Diverse Interactions of Sterols with Amyloid Precursor Protein Transmembrane Domain Can Shift Distribution Between Alternative Amyloid-β Production Cascades in Manner Dependent on Local Lipid Environment

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(2), С. 553 - 553

Опубликована: Янв. 10, 2025

Alzheimer's disease (AD) pathogenesis is correlated with the membrane content of various lipid species, including cholesterol, whose interactions amyloid precursor protein (APP) have been extensively explored. Amyloid-β peptides triggering AD are products APP cleavage by secretases, which differ depending on and secretase location relative to ordered or disordered microdomains. We used high-resolution NMR probe cholesterol analog transmembrane domain in two membrane-mimicking systems resembling perturbed environments (bicelles/micelles). In bicelles, spin-labeled sterol interacted peptide near amphiphilic juxtamembrane region N-terminal part helix, as described earlier for cholesterol. Upon transition into micellar environment, another interaction site appeared where polar head was buried hydrophobic core hinge region. MD simulations, moved between three sites, sliding along groove formed glycine residues composing dimerization interfaces flexible domain. Because environment modulates interactions, role lipids defined state entire subsystem rather than effects individual species. Cholesterol can interplay other (polyunsaturated, gangliosides, etc.), determining outcome amyloid-β production cascades.

Язык: Английский

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Postoperative delirium risk in patients with hyperlipidemia: A prospective cohort study

Journal of Clinical Anesthesia, Год журнала: 2024, Номер 98, С. 111573 - 111573

Опубликована: Авг. 2, 2024

Язык: Английский

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Blood-Based Biomarkers in Alzheimer’s Disease: Advancing Non-Invasive Diagnostics and Prognostics

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(20), С. 10911 - 10911

Опубликована: Окт. 10, 2024

Alzheimer’s disease (AD), the most prevalent form of dementia, is expected to rise dramatically in incidence due global population aging. Traditional diagnostic approaches, such as cerebrospinal fluid analysis and positron emission tomography, are expensive invasive, limiting their routine clinical use. Recent advances blood-based biomarkers, including amyloid-beta, phosphorylated tau, neurofilament light, offer promising non-invasive alternatives for early AD detection monitoring. This review synthesizes current research on these highlighting potential track pathology enhance accuracy. Furthermore, this uniquely integrates recent findings protein-protein interaction networks microRNA pathways, exploring novel combinations proteomic, genomic, epigenomic biomarkers that provide new insights into AD’s molecular mechanisms. Additionally, we discuss integration with advanced neuroimaging techniques, emphasizing revolutionize diagnostics. Although large-scale validation still needed, represent a critical advancement toward more accessible, cost-effective, tools AD.

Язык: Английский

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Bromelain prevents Alzheimer's disease progression by suppressing oxidative stress and upregulating apolipoprotein A1 in 5x familial Alzheimer's disease transgenic mice

Journal of Agriculture and Food Research, Год журнала: 2025, Номер unknown, С. 101927 - 101927

Опубликована: Апрель 1, 2025

Язык: Английский

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Recent Insights into the Neurobiology of Alzheimer’s Disease and Advanced Treatment Strategies

Molecular Neurobiology, Год журнала: 2024, Номер unknown

Опубликована: Авг. 5, 2024

Язык: Английский

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Hypercholesterolemia and Alzheimer’s Disease: Unraveling the Connection and Assessing the Efficacy of Lipid-Lowering Therapies

Journal of Alzheimer s Disease, Год журнала: 2024, Номер 101(s1), С. S371 - S393

Опубликована: Окт. 18, 2024

This article examines the relationship between cholesterol levels and Alzheimer's disease (AD), beginning with early observation that individuals who died from heart attacks often had brain amyloid deposition. Subsequent animal model research proved high could hasten accumulation. In contrast, cholesterol-lowering treatments appeared to counteract this effect. Human autopsy studies reinforced cholesterol-AD connection, revealing higher during midlife significantly correlated pathology. effect was especially pronounced in aged 40 55. Epidemiological data supported human tissue observations suggested managing reduce risk of developing AD. We analyze main observational clinical trials on efficacy statins. While suggest a potential protective against AD, have not consistently shown benefit. The failure these demonstrate clear advantage is partially attributed multiple factors, including timing statin therapy, type appropriate selection patients for treatment. Many failed target might benefit most intervention, such as high-risk like APOE4 carriers. review addresses how implicated AD through various biological pathways, preventive role management by studies, difficulties encountered trials, particularly related use. paper highlights need explore alternate therapeutic targets mechanisms escape intervention.

Язык: Английский

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Non-canonical pathways associated to Amyloid beta and tau protein dyshomeostasis in Alzheimer’s disease: A narrative review

Ageing Research Reviews, Год журнала: 2024, Номер 102, С. 102578 - 102578

Опубликована: Ноя. 13, 2024

Alzheimer's Disease (AD) is the most common form of dementia among elderly people. This disease imposes a significant burden on healthcare system, society, and economy due to increasing global aging population. Current trials with drugs or bioactive compounds aimed at reducing cerebral Amyloid beta (Aβ) plaques tau protein neurofibrillary tangles, which are two main hallmarks this devastating neurodegenerative disease, have not provided results in terms their neuropathological outcomes nor met expected clinical end-points. Ageing, genetic environmental risk factors, along different symptoms suggest that AD complex heterogeneous disorder multiple interconnected pathological pathways rather than single entity. In present review, we highlight discuss various non-canonical, Aβ-independent mechanisms, like gliosis, unhealthy dietary intake, lipid sugar signaling, cerebrovascular damage contribute onset development AD. We emphasize challenging traditional "amyloid cascade hypothesis" may improve our understanding age-related syndrome help fight progressive cognitive decline

Язык: Английский

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Exploring the Dynamic Changes of Brain Lipids, Lipid Rafts, and Lipid Droplets in Aging and Alzheimer’s Disease

Biomolecules, Год журнала: 2024, Номер 14(11), С. 1362 - 1362

Опубликована: Окт. 26, 2024

Aging induces complex changes in the lipid profiles across different areas of brain. These can affect function brain cells and may contribute to neurodegenerative diseases such as Alzheimer's disease. Research shows that while overall profile human remains quite steady throughout adulthood, specific occur with age, especially after age 50. include a slow decline total content shifts composition fatty acids, particularly glycerophospholipids cholesterol levels, which vary depending on region. Lipid rafts play crucial role maintaining membrane integrity facilitating cellular signaling. In context disease, have been associated development For example, alterations raft lead increased accumulation amyloid β (Aβ) peptides, contributing neurotoxic effects. droplets store neutral lipids are key for energy metabolism. As organisms dynamics change, evidence suggesting metabolic activity over time. This reduced an imbalance synthesis mobilization, processes. model like Drosophila, studies shown metabolism be influenced by diet insulin signaling pathways, balance. The interplay between metabolism, oxidative stress, inflammation is critical aging peroxidation, consequence formation reactive aldehydes further damage neurons. Inflammatory processes also disrupt pathology AD. Consequently, oxidized integrity, influencing pathways involved neuronal survival function.

Язык: Английский

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Myelin Lipid Alterations in Neurodegenerative Diseases: Landscape and Pathogenic Implications

Antioxidants and Redox Signaling, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 22, 2024

Lipids, which constitute the highest portion (over 50%) of brain dry mass, are crucial for integrity, energy homeostasis, and signaling regulation. Emerging evidence revealed that lipid profile alterations abnormal metabolism occur during normal aging in different forms neurodegenerative diseases. Moreover, increasing genome-wide association studies have validated new targets on lipid-associated pathways involved disease development. Myelin, protective sheath surrounding axons, is efficient neural transduction. As primary site enriched with lipids, impairments myelin increasingly recognized as playing significant complex roles various diseases, beyond simply being secondary effects neuronal loss.

Язык: Английский

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Altered Brain Cholesterol Machinery in a Down Syndrome Mouse Model: A Possible Common Feature with Alzheimer’s Disease

Antioxidants, Год журнала: 2024, Номер 13(4), С. 435 - 435

Опубликована: Апрель 3, 2024

Down syndrome (DS) is a complex chromosomal disorder considered as genetically determined form of Alzheimer’s disease (AD). Maintenance brain cholesterol homeostasis essential for functioning and development, its dysregulation associated with AD neuroinflammation oxidative damage. Brain imbalances also likely occur in DS, concurring the precocious AD-like neurodegeneration. In this pilot study, we analyzed, Ts2Cje (Ts2) mouse model expression genes encoding key enzymes involved metabolism levels main precursors products (i.e., oxysterols). The results showed, Ts2 mice compared to euploid mice, downregulation transcription 3-hydroxy-3-methylglutaryl-CoA reductase 24-dehydrocholesterol reductase, latter originally recognized an indicator AD, consequent reduction total levels. Moreover, responsible oxidation amounts resulting oxysterols were modified brains, autoxidation increased, suggesting exacerbation cerebral stress. We observed enhanced inflammatory response underlined by upregulation α-interferon interleukin-6, two cytokines whose synthesis increased brains patients. Overall, these suggest that DS share cycle derangements altered oxysterol levels, which may contribute events both diseases.

Язык: Английский

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