Simvastatin, Its Antimicrobial Activity and Its Prevention of Alzheimer’s Disease DOI Creative Commons
Sudip Dhakal, Ian Macreadie

Microorganisms, Год журнала: 2024, Номер 12(6), С. 1133 - 1133

Опубликована: Июнь 1, 2024

Simvastatin, a blockbuster drug for treating hypercholesterolemia, has multifactorial benefits as an antimicrobial agent and plays preventative role in reducing the incidence of Alzheimer’s Disease (AD). Although most beneficial effects simvastatin have been attributed to its ability reduce cholesterol levels, recent scientific studies suggested that are largely due pleiotropic targeting other pathways, e.g., by inhibiting protein lipidation. There certain can be predicted from inhibition mevalonate pathway; however, some proteostasis lead reduced levels amyloid beta, key contributor AD. This review discusses use anti-AD drug.

Язык: Английский

Non-linear relationship between serum cholesterol levels and cognitive change among older people in the preclinical and prodromal stages of dementia: a retrospective longitudinal study in Taiwan DOI Creative Commons
Hsin-Te Chang,

Po‐Chi Chan,

Pai‐Yi Chiu

и другие.

BMC Geriatrics, Год журнала: 2024, Номер 24(1)

Опубликована: Май 30, 2024

Abstract Background Adverse effects of rigorously lowering low-density lipoprotein cholesterol on cognition have been reported; therefore, we aimed to study the contribution serum in cognitive decline older people with or without dementia. Methods Cognitive function was assessed by Abilities Screening Instrument (CASI). We investigated associations between using multiple regressions controlling for demographics, vascular risk factors, and treatments. Results Most CASI scores could be explained non-linear inverted U-shaped relationships ( R 2 = 0.003–0.006, p < 0.016, Šidákcorrection). The were most evident changes at preclinical prodromal stages dementia (R 0.02–0.064, values 0.016). There no differences level individuals 1st decile 10th groups 0.266–0.972). However, triglyceride stable normal functions showed significant improvement compared those t (202) 2.275, 0.05). Conclusion These findings implicate that may not suitable prevention among people, especially

Язык: Английский

Процитировано

8
Enhanced delivery of antibodies across the blood-brain barrier via TEMs with inherent receptor-mediated phagocytosis DOI Creative Commons
Suzanne C. Edavettal,

Pilar Cejudo-Martı́n,

B. Dasgupta

и другие.

Med, Год журнала: 2022, Номер 3(12), С. 860 - 882.e15

Опубликована: Окт. 17, 2022

The near impermeability of the blood-brain barrier (BBB) and unique neuroimmune environment CNS prevents effective use antibodies in neurological diseases. Delivery biotherapeutics to brain can be enabled through receptor-mediated transcytosis via proteins such as transferrin receptor, although limitations ability Fc-mediated effector function clear pathogenic targets introduce safety liabilities. Hence, novel delivery approaches with alternative clearance mechanisms are warranted.Binders that optimized transport across BBB, known transcytosis-enabling modules (TEMs), were identified using a combination antibody discovery techniques pharmacokinetic analyses. Functional activity TEMs subsequently evaluated by imaging for myeloid cells phagocytose target cells.We demonstrated significantly enhanced exposure therapeutic optimal receptor or CD98 TEMs. We found these also mediated efficient tau aggregates HER2+ tumor non-classical phagocytosis mechanism direct engagement cells. This mode potentially avoids drawbacks FcγR-mediated neurotoxic release proinflammatory cytokines immune cell exhaustion.Our study reports new platform harnesses maximize uptake uses efficiently pathologic believe findings will transform treat diseases.This research was funded Janssen, Pharmaceutical Companies Johnson & Johnson.

Язык: Английский

Процитировано

37
Super-resolution imaging unveils the self-replication of tau aggregates upon seeding DOI Creative Commons
Eleni Dimou, Panagiotis Katsinelos, Georg Meisl

и другие.

Cell Reports, Год журнала: 2023, Номер 42(7), С. 112725 - 112725

Опубликована: Июль 1, 2023

Tau is a soluble protein interacting with tubulin to stabilize microtubules. However, under pathological conditions, it becomes hyperphosphorylated and aggregates, process that can be induced by treating cells exogenously added tau fibrils. Here, we employ single-molecule localization microscopy resolve the aggregate species formed in early stages of seeded aggregation. We report entry sufficient assemblies into cytosol induces self-replication small doubling time 5 h inside HEK 1 day murine primary neurons, which then grow Seeding occurs vicinity microtubule cytoskeleton, accelerated proteasome, results release media. In absence seeding, still spontaneously form aggregates at lower levels. Overall, our work provides quantitative picture templated aggregation cells.

Язык: Английский

Процитировано

19
The type‐I interferon response potentiates seeded tau aggregation and exacerbates tau pathology DOI Creative Commons
Sophie Sanford, Lauren V. C. Miller, Marina Vaysburd

и другие.

Alzheimer s & Dementia, Год журнала: 2023, Номер 20(2), С. 1013 - 1025

Опубликована: Окт. 17, 2023

Abstract INTRODUCTION Signatures of a type‐I interferon (IFN‐I) response are observed in the post mortem brain Alzheimer's disease (AD) and other tauopathies. However, effect IFN‐I on pathological tau accumulation remains unclear. METHODS We examined effects signaling primary neural culture models seeded aggregation P301S‐tau transgenic mouse context genetic deletion receptor (IFNAR). RESULTS Polyinosinic:polycytidylic acid (PolyI:C), synthetic analog viral nucleic acids, evoked potent cytokine that enhanced an IFN‐I‐dependent manner. IFN‐I‐induced vulnerability could be pharmacologically prevented was intrinsic to neurons. Aged mice lacking Ifnar1 had significantly reduced pathology compared with intact IFN signaling. DISCUSSION identify critical role for potentiating aggregation. is therefore identified as potential therapeutic target AD Highlights Type‐I promotes cultures. IFNAR inhibition prevents driven sensitivity Tau aged IFNAR.

Язык: Английский

Процитировано

16
Human tau mutations in cerebral organoids induce a progressive dyshomeostasis of cholesterol DOI Creative Commons
Stella M.K. Glasauer,

Susan K. Goderie,

Jennifer N. Rauch

и другие.

Stem Cell Reports, Год журнала: 2022, Номер 17(9), С. 2127 - 2140

Опубликована: Авг. 18, 2022

Mutations in the MAPT gene that encodes tau lead to frontotemporal dementia (FTD) with pathology evident both cerebral neurons and glia. Human organoids (hCOs) from individuals harboring pathogenic mutations can reveal earliest downstream effects on molecular pathways within a developmental context, generating interacting We found hCOs carrying V337M R406W mutations, cholesterol biosynthesis pathway astrocytes was top upregulated set compared isogenic controls by single-cell RNA sequencing (scRNA-seq). The 15 genes included HMGCR, ACAT2, STARD4, LDLR, SREBF2. This result confirmed homozygous mutant cell line immunostaining sterol measurements. Cholesterol abundance brain is tightly regulated efflux biosynthetic enzyme levels astrocytes, dysregulation cause aberrant phosphorylation of tau. Our findings suggest dyshomeostasis an early event etiology neurodegeneration caused mutations.

Язык: Английский

Процитировано

27
Unifying biology of neurodegeneration in lysosomal storage diseases DOI Creative Commons

Anna Ludlaim,

Simon N. Waddington, Tristan R. McKay

и другие.

Journal of Inherited Metabolic Disease, Год журнала: 2025, Номер 48(1)

Опубликована: Янв. 1, 2025

Язык: Английский

Процитировано

0
Visualize neuronal membrane cholesterol with split- fluorescent protein tagged YDQA sensor DOI Creative Commons
Yi Xu,

S Li,

Yiran Xu

и другие.

Journal of Lipid Research, Год журнала: 2025, Номер unknown, С. 100781 - 100781

Опубликована: Март 1, 2025

Язык: Английский

Процитировано

0
Nutrition in Alzheimer’s disease: a review of an underappreciated pathophysiological mechanism DOI Open Access
Jiwei Jiang, Hanping Shi,

Shirui Jiang

и другие.

Science China Life Sciences, Год журнала: 2023, Номер 66(10), С. 2257 - 2279

Опубликована: Апрель 7, 2023

Язык: Английский

Процитировано

11
Aggregation Behavior of Amyloid Beta Peptide Depends Upon the Membrane Lipid Composition DOI

Lipika Mirdha

The Journal of Membrane Biology, Год журнала: 2024, Номер 257(3-4), С. 151 - 164

Опубликована: Июнь 18, 2024

Язык: Английский

Процитировано

4
The interaction between dysfunction of vasculature and tauopathy in Alzheimer's disease and related dementias DOI Creative Commons
Chuyao Huang,

Zhenwen Wei,

Ningxiang Zheng

и другие.

Alzheimer s & Dementia, Год журнала: 2025, Номер 21(2)

Опубликована: Фев. 1, 2025

Abstract Tauopathy is one of the pathological features Alzheimer's disease and related dementias (ADRD). At present, there have been many studies on formation, deposition, intercellular transmission tau in neurons immune cells. The vasculature an important component central nervous system. This review discusses interaction between detail from three aspects. (1) vascular risk factors (VRFs) discussed this include diabetes mellitus (DM), abnormal blood pressure (BP), hypercholesterolemia. (2) In ADRD pathology, hyperphosphorylation deposition interact with disrupted vasculature, such as different cells (endothelial cells, smooth muscular pericytes), blood−brain barrier (BBB), cerebral lymphatic (3) functions are regulated by various signaling transductions. Endothelial nitric oxide synthase/nitric oxide, calcium signaling, Rho/Rho‐associated coiled‐coil containing Kinase, receptors for advanced glycation end products review. Our findings indicate that prevention treatment health may be a potential target combination therapy. Highlights Persistent VRFs increase early disruption mechanisms strongly associated pathology ADRD. Cell dysfunction causes BBB leakage drainage incapacity system, which interacts pathology. Signaling molecules regulate vasodilation contraction, angiogenesis, CBF. Abnormal transduction to deposition.

Язык: Английский

Процитировано

0