Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Wnt Signaling Deregulation in the Aging and Alzheimer's Brain.

ABSTRACT: Growing evidence suggests that synaptic signaling is compromised in the aging brain and in Alzheimer's disease (AD), contributing to synaptic decline. Wnt signaling is a prominent pathway at the synapse and is required for synaptic plasticity and maintenance in the adult brain. In this review, we summarize the current knowledge on deregulation of Wnt signaling in the context of aging and AD. Emerging studies suggest that enhancing Wnt signaling could boost synaptic function during aging, and ameliorate synaptic pathology in AD. Although further research is needed to determine the precise contribution of deficient Wnt signaling to AD pathogenesis, targeting Wnt signaling components may provide novel therapeutic avenues for synapse protection or restoration in the brain.

SUBMITTER: Palomer E

PROVIDER: S-EPMC6538920 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Wnt Signaling Deregulation in the Aging and Alzheimer's Brain.

Palomer Ernest E Buechler Johanna J Salinas Patricia C PC

Frontiers in cellular neuroscience 20190522

Growing evidence suggests that synaptic signaling is compromised in the aging brain and in Alzheimer's disease (AD), contributing to synaptic decline. Wnt signaling is a prominent pathway at the synapse and is required for synaptic plasticity and maintenance in the adult brain. In this review, we summarize the current knowledge on deregulation of Wnt signaling in the context of aging and AD. Emerging studies suggest that enhancing Wnt signaling could boost synaptic function during aging, and ame ...[more]

PMID: 31191253

Similar Datasets

Deregulation of brain insulin signaling in Alzheimer's disease.

Project description:Contrary to the previous belief that insulin does not act in the brain, studies in the last three decades have demonstrated important roles of insulin and insulin signal transduction in various functions of the central nervous system. Deregulated brain insulin signaling and its role in molecular pathogenesis have recently been reported in Alzheimer's disease (AD). In this article, we review the roles of brain insulin signaling in memory and cognition, the metabolism of amyloid β precursor protein, and tau phosphorylation. We further discuss deficiencies of brain insulin signaling and glucose metabolism, their roles in the development of AD, and recent studies that target the brain insulin signaling pathway for the treatment of AD. It is clear now that deregulation of brain insulin signaling plays an important role in the development of sporadic AD. The brain insulin signaling pathway also offers a promising therapeutic target for treating AD and probably other neurodegenerative disorders.

| S-EPMC5562654 | biostudies-other

Aging brain microenvironment decreases hippocampal neurogenesis through Wnt-mediated survivin signaling.

Project description:Accumulating evidence suggests that adult hippocampal neurogenesis relies on the controlled and continued proliferation of neural progenitor cells (NPCs). With age, neurogenesis decreases through mechanisms that remain unclear but are believed to involve changes in the NPC microenvironment. Here, we provide evidence that NPC proliferation in the adult brain is in part regulated by astrocytes via Wnt signaling and that this cellular cross-talk is modified in the aging brain, leading to decreased proliferation of NPCs. Furthermore, we show that astrocytes regulate the NPC cell cycle by acting on the expression levels of survivin, a known mitotic regulator. Among cell cycle genes found down-regulated in aged NPCs, survivin was the only one that restored NPC proliferation in the aged brain. Our results provide a mechanism for the gradual loss of neurogenesis in the brain associated with aging and suggest that targeted modulation of survivin expression directly or through Wnt signaling could be used to stimulate adult neurogenesis.

| S-EPMC3350615 | biostudies-literature

Distinguishing normal brain aging from the development of Alzheimer's disease: inflammation, insulin signaling and cognition.

Project description:As populations age, prevalence of Alzheimer's disease (AD) is rising. Over 100 years of research has provided valuable insights into the pathophysiology of the disease, for which age is the principal risk factor. However, in recent years, a multitude of clinical trial failures has led to pharmaceutical corporations becoming more and more unwilling to support drug development in AD. It is possible that dependence on the amyloid cascade hypothesis as a guide for preclinical research and drug discovery is part of the problem. Accumulating evidence suggests that amyloid plaques and tau tangles are evident in non-demented individuals and that reducing or clearing these lesions does not always result in clinical improvement. Normal aging is associated with pathologies and cognitive decline that are similar to those observed in AD, making differentiation of AD-related cognitive decline and neuropathology challenging. In this mini-review, we discuss the difficulties with discerning normal, age-related cognitive decline with that related to AD. We also discuss some neuropathological features of AD and aging, including amyloid and tau pathology, synapse loss, inflammation and insulin signaling in the brain, with a view to highlighting cognitive or neuropathological markers that distinguish AD from normal aging. It is hoped that this review will help to bolster future preclinical research and support the development of clinical tools and therapeutics for AD.

| S-EPMC6128051 | biostudies-literature

Deregulation of Wnt/?-catenin signaling through genetic or epigenetic alterations in human neuroendocrine tumors.

Project description:Carcinoid tumors are rare neuroendocrine tumors (NETs) that are increasing in incidence. Mutation and altered expression of Wnt/?-catenin signaling components have been described in many tumors but have not been well-studied in NETs. Here, we observed accumulation of ?-catenin in the cytoplasm and/or nucleus in 25% of clinical NET tissues. By mutational analysis, the mutations of ?-catenin (I35S) and APC (E1317Q, T1493T) were identified in NET cells and the tissues. Expression of representative Wnt inhibitors was absent or markedly decreased in BON, a human pancreatic carcinoid cell line; treatment with 5-aza-2'-deoxycytidine (5-aza-CdR) increased expression levels of the Wnt inhibitors. Methylation analyses demonstrated that CpG islands of SFRP-1 and Axin-2 were methylated, whereas the promoters of DKK-1, DKK-3 and WIF-1 were unmethylated in four NET cells. Aberrant methylation of SFRP-1 was particularly observed in most of clinical NET tissues. In addition, the repression of these unmethylated genes was associated with histone H3 lysine 9 dimethylation (H3K9me2) in BON cells. Together, 5-aza-CdR treatment inhibited cell proliferation and decreased the protein levels of H3K9me2 and G9a. Moreover, a novel G9a inhibitor, UNC0638, suppressed BON cell proliferation through inhibition of Wnt/?-catenin pathway. Overexpression of the inhibitory genes, particularly SFRP-1 and WIF-1 in BON cells, resulted in suppression of anchorage-independent growth and inhibition of tumor growth in mice. Our findings suggest that aberrant Wnt/?-catenin signaling, through either mutations or epigenetic silencing of Wnt antagonists, contributes to the pathogenesis and growth of NETs and have important clinical implications for the prognosis and treatment of NETs.

| S-EPMC3643417 | biostudies-literature

Canonical Wnt Signaling Ameliorates Aging of Intestinal Stem Cells.

Project description:Although intestinal homeostasis is maintained by intestinal stem cells (ISCs), regeneration is impaired upon aging. Here, we first uncover changes in intestinal architecture, cell number, and cell composition upon aging. Second, we identify a decline in the regenerative capacity of ISCs upon aging because of a decline in canonical Wnt signaling in ISCs. Changes in expression of Wnts are found in stem cells themselves and in their niche, including Paneth cells and mesenchyme. Third, reactivating canonical Wnt signaling enhances the function of both murine and human ISCs and, thus, ameliorates aging-associated phenotypes of ISCs in an organoid assay. Our data demonstrate a role for impaired Wnt signaling in physiological aging of ISCs and further identify potential therapeutic avenues to improve ISC regenerative potential upon aging.

| S-EPMC5987258 | biostudies-literature

H3K18 lactylation of senescent microglia potentiates brain aging and Alzheimer's disease through the NFκB signaling pathway.

Project description:Cellular senescence serves as a fundamental and underlying activity that drives the aging process, and it is intricately associated with numerous age-related diseases, including Alzheimer's disease (AD), a neurodegenerative aging-related disorder characterized by progressive cognitive impairment. Although increasing evidence suggests that senescent microglia play a role in the pathogenesis of AD, their exact role remains unclear. In this study, we quantified the levels of lactic acid in senescent microglia, and hippocampus tissues of naturally aged mice and AD mice models (FAD4T and APP/PS1). We found lactic acid levels were significantly elevated in these cells and tissues compared to their corresponding counterparts, which increased the level of pan histone lysine lactylation (Kla). We aslo identified all histone Kla sites in senescent microglia, and found that both the H3K18 lactylation (H3K18la) and Pan-Kla were significantly up-regulated in senescent microglia and hippocampus tissues of naturally aged mice and AD modeling mice. We demonstrated that enhanced H3K18la directly stimulates the NFκB signaling pathway by increasing binding to the promoter of Rela (p65) and NFκB1(p50), thereby upregulating senescence-associated secretory phenotype (SASP) components IL-6 and IL-8. Our study provides novel insights into the physiological function of Kla and the epigenetic regulatory mechanism that regulates brain aging and AD. Specifically, we have identified the H3K18la/NFκB axis as a critical player in this process by modulating IL-6 and IL-8. Targeting this axis may be a potential therapeutic strategy for delaying aging and AD by blunting SASP.

| S-EPMC10494370 | biostudies-literature

Phosphatase WIP1 regulates adult neurogenesis and WNT signaling during aging.

Project description:The number of newly formed neurons declines rapidly during aging, and this decrease in neurogenesis is associated with decreased function of neural stem/progenitor cells (NPCs). Here, we determined that a WIP1-dependent pathway regulates NPC differentiation and contributes to the age-associated decline of neurogenesis. Specifically, we found that WIP1 is expressed in NPCs of the mouse subventricular zone (SVZ) and aged animals with genetically enhanced WIP1 expression exhibited higher NPC numbers and neuronal differentiation compared with aged WT animals. Additionally, augmenting WIP1 expression in aged animals markedly improved neuron formation and rescued a functional defect in fine odor discrimination in aged mice. We identified the WNT signaling pathway inhibitor DKK3 as a key downstream target of WIP1 and found that expression of DKK3 in the SVZ is restricted to NPCs. Using murine reporter strains, we determined that DKK3 inhibits neuroblast formation by suppressing WNT signaling and Dkk3 deletion or pharmacological activation of the WNT pathway improved neuron formation and olfactory function in aged mice. We propose that WIP1 controls DKK3-dependent inhibition of neuronal differentiation during aging and suggest that regulating WIP1 levels could prevent certain aspects of functional decline of the aging brain.

| S-EPMC4071391 | biostudies-literature

Homeostatic disinhibition in the aging brain and Alzheimer's disease.

Project description:In this article, we propose that impaired efficiency of glutamatergic synaptic transmission and a compensatory reduction in inhibitory neurotransmission, a process called homeostatic disinhibition, occurs in the aging brain and more dramatically in Alzheimer's disease (AD). Homeostatic disinhibition may help understand certain features of the aging brain and AD, including: 1) the increased risk for epileptic seizures, especially in the early phase of the disease; 2) the reduced ability to generate ?-oscillations; and 3) the increase in neuronal activity as measured by functional MRI. Homeostatic disinhibition may be the major mechanism that activates cognitive reserve. Modulating neuronal activity may therefore be a viable therapeutic strategy in AD that can complement existing anti-amyloid strategies. Specifically, enhancing endogenous glutamatergic synaptic transmission through increased co-agonist signaling or through positive allosteric modulation of metabotropic glutamatergic receptors appears as an attractive strategy. Alternatively, further reduction of GABAergic signaling may work as well, although care has to be taken to prevent epileptic seizures.

| S-EPMC4543386 | biostudies-literature

Metabolic brain networks in aging and preclinical Alzheimer's disease.

Project description:Metabolic brain networks can provide insight into the network processes underlying progression from healthy aging to Alzheimer's disease. We explore the effect of two Alzheimer's disease risk factors, amyloid-? and ApoE ?4 genotype, on metabolic brain networks in cognitively normal older adults (N = 64, ages 69-89) compared to young adults (N = 17, ages 20-30) and patients with Alzheimer's disease (N = 22, ages 69-89). Subjects underwent MRI and PET imaging of metabolism (FDG) and amyloid-? (PIB). Normal older adults were divided into four subgroups based on amyloid-? and ApoE genotype. Metabolic brain networks were constructed cross-sectionally by computing pairwise correlations of metabolism across subjects within each group for 80 regions of interest. We found widespread elevated metabolic correlations and desegregation of metabolic brain networks in normal aging compared to youth and Alzheimer's disease, suggesting that normal aging leads to widespread loss of independent metabolic function across the brain. Amyloid-? and the combination of ApoE ?4 led to less extensive elevated metabolic correlations compared to other normal older adults, as well as a metabolic brain network more similar to youth and Alzheimer's disease. This could reflect early progression towards Alzheimer's disease in these individuals. Altered metabolic brain networks of older adults and those at the highest risk for progression to Alzheimer's disease open up novel lines of inquiry into the metabolic and network processes that underlie normal aging and Alzheimer's disease.

| S-EPMC5842784 | biostudies-literature

Epigenetic deregulation of MLF1 drives intrahepatic cholangiocarcinoma progression through EGFR/AKT and Wnt/β-catenin signaling.

Project description:BackgroundIntrahepatic cholangiocarcinoma (iCCA) is an aggressive malignancy with multiple etiologies and is largely refractory to current treatment strategies. Myeloid leukemia factor 1 (MLF1) is associated with human cancer progression. Nevertheless, the function of MLF1 in iCCA remains unknown.MethodsWe performed expression analyses of MLF1 in human iCCA. In vitro and in vivo experiments were conducted to investigate the role of MLF1 in iCCA progression. The upstream regulatory mechanism of MLF1 upregulation in iCCA was deciphered by luciferase and DNA methylation analyses.ResultsMLF1 was significantly upregulated in clinical iCCA tissue specimens and human iCCA cell lines. MLF1 was positively correlated with KRT19 and MUC1 expression and epithelial-mesenchymal transition (EMT) gene set enrichment score in clinical iCCA. High MLF1 expression was independently associated with worse prognoses in iCCA patients after curative resection. In addition, experimental knockdown of MLF1 attenuated, while overexpression of MLF1 promoted the proliferation, invasiveness, and growth of iCCA cells in vitro and in vivo. Mechanically, MLF1 comodulated EGFR/AKT and Wnt/β-catenin signalings through regulating EGFR, AKT, WNT3, and p-GSK3β expression. Promoter CpG sites' hypermethylation-induced downregulation of miR-29c-3p contributed to MLF1 upregulation in iCCA patients. The upregulation of DNA methyltransferase (DNMT)1, 3A, and 3B downregulated miR-29c-3p by dictating promoter DNA methylation pattern. MiR-29c-3p showed therapeutic potential by targeting MLF1 in iCCA.ConclusionsOur results demonstrated that hypermethylation-mediated miR-29c-3p downregulation contributes to MLF1 upregulation in iCCA, which resulted in tumor cells' proliferation and metastasis through comodulating EGFR/AKT and Wnt/β-catenin signalings.

| S-EPMC10368384 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data