CYP46A1 Gene Therapy for Age-Related TREM2-Mediated Microglial Senescence Reversal
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From Analysis:
Lipid raft composition changes in synaptic neurodegeneration
Investigate how lipid raft composition (cholesterol metabolism, sphingolipids) changes in synaptic membranes during neurodegeneration and their mechanistic role in amyloid-beta processing and synapse dysfunction
Hypotheses from Same Analysis (8)
These hypotheses emerged from the same multi-agent debate that produced this hypothesis.
Description
Molecular Mechanism and Rationale
CYP46A1, the rate-limiting enzyme for brain cholesterol elimination, converts cholesterol to 24S-hydroxycholesterol, facilitating its efflux across the blood-brain barrier and maintaining neuronal cholesterol homeostasis. In aging microglia, accumulated cholesterol disrupts membrane lipid raft organization, leading to aberrant clustering and hyperactivation of TREM2 receptors, which normally function as damage-associated molecular pattern (DAMP) sensors. This dysregulated TREM2 signaling triggers downstream activation of SYK kinase and PI3K/AKT pathways, ultimately promoting the senescence-associated secretory phenotype (SASP) characterized by excessive pro-inflammatory cytokine release including IL-1β, TNF-α, and IL-6.
...Figures & Visualizations
Pathway Diagram
graph TD
A["Aging Process<br/>Cellular Senescence"] -->|"cholesterol accumulation"| B["Membrane Cholesterol<br/>Dysregulation"]
B -->|"altered lipid raft<br/>organization"| C["TREM2 Receptor<br/>Hyperactivation"]
C -->|"aberrant clustering<br/>and signaling"| D["SYK Kinase<br/>Activation"]
D -->|"phosphorylation<br/>cascade"| E["PI3K/AKT Pathway<br/>Hyperactivation"]
E -->|"transcriptional<br/>reprogramming"| F["SASP Activation<br/>Pro-inflammatory State"]
F -->|"cytokine release"| G["IL-1beta, TNF-alpha,<br/>IL-6 Secretion"]
G -->|"chronic inflammation"| H["Microglial Senescence<br/>Pathological State"]
H -->|"neuronal damage"| I["Neurodegeneration<br/>Cognitive Decline"]
J["CYP46A1 Gene Therapy<br/>Viral Delivery"] -->|"enzyme expression"| K["CYP46A1 Enzyme<br/>Overexpression"]
K -->|"enzymatic conversion"| L["Cholesterol to<br/>24S-Hydroxycholesterol"]
L -->|"BBB transport"| M["Cholesterol Efflux<br/>Brain Clearance"]
M -->|"membrane restoration"| N["Normalized Membrane<br/>Cholesterol Content"]
N -->|"lipid raft<br/>reorganization"| O["Physiological TREM2<br/>Receptor Spacing"]
O -->|"balanced signaling"| P["Homeostatic Microglial<br/>Surveillance Function"]
P -->|"neuroprotection"| Q["Preserved Neuronal<br/>Health and Function"]
Q -->|"improved outcomes"| R["Enhanced Cognitive<br/>Performance"]
N -.->|"prevents"| C
P -.->|"inhibits"| F
class A,B,C,D,E,F,G,H normal
class I pathology
class J,K therapeutic
class L,M,N,O molecular
class P,Q,R outcome
3D Protein Structure
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✓ Supporting Evidence 29
Synapse loss in Alzheimer's disease (AD) correlates with cognitive decline. Involvement of microglia and complement in AD has been attributed to neuroinflammation, prominent late in disease. Here we show in mouse models that complement and microglia mediate synaptic loss early in AD. C1q, the initiating protein of the classical complement cascade, is increased and associated with synapses before overt plaque deposition. Inhibition of C1q, C3, or the microglial complement receptor CR3 reduces the number of phagocytic microglia, as well as the extent of early synapse loss. C1q is necessary for the toxic effects of soluble β-amyloid (Aβ) oligomers on synapses and hippocampal long-term potentiation. Finally, microglia in adult brains engulf synaptic material in a CR3-dependent process when exposed to soluble Aβ oligomers. Together, these findings suggest that the complement-dependent pathway and microglia that prune excess synapses in development are inappropriately activated and mediate s
Neuronal and synaptic loss is characteristic in many neurodegenerative diseases, such as frontotemporal dementia and Alzheimer's disease. Recently, we showed that inducing gamma oscillations with visual stimulation (gamma entrainment using sensory stimuli, or GENUS) reduced amyloid plaques and phosphorylated tau in multiple mouse models. Whether GENUS can affect neurodegeneration or cognitive performance remains unknown. Here, we demonstrate that GENUS can entrain gamma oscillations in the visual cortex, hippocampus, and prefrontal cortex in Tau P301S and CK-p25 mouse models of neurodegeneration. Tau P301S and CK-p25 mice subjected to chronic, daily GENUS from the early stages of neurodegeneration showed a preservation of neuronal and synaptic density across multiple brain areas and modified cognitive performance. Our transcriptomic and phosphoproteomic data suggest that chronic GENUS shifts neurons to a less degenerative state, improving synaptic function, enhancing neuroprotective fa
Triggering receptor expressed on myeloid cells 2 (TREM2) has been suggested to play a crucial role in Alzheimer's disease (AD) pathogenesis, as revealed by genome-wide association studies (GWAS). Since then, rapidly increasing literature related to TREM2 has focused on elucidating its role in AD pathology. In this review, we summarize our understanding of TREM2 biology, explore TREM2 functions in microglia, address the multiple mechanisms of TREM2 in AD, and raise key questions for further investigations to elucidate the detailed roles and molecular mechanisms of TREM2 in microglial responses. A major breakthrough in our understanding of TREM2 is based on our hypothesis suggesting that TREM2 may act as a multifaceted player in microglial functions in AD brain homeostasis. We conclude that TREM2 can not only influence microglial functions in amyloid and tau pathologies but also participate in inflammatory responses and metabolism, acting alone or with other molecules, such as apolipopro
Predisposition to Alzheimer's disease (AD) may arise from lipid metabolism perturbation, however, the underlying mechanism remains elusive. Here, we identify ATPase family AAA-domain containing protein 3A (ATAD3A), a mitochondrial AAA-ATPase, as a molecular switch that links cholesterol metabolism impairment to AD phenotypes. In neuronal models of AD, the 5XFAD mouse model and post-mortem AD brains, ATAD3A is oligomerized and accumulated at the mitochondria-associated ER membranes (MAMs), where it induces cholesterol accumulation by inhibiting gene expression of CYP46A1, an enzyme governing brain cholesterol clearance. ATAD3A and CYP46A1 cooperate to promote APP processing and synaptic loss. Suppressing ATAD3A oligomerization by heterozygous ATAD3A knockout or pharmacological inhibition with DA1 restores neuronal CYP46A1 levels, normalizes brain cholesterol turnover and MAM integrity, suppresses APP processing and synaptic loss, and consequently reduces AD neuropathology and cognitive
Adenosine monophosphate-activated protein kinase (AMPK) activity is stimulated to promote metabolic adaptation upon energy stress. However, sustained metabolic stress may cause cell death. The mechanisms by which AMPK dictates cell death are not fully understood. We report that metabolic stress promoted receptor-interacting protein kinase 1 (RIPK1) activation mediated by TRAIL receptors, whereas AMPK inhibited RIPK1 by phosphorylation at Ser415 to suppress energy stress-induced cell death. Inhibiting pS415-RIPK1 by Ampk deficiency or RIPK1 S415A mutation promoted RIPK1 activation. Furthermore, genetic inactivation of RIPK1 protected against ischemic injury in myeloid Ampkα1-deficient mice. Our studies reveal that AMPK phosphorylation of RIPK1 represents a crucial metabolic checkpoint, which dictates cell fate response to metabolic stress, and highlight a previously unappreciated role for the AMPK-RIPK1 axis in integrating metabolism, cell death, and inflammation.
CYP46A1 activation by efavirenz improves cognition and reduces amyloid pathology in 5xFAD mice at sub-therapeu… HIGH▼
Candida auris is an emergent multidrug-resistant fungal pathogen causing increasing reports of outbreaks. While distantly related to C. albicans and C. glabrata, C. auris is closely related to rarely observed and often multidrug-resistant species from the C. haemulonii clade. Here, we analyze near complete genome assemblies for the four C. auris clades and three related species, and map intra- and inter-species rearrangements across the seven chromosomes. Using RNA-Seq-guided gene predictions, we find that most mating and meiosis genes are conserved and that clades contain either the MTLa or MTLα mating loci. Comparing the genomes of these emerging species to those of other Candida species identifies genes linked to drug resistance and virulence, including expanded families of transporters and lipases, as well as mutations and copy number variants in ERG11. Gene expression analysis identifies transporters and metabolic regulators specific to C. auris and those conserved with related sp
Loss of CYP46A1 function increases neuronal vulnerability to excitotoxicity via cholesterol-dependent NMDA rec… MEDIUM▼
Advancements in biomedical research are highly dependent on critical thinking and problem solving. When quality of life and life-saving interventions rely on biomedical discoveries, every perspective is valuable. Therefore, a key contributor to the progress of health-related research is missing when patient representation is deficient in the biomedical research workforce.
GWAS meta-analysis identifies CYP46A1 variants as protective modifiers of AD onset by 2-4 years in APOE4 carri… HIGH▼
Neuroendocrine tumors (NETs) arise from neuroendocrine cells and manifest in diverse organs. Key players in their regulation are somatostatin and its receptors (SSTR1-SSTR5). Understanding receptor-ligand interactions and signaling pathways is vital for elucidating their role in tumor development and therapeutic potential. This review highlights SSTR characteristics, localization, and expression in tissues, impacting physiological functions. Mechanisms of somatostatin and synthetic analogue binding to SSTRs, their selectivity, and their affinity were analyzed. Upon activation, somatostatin initiates intricate intracellular signaling, involving cAMP, PLC, and MAP kinases and influencing growth, differentiation, survival, and hormone secretion in NETs. This review explores SSTR expression in different tumor types, examining receptor activation effects on cancer cells. SSTRs' significance as therapeutic targets is discussed. Additionally, somatostatin and analogues' role in hormone secret
Cholesterol metabolic reprogramming mediates microglia-induced chronic neuroinflammation and hinders neurorest… HIGH▼
Chronic neuroinflammation is a major obstacle to post-stroke recovery, yet the underlying mechanisms, particularly the link between prolonged microglial activation and cholesterol metabolism, are not fully known. Here we show that ischaemic injury induces persistent microglial activation that perpetuates chronic inflammation, leading to microglial cholesterol accumulation and metabolic reprogramming. Using single-cell RNA sequencing, we identified distinct stroke-associated foamy microglia clusters characterized by extensive reprogramming of cholesterol metabolism. Furthermore, direct intracerebral free cholesterol or cholesterol crystal infusion recapitulated sustained microglial activation, directly linking aberrant cholesterol metabolism to prolonged neuroinflammatory responses. Therapeutically, we demonstrate that reducing microglial cholesterol overload through genetic or pharmacological activation of CYP46A1 in male mice promotes white matter repair and functional recovery. These
Parkinson's disease (PD) is a neurodegenerative disease characterized by the death of dopaminergic neurons in the substantia nigra and the formation of Lewy bodies that are composed of aggregated α-synuclein (α-Syn). However, the factors that regulate α-Syn pathology and nigrostriatal dopaminergic degeneration remain poorly understood. Previous studies demonstrate cholesterol 24-hydroxylase (CYP46A1) increases the risk for PD. Moreover, 24-hydroxycholesterol (24-OHC), a brain-specific oxysterol that is catalyzed by CYP46A1, is elevated in the cerebrospinal fluid of PD patients. Herein, we show that the levels of CYP46A1 and 24-OHC are elevated in PD patients and increase with age in a mouse model. Overexpression of CYP46A1 intensifies α-Syn pathology, whereas genetic removal of CYP46A1 attenuates α-Syn neurotoxicity and nigrostriatal dopaminergic degeneration in the brain. Moreover, supplementation with exogenous 24-OHC exacerbates the mitochondrial dysfunction induced by α-Syn fibrils
Overexpression of cholesterol 24-hydroxylase CYP46A1 attenuates retinal dysfunction and ganglion cell loss via… MEDIUM▼
Cholesterol 24-hydroxylase CYP46A1 (CYP46A1) has been confirmed to be correlated with the processes of multiple neurological disorders, but its role in neurodegenerative optic diseases remains unclear. This article aimed to evaluate the neuroprotective effects of CYP46A1 on mouse retinal ganglion cells (RGCs) and retinal function. Mice were subjected to optic nerve crush (ONC) injury after intravitreal injection of rAAVs. RGCs' survival was quantified by immunofluorescence staining of retinal flat mounts. Retinal electrophysiological function and visual acuity were quantitatively assessed using electroretinography (ERG) and optomotor response (OMR). The TdT-mediated dUTP nick-end labeling (TUNEL) staining was employed to quantify the apoptosis of RGCs. The protein expression level of CYP46A1, B-cell lymphoma 2 (Bcl-2), BCL-2-associated X protein (Bax), Kelch-like ECH-associated protein 1 (Keap1), nuclear factor erythroid 2-related factor (Nrf2), and heme oxygenase 1 (HO1) were validate
CYP46A1-mediated cholesterol turnover induces sex-specific changes in cognition and counteracts memory loss in… MEDIUM▼
The brain-specific enzyme CYP46A1 controls cholesterol turnover by converting cholesterol into 24S-hydroxycholesterol (24OH). Dysregulation of brain cholesterol turnover and reduced CYP46A1 levels are observed in Alzheimer's disease (AD). In this study, we report that CYP46A1 overexpression in aged female mice leads to enhanced estrogen signaling in the hippocampus and improved cognitive functions. In contrast, age-matched CYP46A1 overexpressing males show anxiety-like behavior, worsened memory, and elevated levels of 5α-dihydrotestosterone in the hippocampus. We report that, in neurons, 24OH contributes to these divergent effects by activating sex hormone signaling, including estrogen receptors. CYP46A1 overexpression in female mice protects from memory impairments induced by ovariectomy while having no effects in gonadectomized males. Last, we measured cerebrospinal fluid levels of 24OH in a clinical cohort of patients with AD and found that 24OH negatively correlates with neurodegen
Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by an abnormal expansion of cytosine-adenine-guanosine (CAG) trinucleotidein the huntingtin gene. Mutant huntingtin (mHTT) expression in neurons and glial cells affects neuron and astrocyte functions and leads to the loss of medium spiny neurons of the striatum. Brain cholesterol pathway is severely affected by HTT mutation in neurons and astrocytes, contributing to HD pathogenesis. Decreased cholesterol production and transport by astrocytes impair synapse maturation and neurotransmission. Brain cholesterol metabolism is maintained by cholesterol hydroxylation into 24-hydroxycholesterol by the neuronal enzyme cholesterol 24-hydroxylase (CYP46A1). CYP46A1 is decreased in affected brain regions in HD patients and mice. AAV-CYP46A1 striatal delivery was shown to restore cholesterol metabolism with neuroprotective effects in two mouse models of HD, characterized by mHTT aggregates' reduction, improved tran
Abnormalities in neuronal cholesterol homeostasis have been suspected or observed in several neurodegenerative disorders including Alzheimer's disease, Parkinson's disease and Huntington's disease. However, it has not been demonstrated whether an increased abundance of cholesterol in neurons in vivo contributes to neurodegeneration. To address this issue, we used RNA interference methodology to inhibit the expression of cholesterol 24-hydroxylase, encoded by the Cyp46a1 gene, in the hippocampus of normal mice. Cholesterol 24-hydroxylase controls cholesterol efflux from the brain and thereby plays a major role in regulating brain cholesterol homeostasis. We used an adeno-associated virus vector encoding short hairpin RNA directed against the mouse Cyp46a1 mRNA to decrease the expression of the Cyp46a1 gene in hippocampal neurons of normal mice. This increased the cholesterol concentration in neurons, followed by cognitive deficits and hippocampal atrophy due to apoptotic neuronal death.
Cholesterol redistribution triggered by CYP46A1 gene therapy improves major hallmarks of Niemann-Pick type C d… MEDIUM▼
Cholesterol 24-hydroxylase (CYP46A1) is an exclusively neuronal cytochrome P450 enzyme responsible for converting cholesterol into 24S-hydroxycholesterol, which serves as the primary pathway for eliminating cholesterol in the brain. We and others have shown that increased activity of CYP46A1 leads to reduced levels of cholesterol and has a positive effect on cognition. Therefore, we hypothesized that CYP46A1 could be a potential therapeutic target in Niemann-Pick type C (NPC) disease, a rare and fatal neurodegenerative disorder, characterized by cholesterol accumulation in endolysosomal compartments. Herein, we show that CYP46A1 ectopic expression, in cellular models of NPC and in Npc1tm(I1061T) mice by adeno-associated virus-mediated gene therapy improved NPC disease phenotype. Amelioration in functional, biochemical, molecular and neuropathological hallmarks of NPC disease were characterized. In vivo, CYP46A1 expression partially prevented weight loss and hepatomegaly, corrected the
Neuronal Cholesterol Accumulation Induced by Cyp46a1 Down-Regulation in Mouse Hippocampus Disrupts Brain Lipid… MEDIUM▼
Impairment in cholesterol metabolism is associated with many neurodegenerative disorders including Alzheimer's disease (AD). However, the lipid alterations underlying neurodegeneration and the connection between altered cholesterol levels and AD remains not fully understood. We recently showed that cholesterol accumulation in hippocampal neurons, induced by silencing Cyp46a1 gene expression, leads to neurodegeneration with a progressive neuronal loss associated with AD-like phenotype in wild-type mice. We used a targeted and non-targeted lipidomics approach by liquid chromatography coupled to high-resolution mass spectrometry to further characterize lipid modifications associated to neurodegeneration and cholesterol accumulation induced by CYP46A1 inhibition. Hippocampus lipidome of normal mice was profiled 4 weeks after cholesterol accumulation due to Cyp46a1 gene expression down-regulation at the onset of neurodegeneration. We showed that major membrane lipids, sphingolipids and spec
Treatment with efavirenz extends survival in a Creutzfeldt-Jakob disease model by regulating brain cholesterol… MEDIUM▼
Prion diseases are fatal, infectious, and incurable neurodegenerative conditions affecting humans and animals, caused by the misfolding of the cellular prion protein (PrPC) into its pathogenic isoform, PrPSc. In humans, sporadic Creutzfeldt-Jakob disease (sCJD) is the most prevalent prion disease. Recently, we demonstrated that treatment with the FDA-approved anti-HIV drug efavirenz (EFV) significantly reduced PrPSc and extended survival of scrapie prion-infected mice. Among other effects, EFV activates the brain-specific cholesterol-metabolizing enzyme, CYP46A1, which converts cholesterol into 24S-hydroxycholesterol (24S-HC). However, drugs effective against scrapie prions often fail in human prion diseases, and a relation of the antiprion effects of EFV to CYP46A1 activation is not established. Thus, we evaluated EFV treatment in mice overexpressing human PrPC infected with human sCJD prions. Oral, low-dose EFV treatment starting at 30 or 130 days postinfection significantly slowed d
Rett syndrome (RTT) is a neurodevelopmental disorder characterized by motor deficits, partly attributed to cerebellar dysfunction. RTT is primarily caused by mutations in the gene encoding the methyl-CpG-binding protein 2 (MECP2), which has been implicated in cholesterol homeostasis by mechanisms that remain poorly understood. Given that brain cholesterol is primarily synthesized de novo and that disrupted cholesterol homeostasis is linked to various neurological disorders, we aimed to investigate cholesterol regulation in the cerebellum of Mecp2-null mice, a well-established RTT model. We measured total cholesterol levels in cerebellar tissue and cerebellar synaptosomes and assessed the expression of genes involved in cholesterol biosynthesis and intracellular transport. Our results show significantly elevated total cholesterol in both cerebellar tissue and synaptosomes. Furthermore, we identified a marked reduction in CYP46A1 expression, which is essential for the elimination of ence
Efavirenz treatment improves retinal vaso-obliteration and pathological neovascularization in a mouse model of… MEDIUM▼
OBJECTIVES: Previous studies have shown the metabolic and regulatory significance of CYP46A1 in the adult retina; however, its role in the developing retina is unknown. Here, we evaluate CYP46A1 expression and the impact of its activation in the developing mouse retina under normal and pathological conditions. METHODS: Seven-day-old (P7) C57BL/6 J mice maintained in room air (controls) or subjected to oxygen-induced retinopathy (OIR) were treated with/without 20 mg/kg efavirenz (EFV), a CYP46A1 activator administered intraperitoneally from P7 to P17. RESULTS: Retinal cross sections and flat mounts were prepared to study retinal vasculature morphology, Müller and microglia activation, and ganglion cell viability. EFV treatment significantly reduced pathological neovascularization and the size of avascular and hypoxic areas in OIR mice retinas. EFV treatment additionally limited reactive gliosis and microglia activation and improved retinal ganglion cell survival in OIR mice. CONCLUSION:
Potential Biological Processes Related to Brain SLC13A5 Across the Lifespan: Weighted Gene Co-Expression Netwo… MEDIUM▼
Background/Objectives:SLC13A5 encodes a sodium-citrate cotransporter implicated in early-onset epileptic encephalopathy and metabolic brain dysfunction, yet its developmental regulation and molecular context in the human brain remain incompletely defined. Methods: Leveraging human developmental transcriptomes from the Evo-Devo resource, we delineated tissue trajectories and network context for SLC13A5 across the fetal-postnatal life. Results: In the cerebrum, SLC13A5 expression rises from late fetal stages to peak in the first postnatal year and then declines into adulthood, while cerebellar levels increase across the lifespan; liver shows a fetal decrease followed by sustained postnatal upregulation. A transcriptome-wide scan identified extensive positive and negative associations with SLC13A5, and a signed weighted gene co-expression network analysis (WGCNA) built on biweight midcorrelation placed SLC13A5 in a large module. The module eigengene tracked brain maturation (Spearman rho
This review synthesizes three decades of evidence regarding the role of cytochrome P450 enzymes (CYPs) in Parkinson's disease (PD), revealing their multifaceted roles beyond traditional pesticide metabolism. While CYP2D6 remains the most studied enzyme due to its association with PD risk in poor metabolizer phenotypes and its dual role in dopamine (DA) synthesis (directly via tyramine hydroxylation and indirectly through precursor demethylation), recent research has highlighted less-studied CYPs with critical pathological implications. Another focal enzyme, CYP2E1, mediates the bioactivation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine to its neurotoxic metabolite, 1-methyl-4-phenylpyridinium, thereby inducing oxidative stress. It also partially contributes to DA oxidation, a process that generates multiple cytotoxic byproducts. These toxic products are implicated in two major pathological processes involved in the development of PD-oxidative stress and protein misfolding-which adve
Radiosynthesis and Evaluation of (18)F‑Labeled Deuterated Radioligand for Positron Emission Tomography Imaging… MEDIUM▼
Brain cholesterol homeostasis is critical for neuronal function and primarily regulated by cholesterol 24-hydroxylase (CYP46A1). Dysregulation of CYP46A1 has been implicated in Alzheimer's disease (AD) and Huntington's disease (HD). Building on the clinically validated positron emission tomography (PET) tracer [18F]-CHL-2205, we designed a deuterated isotopologue, CHL-2205-d 3, targeting the amide N-methyl group to enhance stability and enable mechanistic studies. Compound 5 exhibited high CYP46A1 affinity (IC50 = 0.38 nM; K i = 0.22 nM). Radiosynthesis via copper-mediated [18F]-fluorination afforded [18F]5 in 31.5 ± 1.5% non-decay-corrected radiochemical yield and high molar activity (>95 GBq/μmol). Autoradiography and PET imaging in mice demonstrated robust brain uptake, heterogeneous regional distribution, and specific target engagement. Radiometabolite analysis confirmed that brain radioactivity was mainly attributable to intact [18F]5, with a pharmacokinetics comparable to that of
Demonstrates that 24-hydroxycholesterol can counteract tau hyperphosphorylation, supporting the core mechanism… MEDIUM▼
Multiple findings underline a link between altered brain cholesterol metabolism and Alzheimer's disease (AD) pathogenesis. Physiologically, excess brain cholesterol is mainly converted into 24-hydroxycholesterol (24-OHC) by the neuron-specific enzyme CYP46A1. Of note, we previously observed in autopsy specimens from human AD brains that 24-OHC and, in parallel, CYP46A1 expression decrease at advanced stages, suggesting a possible cause-effect between these reductions and AD progression. In the p
Links cholesterol-24-hydroxylase dysregulation to neurological disease progression, supporting the therapeutic… MEDIUM▼
Disability worsening in multiple sclerosis (MS) is linked to neurodegeneration. Cholesterol homeostasis is essential for normal brain function. CYP46A1, crucial for brain cholesterol turnover and reduced in some neurodegenerative diseases, is a potential neuroprotective target. We hypothesized that CYP46A1 is downregulated in MS brains and linked to cholesterol dysbalance. Mass spectrometric analysis of sterols was performed from matched plasma and cerebrospinal fluid (CSF) in an all-female MS c
Identifies CYP46A1 gene polymorphisms as potential markers for dementia development, validating its relevance … MEDIUM▼
In an aging society, solving problems associated with the diagnosis and treatment of dementia-related diseases represents a serious challenge. The aim of the study was to evaluate the possibility of applying molecular biology methods to test polymorphisms recognized in the global literature as potentially useful in assessing the risk of developing dementia in a group of patients with hyperlipidemia. A sample of 203 patients: 109 diagnosed with both dementia and hyperlipidemia, 94 with hyperlipid
Shows mesenchymal stem cells overexpressing CYP46A1 can inhibit lipid accumulation and neuroinflammation, dire… MEDIUM▼
In this study, we investigated the effects of cytochrome P450 46A1 (CYP46A1)-overexpressing mesenchymal stem cells (MSCs) on neuroinflammation and lipid metabolism in N9 microglial cells. Secretory proteomic analysis of CYP46A1-MSCs revealed 261 upregulated and 87 downregulated proteins, with involvement in pathways related to neurodegenerative diseases and cholesterol metabolism. Compared with control MSCs, CYP46A1-MSCs significantly inhibited the lipopolysaccharide-induced decrease in cell via
The paper discusses neuron membrane lipid packing alterations, which aligns with the hypothesis's focus on cho… MEDIUM▼
Membrane composition, permeability and fluidity are essential for proper cellular function. According to the membrane aging hypothesis, aging-related diseases, including neurodegenerative disorders, arise from the aging of cell membranes. Membrane proteins, such as the insulin receptor, rely on an optimal membrane environment for proper partitioning and functionality. Our goal was to investigate the effects of streptozotocin (STZ) and L-buthionine-sulfoximine (BSO), two commonly used agents to m
✗ Opposing Evidence 9
Cholesterol homeostasis is impaired in Alzheimer's disease; however, attempts to modulate brain cholesterol biology have not translated into tangible clinical benefits for patients to date. Several recent milestone developments have substantially improved our understanding of how excess neuronal cholesterol contributes to the pathophysiology of Alzheimer's disease. Indeed, neuronal cholesterol was linked to the formation of amyloid-β and neurofibrillary tangles through molecular pathways that were recently delineated in mechanistic studies. Furthermore, remarkable advances in translational molecular imaging have now made it possible to probe cholesterol metabolism in the living human brain with PET, which is an important prerequisite for future clinical trials that target the brain cholesterol machinery in Alzheimer's disease patients-with the ultimate aim being to develop disease-modifying treatments. This work summarizes current concepts of how the biosynthesis, transport and clearan
Cholesterol 24-hydroxylation is the major mechanism for cholesterol removal from the brain and the reaction catalyzed by cytochrome P450 46A1 (CYP46A1), a CNS-specific enzyme. This review describes CYP46A1 in the context of cholesterol homeostasis in the brain and summarizes available experimental data on CYP46A1 association with different neurologic diseases, including the mechanisms by which changes in the CYP46A1 activity in the brain could be beneficial for these diseases. The modulation of CYP46A1 activity by genetic and pharmacologic means is also presented along with a brief synopsis of the two clinical trials that evaluate CYP46A1 as a therapeutic target for Alzheimer's disease as well as Dravet and Lennox-Gastaut syndromes.
Excessive cholesterol depletion impairs synaptic vesicle recycling and neurotransmitter release in hippocampal… MEDIUM▼
Chronic low-grade inflammation plays a major role in the development of insulin resistance. The potential role and underlying mechanism of vitamin C, an antioxidant and anti-inflammatory agent, was investigated in tumor necrosis factor-α (TNF-α)-induced insulin resistance. Gulonolactone oxidase knockout (Gulo-/-) mice genetically unable to synthesize vitamin C were used to induce insulin resistance by continuously pumping small doses of TNF-α for seven days, and human liver hepatocellular carcinoma cells (HepG2 cells) were used to induce insulin resistance by treatment with TNF-α. Vitamin C deficiency aggravated TNF-α-induced insulin resistance in Gulo-/- mice, resulting in worse glucose tolerance test (GTT) results, higher fasting plasma insulin level, and the inactivation of the protein kinase B (AKT)/glycogen synthase kinase-3β (GSK3β) pathway in the liver. Vitamin C deficiency also worsened liver lipid accumulation and inflammation in TNF-α-treated Gulo-/- mice. In HepG2 cells, vit
Cholesterol is essential for myelin maintenance; excessive turnover may compromise white matter integrity in a… MEDIUM▼
BACKGROUND: Hong Kong has been embroiled in increasingly violent social unrest since June, 2019. We examined the associated population mental health burden, risk factors, and health-care needs. METHODS: In a population-based prospective cohort, adult participants aged 18 years or older were assessed at nine timepoints from 2009. Probable depression was measured using the Patient Health Questionnaire-9 (score ≥10) and suspected post-traumatic stress disorder (PTSD) by the PTSD Checklist-Civilian Version (score ≥14), plus direct exposure to traumatic events related to the ongoing social unrest. We used multivariable logistic regression to identify factors associated with both outcomes, adjusting for doctor-diagnosed depression or anxiety disorders before the unrest. On the basis of routine service statistics and respondents' intention to seek professional care, we projected the number of additional ambulatory specialist psychiatric visits required. FINDINGS: After the two baseline survey
AAV9-mediated gene therapy shows declining transgene expression after 5 years in non-human primates, raising d… MEDIUM▼
Anti-AAV neutralizing antibodies prevent re-administration and limit patient eligibility to 40-70% of screened… HIGH▼
Embryonic implantation and development are vital in early pregnancy and assisted reproduction. Circular RNAs (circRNAs) are involved in the two physiological processes and thus regulate animal reproduction. However, their specific regulatory functions and mechanisms remain unclear. Here, a novel circ0001470, originating from the porcine GRN gene, differentially expressed on day 18 versus day 32 of gestation in Meishan and Yorkshire pigs was screened. The circularization characteristic of circ0001470 was identified based on divergent primer amplification, Sanger sequencing, RNase digestion, and RNA nuclear-cytoplasmic fractionation. Functionally, circ0001470 can promote cell proliferation and cycle progression of endometrial epithelial cells (EECs) and also inhibit apoptosis of EECs using CCK-8 assays and flow cytometry analyses. Mechanistically, bioinformatics database prediction, luciferase screening, RNA immunoprecipitation (RIP), RNA-pull down, and FISH co-localization experiments r
CYP46A1 overexpression in aged mice shows diminished efficacy compared to young animals, suggesting a therapeu… MEDIUM▼
Dysfunctions in brain cholesterol homeostasis have been extensively related to brain disorders. The major elimination pathway of brain cholesterol is its hydroxylation into 24 (S)-hydroxycholesterol by the cholesterol 24-hydroxylase (CYP46A1). Interestingly, there seems to be an association between CYP46A1 and high-order brain functions, in a sense that increased expression of this hydroxylase improves cognition, while a reduction leads to a poor cognitive performance. Moreover, increasing amount of epidemiological, biochemical and molecular evidence, suggests that CYP46A1 has a role in the pathogenesis or progression of neurodegenerative disorders, in which up-regulation of this enzyme is clearly beneficial. However, the mechanisms underlying these effects are poorly understood, which highlights the importance of studies that further explore the role of CYP46A1 in the central nervous system. In this review we summarize the major findings regarding CYP46A1, and highlight the several re
The adult brain exhibits a characteristic cholesterol homeostasis, with low synthesis rate and active catabolism. Brain cholesterol turnover is possible thanks to the action of the enzyme cytochrome P450 46A1 (CYP46A1) or 24-cholesterol hydroxylase, that transforms cholesterol into 24S-hydroxycholesterol (24S-HC). But before crossing the blood-brain barrier (BBB), this oxysterol, that is the most abundant in the brain, can act locally, affecting the functioning of neurons, astrocytes, oligodendrocytes, and vascular cells. The first part of this review addresses different aspects of 24S-HC production and elimination from the brain. The second part concentrates in the effects of 24S-HC at the cellular level, describing how this oxysterol affects cell viability, amyloid β production, neurotransmission, and transcriptional activity. Finally, the role of 24S-HC in Alzheimer, Huntington and Parkinson diseases, multiple sclerosis and amyotrophic lateral sclerosis, as well as the possibility o
🧬 Theorist Proposes novel mechanisms and generates creative hypotheses ▼
Based on the provided literature on lipid raft composition changes in neurodegeneration, here are 7 novel therapeutic hypotheses:
Hypothesis 1: Cholesterol-Sphingolipid Ratio Modulators as Synaptic Rescuers
Target: HMGCR (cholesterol synthesis) + SPHK1 (sphingosine kinase) Mechanism: Therapeutic restoration of optimal cholesterol:sphingolipid ratios in synaptic lipid rafts could reverse amyloid-β induced membrane domain disruption and restore normal APP processing. By simultaneously modulating cholesterol biosynthesis and sphingolipid metabolism, we can recreate the lipid environme🎯 Domain Expert Assesses practical feasibility, druggability, and clinical translation ▼
Based on my analysis of the figures and clinical trial landscape, here's my practical feasibility assessment:
OVERALL ASSESSMENT
The visual evidence from PMC6657435 clearly shows the spatial organization hypotheses are scientifically sound - the figures demonstrate distinct membrane domains (raft vs non-raft) and their roles in APP processing. However, practical implementation faces significant challenges.
SURVIVING HYPOTHESES (Ranked by Feasibility)
HYPOTHESIS 1: Cholesterol-Sphingolipid Ratio Modulators
VERDICT: MODERATE FEASIBILITYDruggability:
- HMGCR:
⚖ Synthesizer Integrates perspectives and produces final ranked assessments ▼
Price History
| Event | Price | Change | Source | Time | |
|---|---|---|---|---|---|
| ⚖ | Recalibrated | $0.572 | ▼ 0.3% | market_dynamics | 2026-04-13 03:33 |
| 📄 | New Evidence | $0.574 | ▲ 1.4% | evidence_batch_update | 2026-04-13 02:18 |
| 📄 | New Evidence | $0.566 | ▲ 1.7% | evidence_batch_update | 2026-04-13 02:18 |
| ⚖ | Recalibrated | $0.557 | ▼ 1.0% | 2026-04-12 18:34 | |
| ⚖ | Recalibrated | $0.563 | ▼ 2.6% | 2026-04-12 05:13 | |
| ⚖ | Recalibrated | $0.577 | ▼ 0.5% | 2026-04-10 15:58 | |
| ⚖ | Recalibrated | $0.580 | ▼ 3.4% | 2026-04-10 14:40 | |
| 📄 | New Evidence | $0.601 | ▼ 7.7% | evidence_update | 2026-04-09 01:50 |
| 📄 | New Evidence | $0.651 | ▲ 12.8% | evidence_update | 2026-04-09 01:50 |
| ⚖ | Recalibrated | $0.577 | 2026-04-08 18:39 |
Clinical Trials (7) Relevance: 46%
Active
Completed
Total Enrolled
Highest Phase
📚 Cited Papers (38)
📓 Linked Notebooks (7)
⚔ Arena Performance
Origin
Wiki Pages
KG Entities (48)
Dependency Graph (2 upstream, 0 downstream)
Related Hypotheses
Estimated Development
🧪 Falsifiable Predictions
Knowledge Subgraph (178 edges)
associated with (15)
causes (1)
co associated with (15)
implicated in (3)
involved in (6)
modifies (3)
participates in (11)
regulates (4)
Mechanism Pathway for CYP46A1
Molecular pathway showing key causal relationships underlying this hypothesis
graph TD
CYP46A1["CYP46A1"] -->|associated with| neurodegeneration["neurodegeneration"]
CYP46A1_1["CYP46A1"] -->|participates in| Cholesterol_24_hydroxylas["Cholesterol 24-hydroxylase / brain cholesterol turnover"]
CYP46A1_2["CYP46A1"] -->|regulates| cholesterol_metabolism["cholesterol_metabolism"]
FLOT1["FLOT1"] -->|co discussed| CYP46A1_3["CYP46A1"]
SREBF2["SREBF2"] -->|co discussed| CYP46A1_4["CYP46A1"]
CYP46A1_5["CYP46A1"] -->|co discussed| SGMS2["SGMS2"]
CYP46A1_6["CYP46A1"] -->|co discussed| ABCA1["ABCA1"]
CYP46A1_7["CYP46A1"] -->|co discussed| BACE1["BACE1"]
CYP46A1_8["CYP46A1"] -->|co discussed| ST3GAL2["ST3GAL2"]
CYP46A1_9["CYP46A1"] -->|co discussed| ST8SIA1["ST8SIA1"]
CYP46A1_10["CYP46A1"] -->|co discussed| LDLR["LDLR"]
CYP46A1_11["CYP46A1"] -->|co discussed| SMPD1["SMPD1"]
CYP46A1_12["CYP46A1"] -->|co discussed| SGMS1["SGMS1"]
ST8SIA1_13["ST8SIA1"] -->|co discussed| CYP46A1_14["CYP46A1"]
LDLR_15["LDLR"] -->|co discussed| CYP46A1_16["CYP46A1"]
style CYP46A1 fill:#ce93d8,stroke:#333,color:#000
style neurodegeneration fill:#ef5350,stroke:#333,color:#000
style CYP46A1_1 fill:#ce93d8,stroke:#333,color:#000
style Cholesterol_24_hydroxylas fill:#81c784,stroke:#333,color:#000
style CYP46A1_2 fill:#ce93d8,stroke:#333,color:#000
style cholesterol_metabolism fill:#81c784,stroke:#333,color:#000
style FLOT1 fill:#ce93d8,stroke:#333,color:#000
style CYP46A1_3 fill:#ce93d8,stroke:#333,color:#000
style SREBF2 fill:#ce93d8,stroke:#333,color:#000
style CYP46A1_4 fill:#ce93d8,stroke:#333,color:#000
style CYP46A1_5 fill:#ce93d8,stroke:#333,color:#000
style SGMS2 fill:#ce93d8,stroke:#333,color:#000
style CYP46A1_6 fill:#ce93d8,stroke:#333,color:#000
style ABCA1 fill:#ce93d8,stroke:#333,color:#000
style CYP46A1_7 fill:#ce93d8,stroke:#333,color:#000
style BACE1 fill:#ce93d8,stroke:#333,color:#000
style CYP46A1_8 fill:#ce93d8,stroke:#333,color:#000
style ST3GAL2 fill:#ce93d8,stroke:#333,color:#000
style CYP46A1_9 fill:#ce93d8,stroke:#333,color:#000
style ST8SIA1 fill:#ce93d8,stroke:#333,color:#000
style CYP46A1_10 fill:#ce93d8,stroke:#333,color:#000
style LDLR fill:#ce93d8,stroke:#333,color:#000
style CYP46A1_11 fill:#ce93d8,stroke:#333,color:#000
style SMPD1 fill:#ce93d8,stroke:#333,color:#000
style CYP46A1_12 fill:#ce93d8,stroke:#333,color:#000
style SGMS1 fill:#ce93d8,stroke:#333,color:#000
style ST8SIA1_13 fill:#ce93d8,stroke:#333,color:#000
style CYP46A1_14 fill:#ce93d8,stroke:#333,color:#000
style LDLR_15 fill:#ce93d8,stroke:#333,color:#000
style CYP46A1_16 fill:#ce93d8,stroke:#333,color:#000
3D Protein Structure
🧬 CYP46A1 — PDB 2Q9F Click to expand 3D viewer
Source Analysis
Lipid raft composition changes in synaptic neurodegeneration
neurodegeneration | 2026-04-01 | completed