Tau biomarkers in Alzheimer's disease: towards implementation in clinical practice and trials

The Lancet Neurology, Год журнала: 2022, Номер 21(8), С. 726 - 734

Опубликована: Май 25, 2022

Язык: Английский

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Brain cell type-specific cholesterol metabolism and implications for learning and memory

Trends in Neurosciences, Год журнала: 2022, Номер 45(5), С. 401 - 414

Опубликована: Фев. 17, 2022

Язык: Английский

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Neuroimaging genetics approaches to identify new biomarkers for the early diagnosis of autism spectrum disorder

Molecular Psychiatry, Год журнала: 2023, Номер 28(12), С. 4995 - 5008

Опубликована: Апрель 17, 2023

Abstract Autism-spectrum disorders (ASDs) are developmental disabilities that manifest in early childhood and characterized by qualitative abnormalities social behaviors, communication skills, restrictive or repetitive behaviors. To explore the neurobiological mechanisms ASD, extensive research has been done to identify potential diagnostic biomarkers through a neuroimaging genetics approach. Neuroimaging helps ASD-risk genes contribute structural functional variations brain circuitry validate biological changes elucidating pathways confer genetic risk. Integrating artificial intelligence models with data lays groundwork for accurate diagnosis facilitates identification of ASD. This review discusses significance approaches gaining better understanding perturbed neurochemical system molecular ASD how these can detect structural, functional, metabolic lead discovery novel

Язык: Английский

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Brain cholesterol and Alzheimer's disease: challenges and opportunities in probe and drug development

Brain, Год журнала: 2024, Номер 147(5), С. 1622 - 1635

Опубликована: Фев. 1, 2024

Cholesterol homeostasis is impaired in Alzheimer's disease; however, attempts to modulate brain cholesterol biology have not translated into tangible clinical benefits for patients date. Several recent milestone developments substantially improved our understanding of how excess neuronal contributes the pathophysiology disease. Indeed, was linked formation amyloid-β and neurofibrillary tangles through molecular pathways that were recently delineated mechanistic studies. Furthermore, remarkable advances translational imaging now made it possible probe metabolism living human with PET, which an important prerequisite future trials target machinery disease patients-with ultimate aim being develop disease-modifying treatments. This work summarizes current concepts biosynthesis, transport clearance are affected Further, strategies reverse these alterations by pharmacotherapy critically discussed wake emerging research tools support assessment only animal models but also

Язык: Английский

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Altered Cholesterol Homeostasis in Huntington’s Disease

Frontiers in Aging Neuroscience, Год журнала: 2022, Номер 14

Опубликована: Апрель 19, 2022

Huntington’s disease (HD) is an autosomal dominant genetic disorder caused by expansion of the CAG repeat in first exon Huntingtin’s gene. The associated neurodegeneration mainly affects striatum and cortex at early stages progressively spreads to other brain structures. Targeting HD its earlier under intense investigation. Numerous drugs were tested, with a rate success only 3.5% approved molecules used as symptomatic treatment. restoration cholesterol metabolism, which central homeostasis strongly altered HD, could be interesting disease-modifying strategy. Cholesterol essential membrane component nervous system (CNS); alterations have deleterious consequences on neuronal functions. levels several sterols, upstream cholesterol, are markedly decreased within mouse model. Transcription biosynthetic genes reduced cell models well post-mortem striatal cortical tissues from patients. Since dynamic metabolism complex, it establish best method target HD. Cholesterol, does not cross blood-brain-barrier, locally synthesized renewed brain. All types CNS synthesize during development but they progress through adulthood, neurons down-regulate their synthesis turn astrocytes for full supply. Cellular reflect balance between synthesis, uptake export, all integrated into context talk glial cells. In this review, we describe latest advances regarding role deregulation functions how determinant factor degeneration progression. pathways major mechanisms sterols regulated will described. From overview, discuss main clinical strategies manipulating CNS, reinstate proper

Язык: Английский

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The translational potential of cholesterol-based therapies for neurological disease

Nature Reviews Neurology, Год журнала: 2023, Номер 19(10), С. 583 - 598

Опубликована: Авг. 29, 2023

Язык: Английский

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Lipidomics analysis in drug discovery and development

Current Opinion in Chemical Biology, Год журнала: 2022, Номер 72, С. 102256 - 102256

Опубликована: Дек. 29, 2022

Despite being a relatively new addition to the Omics' landscape, lipidomics is increasingly recognized as an important tool for identification of druggable targets and biochemical markers. In this review we present recent advances lipid analysis in drug discovery development. We cover current state art technologies which are constantly evolving meet demands terms sensitivity selectivity. A careful selection examples then provided, illustrating versatility development process. Integration with other omics', stem-cell technologies, metabolic flux will open avenues deciphering pathophysiological mechanisms novel biomarkers.

Язык: Английский

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Intestinal Microbiota Remodeling Protects Mice from Western Diet-Induced Brain Inflammation and Cognitive Decline

Cells, Год журнала: 2022, Номер 11(3), С. 504 - 504

Опубликована: Фев. 1, 2022

It has been shown that the Western diet (WD) induces systemic inflammation and cognitive decline. Moreover, probiotic supplementation antibiotic treatment reduce diet-induced hepatic inflammation. The current study examines whether shaping gut microbes by Bifidobacterium infantis (B. infantis) brain improve neuroplasticity. Furthermore, significance of bile acid (BA) signaling in regulating was studied. Mice were fed a control (CD) or WD for seven months. B. supplemented to WD-fed mice inflammation, lipid, metabolomes, neuroplasticity measured long-term potentiation (LTP). Broad-spectrum coverage antibiotics cholestyramine treatments performed impact WD-associated BA Probiotic inhibited reducing IL6, TNFα, CD11b levels. improved LTP increased PSD95 BDNF levels, which reduced due intake. Additionally, cecal cholesterol, ceramide enhanced saturated fatty acids. treatment, as well cholestyramine, diminished WD-induced inflammatory signaling. Our findings support theory intestinal microbiota remodeling reduces activates receptor signaling, improves

Язык: Английский

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A CYPome-wide study reveals new potential players in the pathogenesis of Parkinson’s disease

Frontiers in Pharmacology, Год журнала: 2023, Номер 13

Опубликована: Янв. 19, 2023

Genetic and environmental factors lead to the manifestation of Parkinson’s disease (PD) but related mechanisms are only rudimentarily understood. Cytochromes P450 (P450s) involved in biotransformation toxic compounds many physiological processes thus predestinated be PD. However, so far SNPs (single nucleotide polymorphisms) CYP2D6 CYP2E1 have been associated with susceptibility Our aim was evaluate role all 57 human P450s their redox partners for etiology pathophysiology PD identify novel potential players which may identification new biomarkers a causative treatment The PPMI (Parkinson’s Progression Markers Initiative) database used extract gene sequences three analyze association occurrence Applying statistical analyses data, corresponding odds ratios (OR) confidence intervals (CI) were calculated. We identified significantly over-represented patients genetic predisposition (GPD patients) or idiopathic (IPD compared HC (healthy controls). Xenobiotic-metabolizing show significant accumulation supporting pathogenesis Moreover, high OR values (>5) catalyzing degradation cholesterol (CYP46A1, CY7B1, CYP39A1) indicate prominent metabolism brain risk. Finally, participating eicosanoids strong over-representation underlining effect inflammation on Also, > 5 patients. Taken together, we demonstrate that 26 out at least 5-fold suggesting these as For first time exceptionally (up 12.9) found. This will deeper insight into origin development applied develop strategies this disease.

Язык: Английский

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Inhibition of ACAT as a Therapeutic Target for Alzheimer's Disease Is Independent of ApoE4 Lipidation

Neurotherapeutics, Год журнала: 2023, Номер 20(4), С. 1120 - 1137

Опубликована: Май 8, 2023

APOE4, encoding apolipoprotein E4 (apoE4), is the greatest genetic risk factor for Alzheimer's disease (AD), compared to common APOE3. While mechanism(s) underlying APOE4-induced AD remains unclear, increasing lipidation of apoE4 an important therapeutic target as apoE4-lipoproteins are poorly lipidated apoE3-lipoproteins. ACAT (acyl-CoA: cholesterol-acyltransferase) catalyzes formation intracellular cholesteryl-ester droplets, reducing free cholesterol (FC) pool. Thus, inhibiting increases FC pool and facilitates lipid secretion extracellular apoE-containing lipoproteins. Previous studies using commercial inhibitors, including avasimibe (AVAS), well ACAT-knock out (KO) mice, exhibit reduced AD-like pathology amyloid precursor protein (APP) processing in familial (FAD)-transgenic (Tg) mice. However, effects AVAS with human remain unknown. In vitro, induced apoE efflux at concentrations measured brains treated treatment male E4FAD-Tg mice (5xFAD+/-APOE4+/+) 6–8 months had no effect on plasma levels or distribution, original mechanism CVD. CNS, indirectly demonstrating engagement. Surrogate efficacy was demonstrated by increase Morris water maze measures memory postsynaptic levels. Amyloid-beta peptide (Aβ) solubility/deposition neuroinflammation were reduced, critical components APOE4-modulated pathology. there lipidation, while amyloidogenic non-amyloidogenic APP significantly reduced. This suggests that AVAS-induced reduction Aβ via sufficient reduce pathology, remained lipidated.

Язык: Английский

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