Generation of a transgenic mouse line for conditional expression of human IL-6

IL-6 is a cytokine that is involved in various physiological and pathological conditions, and approaches using gain-of-function transgenic animals have contributed in elucidating IL-6 function. However, studies of the multiple functions of IL-6 in vivo are very time consuming because they require the generation of transgenic mice that harbor the gene encoding IL-6 under the control of specific promoters to mimic different pathologies. Here, we report the establishment of a conditional human IL-6 transgenic mouse, LGL-IL6, which conditionally expresses human IL-6 by taking advantage of the well-characterized Cre recombinase drivers

Association Between Appetite and Sarcopenia in Patients With Mild Cognitive Impairment and Early-Stage Alzheimer's Disease: A Case-Control Study

Background: Sarcopenia is frequently seen in patients with mild cognitive impairment (MCI) and early-stage Alzheimer's disease (AD). While appetite loss and physical inactivity, which are also frequently seen in dementia, appear to contribute to sarcopenia, to date, no study has investigated this association.Objective: The aim of this study was to examine factors associated with sarcopenia, including appetite and physical activity, in patients with MCI and early-stage AD.Methods: The study subjects comprised 205 outpatients (MCI, n = 151; early-stage AD, n = 54) who were being treated at the Memory Clinic, National Center for Geriatrics, and Gerontology and had a Mini-Mental State Examination (MMSE) score of 21 or higher. All subjects were assessed for appetite by using the Council on Nutrition Appetite Questionnaire (CNAQ). Confounding variables assessed included physical activity, activities of daily living, mood, body mass index (BMI), nutritional status, and medications. Sarcopenia was defined as low muscle mass and low handgrip strength or slow gait speed. Multivariate logistic regression analyses were performed with adjustment for age, gender, education, and confounding variables to examine the association of sarcopenia with physical activity and appetite. Furthermore, sub-analyses were also conducted to clarify the relationship between CNAQ sub-items and sarcopenia.Results: The prevalence of sarcopenia among the subjects was 14.6% (n = 30). Patients with sarcopenia had lower CNAQ scores (those with sarcopenia, 26.7 ± 3.5; those without, 29.1 ± 2.5). Multivariate analysis showed that BMI (odds ratio [OR], 0.675; 95% confidence interval [CI], 0.534–0.853), polypharmacy (OR, 4.489; 95% CI, 1.315–15.320), and CNAQ (OR, 0.774; 95% CI, 0.630–0.952) were shown to be associated with sarcopenia. Physical activity was not associated with sarcopenia. Of the sub-items of the CNAQ, appetite (OR, 0.353; 95% CI, 0.155–0.805), feeling full (OR, 0.320; 95% CI = 0.135–0.761), and food tastes compared to when younger (OR, 0.299; 95% CI, 0.109–0.818) were shown to be associated with sarcopenia.Conclusions: These results suggest that appetite could be a modifiable risk factor for sarcopenia in patients with MCI and early-stage AD. A comprehensive approach to improving appetite may prove effective in preventing sarcopenia

The matrix vesicle cargo miR-125b accumulates in the bone matrix, inhibiting bone resorption in mice

Communication between osteoblasts and osteoclasts plays a key role in bone metabolism. We describe here an unexpected role for matrix vesicles (MVs), which bud from boneforming osteoblasts and have a well-established role in initiation of bone mineralization, in osteoclastogenesis. We show that the MV cargo miR-125b accumulates in the bone matrix, with increased accumulation in transgenic (Tg) mice overexpressing miR-125b in osteoblasts. Bone formation and osteoblasts in Tg mice are normal, but the number of bone-resorbing osteoclasts is reduced, leading to higher trabecular bone mass. miR-125b in the bone matrix targets and degrades Prdm1, a transcriptional repressor of anti-osteoclastogenic factors, in osteoclast precursors. Overexpressing miR-125b in osteoblasts abrogates bone loss in different mouse models. Our results show that the MV cargo miR-125b is a regulatory element of osteoblast-osteoclast communication, and that bone matrix provides extracellular storage of miR-125b that is functionally active in bone resorption.T.M. and Y.T. were supported in part by MEXT KAKENHI (JP16K11443, T.M.; JP26861548, Y.T.). Y.Y. was supported by MEXT KAKENHI (JP18K19647), the Raffinee International Foundation and the Ono Pharmaceutical Foundation.Supplementary information is available for this paper at https://doi.org/10.1038/s42003-020-0754-2

Risk prediction models for dementia constructed by supervised principal component analysis using miRNA expression data

Alzheimer’s disease (AD) is the most common subtype of dementia, followed by Vascular Dementia (VaD), and Dementia with Lewy Bodies (DLB). Recently, microRNAs (miRNAs) have received a lot of attention as the novel biomarkers for dementia. Here, using serum miRNA expression of 1,601 Japanese individuals, we investigated potential miRNA biomarkers and constructed risk prediction models, based on a supervised principal component analysis (PCA) logistic regression method, according to the subtype of dementia. The final risk prediction model achieved a high accuracy of 0.873 on a validation cohort in AD, when using 78 miRNAs: Accuracy = 0.836 with 86 miRNAs in VaD; Accuracy = 0.825 with 110 miRNAs in DLB. To our knowledge, this is the first report applying miRNA-based risk prediction models to a dementia prospective cohort. Our study demonstrates our models to be effective in prospective disease risk prediction, and with further improvement may contribute to practical clinical use in dementia

Postprandial Hyperglycemia Is Associated With White Matter Hyperintensity and Brain Atrophy in Older Patients With Type 2 Diabetes Mellitus

Type 2 diabetes mellitus is associated with neurodegeneration and cerebrovascular disease. However, the precise mechanism underlying the effects of glucose management on brain abnormalities is not fully understood. The differential impacts of glucose alteration on brain changes in patients with and without cognitive impairment are also unclear. This cross-sectional study included 57 older type 2 diabetes patients with a diagnosis of Alzheimer’s disease (AD) or normal cognition (NC). We examined the effects of hypoglycemia, postprandial hyperglycemia and glucose fluctuations on regional white matter hyperintensity (WMH) and brain atrophy among these patients. In a multiple regression analysis, postprandial hyperglycemia was independently associated with frontal WMH in the AD patients. In addition, postprandial hyperglycemia was significantly associated with brain atrophy, regardless of the presence of cognitive decline. Altogether, our findings indicate that postprandial hyperglycemia is associated with WMH in AD patients but not NC patients, which suggests that AD patients are more susceptible to postprandial hyperglycemia associated with WMH

Regulation of Toll-like receptor signaling by NDP52-mediated selective autophagy is normally inactivated by A20

Toll-like receptor (TLR) signaling is linked to autophagy that facilitates elimination of intracellular pathogens. However, it is largely unknown whether autophagy controls TLR signaling. Here, we report that poly(I:C) stimulation induces selective autophagic degradation of the TLR adaptor molecule TRIF and the signaling molecule TRAF6, which is revealed by gene silencing of the ubiquitin-editing enzyme A20. This type of autophagy induced formation of autophagosomes and could be suppressed by an autophagy inhibitor and lysosomal inhibitors. However, this autophagy was not associated with canonical autophagic processes, including involvement of Beclin-1 and conversion of LC3-I to LC3-II. Through screening of TRIF-interacting ‘autophagy receptors’ in human cells, we identified that NDP52 mediated the selective autophagic degradation of TRIF and TRAF6 but not TRAF3. NDP52 was polyubiquitinated by TRAF6 and was involved in aggregation of TRAF6, which may result in the selective degradation. Intriguingly, only under the condition of A20 silencing, NDP52 could effectively suppress poly(I:C)-induced proinflammatory gene expression. Thus, this study clarifies a selective autophagic mechanism mediated by NDP52 that works downstream of TRIF–TRAF6. Furthermore, although A20 is known as a signaling fine-tuner to prevent excess TLR signaling, it paradoxically downregulates the fine-tuning effect of NDP52 on TLR signaling

Multiancestry analysis of the HLA locus in Alzheimer's and Parkinson's diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

11 páginas, 4 figuras, 2 tablas. Datasets en su material suplementario. This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2302720120/-/DCSupplemental.Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson's disease (PD) and Alzheimer's disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.This work was supported by the Michael J. Fox Foundation grant MJFF-020161 (E.M., Z.G.-O.), NIH and National Institute of Aging grants AG060747 (M.D.G.), AG066206 (Z.H.), AG066515 (Z.H., M.D.G.), the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie (grant agreement No. 890650, Y.L.G.), the Alzheimer’s Association (AARF-20-683984, M.E.B.), and the Iqbal Farrukh and Asad Jamal Fund, a grant from the EU Joint Programme—Neurodegenerative Disease Research (European Alzheimer DNA BioBank, EADB; JPND), the Japan Agency for Medical Research and Development JP21dk0207045 (T.I.), JP21dk020704 (K.O., S.N.), JP21km040550 (K.O.), the Einstein Center for Neurosciences in Berlin (S.M.Y.), the Swedish Research Council (#2018-02532, H.Z.), the European Research Council (#681712, H.Z.), and the Swedish State Support for Clinical Research (#ALFGBG-720931, H.Z.). Inserm UMR1167 is also funded by the Inserm, Institut Pasteur de Lille, Lille Métropole Communauté Urbaine, and the French government’s LABEX DISTALZ program (development of innovative strategies for a transdisciplinary approach to AD). Additional funders of individual investigators and institutions who contributed to data collection and genotyping are provided in SI Appendix.Peer reviewe

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

MyD88 signaling causes autoimmune sialadenitis through formation of high endothelial venules and upregulation of LT beta receptor-mediated signaling

Autoimmune sialadenitis (AS), chronic inflammation of the salivary glands (SGs) with focal lymphocyte infiltration, appears in autoimmune diseases such as Sjogren's syndrome. The pathological role of MyD88-dependent innate immune signaling in autoimmune diseases including AS has been studied using mouse models, such as NOD mice. Although AS development in NOD mice was reported to be suppressed by Myd88 deficiency, its specific role remains unclear. Here, we determined the potent suppressive effects of Myd88 deficiency on AS development in lupus-prone B6/lpr mice, which have lymphoproliferation abnormalities, and also in NOD mice, which have no lymphoproliferation abnormalities. This indicates that MyD88 signaling triggers AS through both lymphoproliferation-dependent and -independent mechanisms. To address the MyD88-dependent lymphoproliferation-independent AS manifestation, SGs from C57BL/6 mice were analyzed. Remarkable upregulation of Glycam1 and high endothelial venule (HEV)-associated changes were unexpectedly found in Myd88(+/+) mice, compared with Myd88(-/-) mice. MyD88-dependent HEV-associated changes were also observed in NOD mice. Additionally, Lta, Ltb, and Ltbr in SGs of NOD mice were lowered by Myd88 deficiency. Interestingly, LT beta R-induced HEV-associated gene expression in cultured cells was impaired by Myd88 deficiency. Our findings highlight novel roles for MyD88 in AS development, which imply the existence of MyD88-dependent HEV formation in ectopic lymphoid neogenesis