Dataset Information

Noggin rescues age-related stem cell loss in the brain of senescent mice with neurodegenerative pathology.

ABSTRACT: Increasing age is the greatest known risk factor for the sporadic late-onset forms of neurodegenerative disorders such as Alzheimer's disease (AD). One of the brain regions most severely affected in AD is the hippocampus, a privileged structure that contains adult neural stem cells (NSCs) with neurogenic capacity. Hippocampal neurogenesis decreases during aging and the decrease is exacerbated in AD, but the mechanistic causes underlying this progressive decline remain largely unexplored. We here investigated the effect of age on NSCs and neurogenesis by analyzing the senescence accelerated mouse prone 8 (SAMP8) strain, a nontransgenic short-lived strain that spontaneously develops a pathological profile similar to that of AD and that has been employed as a model system to study the transition from healthy aging to neurodegeneration. We show that SAMP8 mice display an accelerated loss of the NSC pool that coincides with an aberrant rise in BMP6 protein, enhanced canonical BMP signaling, and increased astroglial differentiation. In vitro assays demonstrate that BMP6 severely impairs NSC expansion and promotes NSC differentiation into postmitotic astrocytes. Blocking the dysregulation of the BMP pathway and its progliogenic effect in vivo by intracranial delivery of the antagonist Noggin restores hippocampal NSC numbers, neurogenesis, and behavior in SAMP8 mice. Thus, manipulating the local microenvironment of the NSC pool counteracts hippocampal dysfunction in pathological aging. Our results shed light on interventions that may allow taking advantage of the brain's natural plastic capacity to enhance cognitive function in late adulthood and in chronic neurodegenerative diseases such as AD.

SUBMITTER: Diaz-Moreno M

PROVIDER: S-EPMC6233090 | biostudies-other | 2018 Nov

REPOSITORIES: biostudies-other

ACCESS DATA

Publications

Noggin rescues age-related stem cell loss in the brain of senescent mice with neurodegenerative pathology.

Díaz-Moreno María M Armenteros Tomás T Gradari Simona S Hortigüela Rafael R García-Corzo Laura L Fontán-Lozano Ángela Á Trejo José Luis JL Mira Helena H

Proceedings of the National Academy of Sciences of the United States of America 20181023 45

Increasing age is the greatest known risk factor for the sporadic late-onset forms of neurodegenerative disorders such as Alzheimer's disease (AD). One of the brain regions most severely affected in AD is the hippocampus, a privileged structure that contains adult neural stem cells (NSCs) with neurogenic capacity. Hippocampal neurogenesis decreases during aging and the decrease is exacerbated in AD, but the mechanistic causes underlying this progressive decline remain largely unexplored. We here ...[more]

PMID: 30352848

Similar Datasets

Project description:PurposeThe molecular mechanisms of age-related bone loss are unclear and without valid drugs yet. The aims of this study were to explore the molecular changes that occur in bone tissue during age-related bone loss, to further clarify the changes in function, and to predict potential therapeutic drugs.MethodsWe collected bone tissues from children, middle-aged individuals, and elderly people for protein sequencing and compared the three groups of proteins pairwise, and the differentially expressed proteins (DEPs) in each group were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). K-means cluster analysis was then used to screen out proteins that continuously increased/decreased with age. Canonical signaling pathways that were activated or inhibited in bone tissue along with increasing age were identified by Ingenuity Pathway Analysis (IPA). Prediction of potential drugs was performed using the Connectivity Map (CMap). Finally, DEPs from sequencing were verified by Western blot, and the drug treatment effect was verified by quantitative real-time PCR.ResultsThe GO and KEGG analyses show that the DEPs were associated with inflammation and bone formation with aging, and the IPA analysis shows that pathways such as IL-8 signaling and acute-phase response signaling were activated, while glycolysis I and EIF2 signaling were inhibited. A total of nine potential drugs were predicted, with rapamycin ranking the highest. In cellular experiments, rapamycin reduced the senescence phenotype produced by the H2O2-stimulated osteocyte-like cell MLO-Y4.ConclusionWith age, inflammatory pathways are activated in bone tissue, and signals that promote bone formation are inhibited. This study contributes to the understanding of the molecular changes that occur in bone tissue during age-related bone loss and provides evidence that rapamycin is a drug of potential clinical value for this disease. The therapeutic effects of the drug are to be further studied in animals.

Project description:BACKGROUND:Autonomic nervous system dysfunction has been previously observed in multiple sclerosis (MS) patients. OBJECTIVE:To assess associations between magnetic resonance imaging-detected neuroinflammatory and neurodegenerative pathology and postural venous flow changes indicative of autonomic nervous system function. METHODS:We used a standardized 3T magnetic resonance imaging protocol to scan 138 patients with MS and 49 healthy controls. Lesion volume and brain volumes were assessed. The cerebral venous flow (CVF) was examined by color-Doppler sonography in supine and upright positions and the difference was calculated as ?CVF. Based on ?CVF, subjects were split into absolute or quartile groups. Student's t test, ?2-test, and analysis of covariance adjusted for age and sex were used accordingly. Benjamini-Hochberg procedure corrected the p-values for multiple comparisons. RESULTS:No differences were found between healthy controls and patients with MS in both supine and upright Doppler-derived CVF, nor in prevalence of abnormal postural venous control. Patients with absolute negative ?CVF had higher disability scores (p?=?0.013), lower gray matter (p?=?0.039) and cortical (p?=?0.044) volumes. The negative ?CVF MS group also showed numerically worse bladder/bowel function when compared to the positive ?CVF (2.3 vs. 1.5, p?=?0.052). Similarly, the lowest quartile ?CVF MS group had higher T1-lesion volumes (p?=?0.033), T2-lesion volumes (p?=?0.032), and lower deep gray matter (p?=?0.043) and thalamus (p?=?0.033) volumes when compared to those with higher ?CVF quartiles. CONCLUSION:No difference in postural venous outflow between patients with MS and healthy controls was found. However, when the abnormal ?CVF is present within the MS population, it may be associated with more inflammatory and neurodegenerative pathology. Further studies should explore whether the orthostatic venous changes are an aging or an MS-related phenomenon and if the etiology is due to impaired autonomic nervous system functioning.

Dataset Information

Noggin rescues age-related stem cell loss in the brain of senescent mice with neurodegenerative pathology.

Publications

Noggin rescues age-related stem cell loss in the brain of senescent mice with neurodegenerative pathology.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets