA rather than through its dNTPase activity as previously suggested. ...
journal_title:Nature medicine
pub_type: 评论,杂志文章
doi:10.1038/nm.3657
更新日期:2014-08-01 00:00:00
abstract::We report the involvement of an evolutionarily conserved set of mycobacterial genes, the esx-3 region, in evasion of bacterial killing by innate immunity. Whereas high-dose intravenous infections of mice with the rapidly growing mycobacterial species Mycobacterium smegmatis bearing an intact esx-3 locus were rapidly l...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm.2420
更新日期:2011-09-04 00:00:00
abstract::Although the treatment of acute myeloid leukemia (AML) has improved substantially in the past three decades, more than half of all patients develop disease that is refractory to intensive chemotherapy. Functional genomics approaches offer a means to discover specific molecules mediating the aberrant growth and surviva...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm.2819
更新日期:2012-07-01 00:00:00
abstract::Systemic inflammation induces various adaptive responses including tachycardia. Although inflammation-associated tachycardia has been thought to result from increased sympathetic discharge caused by inflammatory signals of the immune system, definitive proof has been lacking. Prostanoids, including prostaglandin (PG) ...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm1231
更新日期:2005-05-01 00:00:00
abstract::Oxygen-regulated protein 150 kD (ORP150) is a novel endoplasmic-reticulum-associated chaperone induced by hypoxia/ischemia. Although ORP150 was sparingly upregulated in neurons from human brain undergoing ischemic stress, there was robust induction in astrocytes. Cultured neurons overexpressing ORP150 were resistant t...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/85463
更新日期:2001-03-01 00:00:00
abstract::Surgery or radiation therapy of metastatic cancer often damages lymph nodes, leading to secondary lymphedema. Here we show, using a newly established mouse model, that collecting lymphatic vessels can be regenerated and fused to lymph node transplants after lymph node removal. Treatment of lymph node-excised mice with...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm1689
更新日期:2007-12-01 00:00:00
abstract::To understand the integrin requirements of T-helper (T(H)) effector subsets, we investigated the contribution of CD18 (beta(2) integrin) to T(H)1 and T(H)2 function in vitro and in relevant disease models. CD18-deficient (Itgb2(-/-)) T cells showed largely normal in vitro function. Compared with wild-type mice, Itgb2(...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm932
更新日期:2003-10-01 00:00:00
abstract::Pulmonary hypertension (PH) is characterized by increased proliferation and apoptosis resistance of pulmonary artery smooth muscle cells (PASMCs). Forkhead box O (FoxO) transcription factors are key regulators of cellular proliferation. Here we show that in pulmonary vessels and PASMCs of human and experimental PH lun...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm.3695
更新日期:2014-11-01 00:00:00
abstract::The occurrence of multiple tumors in an organ heralds a rapidly fatal course. Although intravascular administration may deliver oncolytic viruses/vectors to each of these tumors, its efficiency is impeded by an antiviral activity present in complement-depleted plasma of rodents and humans. Here, this activity was show...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/11320
更新日期:1999-08-01 00:00:00
abstract::Huntington's disease is caused by an expanded polyglutamine repeat in the huntingtin protein (HTT), but the pathophysiological sequence of events that trigger synaptic failure and neuronal loss are not fully understood. Alterations in N-methyl-D-aspartate (NMDA)-type glutamate receptors (NMDARs) have been implicated. ...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm.3246
更新日期:2013-08-01 00:00:00
abstract::A characteristic feature of Creutzfeldt-Jakob disease (CJD) is the accumulation in the brain of the amyloid protease-resistant protein PrPres. PrPres derives from a host-encoded, protease-sensitive isoform, PrPsen. Mutations of this protein are linked to familial variants of the disease, and the presence of a methioni...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm0597-521
更新日期:1997-05-01 00:00:00
abstract::Natural killer (NK) cells play an essential role in antiviral immunity, but knowledge of their function in secondary lymphoid organs is incomplete. Lymph node follicles constitute a major viral reservoir during infections with HIV-1 and simian immunodeficiency virus of macaques (SIVmac). In contrast, during nonpathoge...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm.4421
更新日期:2017-11-01 00:00:00
abstract::Multiple sclerosis is an autoimmune disease of the central nervous system (CNS) that is initiated when self-reactive T cells enter the brain and become locally activated after encountering their specific nervous antigens. When and where the disease-relevant antigen encounters occur is unclear. Here we combined fluores...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm.3182
更新日期:2013-06-01 00:00:00
abstract::Movement towards or away from a given stimulus guides the directional migration of prokaryotes, simple eukaryotes and neurons. As bi-directional cues may influence entry and exit of immune effector cells from tissue sites, we evaluated the migratory responses of T-cell subsets to varying concentrations of the chemokin...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/75022
更新日期:2000-05-01 00:00:00
abstract::How should clinical trials be improved? Ken Getz, a senior fellow at the Tufts Center for the Study of Drug Development, has been thinking up answers to this question for two decades. In 2003, Getz took on a new challenge when he launched the Center for Information & Study on Clinical Research, a nonprofit focused on ...
journal_title:Nature medicine
pub_type: 面试
doi:10.1038/nm0210-154
更新日期:2010-02-01 00:00:00
abstract::Major depressive disorder is a devastating psychiatric disease that afflicts up to 17% of the world's population. Postmortem brain analyses and imaging studies of patients with depression have implicated basal lateral amygdala (BLA) dysfunction in the pathophysiology of depression. However, the circuit and molecular m...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/s41591-018-0299-9
更新日期:2019-02-01 00:00:00