Anti-Inflammatory Role of the Klotho Protein and Relevance to Aging DOI Open Access
Gérald J. Prud’homme, Qinghua Wang

Published: Aug. 5, 2024

The α-Klotho protein (hereafter Klotho) is an obligate coreceptor for fibroblast growth factor 23 (FGF23). It produced in the kidneys, brain and other sites. Klotho insufficiency causes hyperphosphatemia anomalies. Importantly, it associated with chronic pathologies (often age-related) that have inflammatory component. This includes atherosclerosis, diabetes Alzheimer’s disease. Its mode of action these diseases not well understood, but inhibits or regulates multiple major pathways. has a membrane form, soluble form (s-Klotho). Cytosolic postulated characterized. s-Klotho endocrine properties are incompletely elucidated. binds to FGF receptor 1c (FGFR1c) widely expressed (including endothelial cells). also attaches FGF23, FGF23/Klotho FGFRs. Thus, might be roaming FGF23 coreceptor, functions. Notably, (cell-bound soluble) counteracts inflammation, appears mitigate related aging (inflammaging). NF-κB NLRP3 inflammasome. inflammasome requires priming by NF-κB, produces active IL-1β, pores cell death (pyroptosis). In accord, countered inflammation injury induced toxins, damage-associated molecular patterns (DAMPs), cytokines, reactive oxygen species (ROS). blocks TGF-β Wnt ligands, which lessens fibrotic Low loss muscle mass (sarcopenia), as occurs diseases. counters inhibitory effects myostatin on muscle, reduces improves repair following injury. Inhibition factors may protective diabetic retinopathy age-related macular degeneration (AMD). review examines functions especially potential applications.

Language: Английский

Astrocytes, via RTP801, contribute to cognitive decline by disrupting GABAergic‐regulated connectivity and driving neuroinflammation in an Alzheimer's disease mouse model DOI Creative Commons
Almudena Chicote‐González, Júlia Solana‐Balaguer, Pol Garcia‐Segura

et al.

Alzheimer s & Dementia, Journal Year: 2025, Volume and Issue: 21(4)

Published: April 1, 2025

Abstract INTRODUCTION Alzheimer's disease (AD) pathogenesis involves astrocytic responses to extracellular amyloid beta deposits and phospho‐tau neurofibrillary tangles, which drive inflammatory activation. RTP801, a stress‐responsive protein, has been implicated in mediating neuroinflammation. Its levels are increased AD hippocampal samples, correlating with severity cognitive decline. METHODS Using astrocyte‐specific RTP801 silencing the hippocampus of 5xFAD mice, we evaluated cognition, neuroinflammation, connectivity by magnetic resonance spectroscopy (MRS) resting‐state functional analyses. Histological biochemical analyses assessed microgliosis, astrogliosis, inflammasome‐related protein levels. RESULTS Astrocytic mice preserved spatial memory, maintained γ‐aminobutyric acid (GABA) levels, brain networks. In addition, significantly reduced markers inflammasome effectors. DISCUSSION contributes AD‐associated decline disrupting GABAergic‐regulated amplifying responses. Targeting may therefore offer therapeutic potential mitigate progression preserving neural reducing Highlights The mouse model presents higher astrocytes. Normalizing prevents restores anxiety‐like behavior model. Knocking down preserves mediates loss Parvalbumin+ interneurons, negatively affecting astro‐ microgliosis expression

Language: Английский

Citations

0
Restoring neuronal excitability and spatial memory through inhibiting amyloid-β-induced hyperactive NF-κB in a rat model of Alzheimer’s disease DOI
Zahra Soleimani, Shima Davoudi,

Fatemeh Saffarzadeh

et al.

Brain Research, Journal Year: 2025, Volume and Issue: 1861, P. 149703 - 149703

Published: May 17, 2025

Language: Английский

Citations

0
Immunity impacts cognitive deficits across neurological disorders DOI Creative Commons
Benjamin C. Shaw, V. Anders,

Rachel A. Tinkey

et al.

Journal of Neurochemistry, Journal Year: 2023, Volume and Issue: unknown

Published: Oct. 29, 2023

Abstract Cognitive deficits are a common comorbidity with neurological disorders and normal aging. Inflammation is associated multiple diseases including classical neurodegenerative dementias such as Alzheimer's disease (AD) autoimmune sclerosis (MS), in which over half of all patients experience some form cognitive deficits. Other degenerative the central nervous system (CNS) frontotemporal lobe dementia (FTLD), Parkinson's (PD) well traumatic brain injury (TBI) psychological like major depressive disorder (MDD), even aging have cytokine‐associated reductions function. Thus, there likely commonality between these secondary inflammation. Neurological increasingly substantial neuroinflammation, CNS‐resident cells secrete cytokines chemokines tumor necrosis factor (TNF)α interleukins (ILs) IL‐1β IL‐6. also respond to wide variety chemokines, can both direct effects on neurons by changing expression ion channels perturbing electrical properties, indirect through glia–glia immune‐glia cross‐talk. There significant overlap cytokine chemokine profiles across diseases, TNFα IL‐6 strongly disorders. Here, we review involvement various AD, MS, FTLD, PD, TBI, MDD, absence dementia. We propose that neuropsychiatric phenotypes observed may be at least partially attributable dysregulation immunity resulting pathological from non‐resident cells. image

Language: Английский

Citations

9
NLRP6 deficiency inhibits neuroinflammation and ameliorates brain injury in ischemic stroke by blocking NLRs inflammasomes activation through proteasomal degradation of pro-caspase-1 DOI Creative Commons
Qi He,

Changchang Meng,

Mengjie Jia

et al.

Neurobiology of Disease, Journal Year: 2024, Volume and Issue: 192, P. 106434 - 106434

Published: Feb. 8, 2024

Innate inflammation is crucial for ischemic stroke development. NLRP6, a nucleotide-binding and oligomerization domain-like receptors (NLRs) family member, regulates innate inflammation. Whether NLRP6 neurological damage neuroinflammation during remains unclear. We report that abundantly expressed in microglia significantly upregulated the brain. The brain injury severity was alleviated NLRP6-deficient mice after stroke, as evidenced by reduced cerebral infarct volume, decreased deficit scores, improved histopathological morphological changes, ameliorated neuronal denaturation, relief of sensorimotor dysfunction. In co-culture OGD/R model, deficiency prevented death attenuated microglial cell injury. blocked several NLRs inflammasomes' activation abrogated inflammasome-related cytokine production decreasing expression common effector pro-caspase-1. pro-caspase-1's protein level inducing proteasomal degradation. These findings confirm neuroprotective role its underlying regulation mechanism provide potential therapeutic target stroke.

Language: Английский

Citations

3
Anti-Inflammatory Role of the Klotho Protein and Relevance to Aging DOI Open Access
Gérald J. Prud’homme, Qinghua Wang

Published: Aug. 5, 2024

The α-Klotho protein (hereafter Klotho) is an obligate coreceptor for fibroblast growth factor 23 (FGF23). It produced in the kidneys, brain and other sites. Klotho insufficiency causes hyperphosphatemia anomalies. Importantly, it associated with chronic pathologies (often age-related) that have inflammatory component. This includes atherosclerosis, diabetes Alzheimer’s disease. Its mode of action these diseases not well understood, but inhibits or regulates multiple major pathways. has a membrane form, soluble form (s-Klotho). Cytosolic postulated characterized. s-Klotho endocrine properties are incompletely elucidated. binds to FGF receptor 1c (FGFR1c) widely expressed (including endothelial cells). also attaches FGF23, FGF23/Klotho FGFRs. Thus, might be roaming FGF23 coreceptor, functions. Notably, (cell-bound soluble) counteracts inflammation, appears mitigate related aging (inflammaging). NF-κB NLRP3 inflammasome. inflammasome requires priming by NF-κB, produces active IL-1β, pores cell death (pyroptosis). In accord, countered inflammation injury induced toxins, damage-associated molecular patterns (DAMPs), cytokines, reactive oxygen species (ROS). blocks TGF-β Wnt ligands, which lessens fibrotic Low loss muscle mass (sarcopenia), as occurs diseases. counters inhibitory effects myostatin on muscle, reduces improves repair following injury. Inhibition factors may protective diabetic retinopathy age-related macular degeneration (AMD). review examines functions especially potential applications.

Language: Английский

Citations

3