Alzheimer's disease pathophysiology in the Retina

Progress in Retinal and Eye Research, Год журнала: 2024, Номер 101, С. 101273 - 101273

Опубликована: Май 15, 2024

The retina is an emerging CNS target for potential noninvasive diagnosis and tracking of Alzheimer's disease (AD). Studies have identified the pathological hallmarks AD, including amyloid β-protein (Aβ) deposits abnormal tau protein isoforms, in retinas AD patients animal models. Moreover, structural functional vascular abnormalities such as reduced blood flow, Aβ deposition, blood-retinal barrier damage, along with inflammation neurodegeneration, been described mild cognitive impairment dementia. Histological, biochemical, clinical studies demonstrated that nature severity pathologies brain correspond. Proteomics analysis revealed a similar pattern dysregulated proteins biological pathways patients, enhanced inflammatory neurodegenerative processes, impaired oxidative-phosphorylation, mitochondrial dysfunction. Notably, investigational imaging technologies can now detect AD-specific deposits, well vasculopathy neurodegeneration living suggesting alterations at different stages links to pathology. Current exploratory ophthalmic modalities, optical coherence tomography (OCT), OCT-angiography, confocal scanning laser ophthalmoscopy, hyperspectral imaging, may offer promise assessment AD. However, further research needed deepen our understanding AD's impact on its progression. To advance this field, future require replication larger diverse cohorts confirmed biomarkers standardized retinal techniques. This will validate aiding early screening monitoring.

Язык: Английский

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Co‐Assembled Nanoparticles toward Multi‐Target Combinational Therapy of Alzheimer's Disease by Making Full Use of Molecular Recognition and Self‐Assembly

Advanced Materials, Год журнала: 2024, Номер 36(28)

Опубликована: Апрель 25, 2024

Abstract The complex pathologies in Alzheimer's disease (AD) severely limit the effectiveness of single‐target pharmic interventions, thus necessitating multi‐pronged therapeutic strategies. While flexibility is essentially demanded constructing such multi‐target systems, for achieving optimal synergies and also accommodating inherent heterogeneity within AD. Utilizing dynamic reversibility supramolecular strategy conferring sufficient tunability component substitution proportion adjustment, amphiphilic calixarenes are poised to be a privileged molecular tool facilely function integration. Herein, taking β‐amyloid (Aβ) fibrillation oxidative stress as model combination pattern, multifunctional integration proposed by co‐assembling guanidinium‐modified calixarene with ascorbyl palmitate loading dipotassium phytate cavity. Serial pivotal events can simultaneously addressed this versatile system, including 1) inhibition Aβ production aggregation, 2) disintegration fibrils, 3) acceleration metabolic clearance, 4) regulation stress, which verified significantly ameliorate cognitive impairment 5×FAD mice, reduced plaque content, neuroinflammation, neuronal apoptosis. Confronted extremely intricate clinical realities AD, presented here exhibits ample adaptability necessary alterations on combinations, thereby may immensely expedite advancement AD combinational therapy through providing an exceptionally convenient platform.

Язык: Английский

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Ageing-Related Neurodegeneration and Cognitive Decline

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(7), С. 4065 - 4065

Опубликована: Апрель 5, 2024

Neuropathological assessment was conducted on 1630 subjects, representing 5% of all the deceased that had been sent to morgue Uppsala University Hospital during a 15-year-long period. Among 1610 were ≥41 years age (range 41 102 years). Overall, hyperphosphorylated (HP) τ observed in brains 98% and amyloid β-protein (Aβ) 64%. The most common alteration Alzheimer disease neuropathologic change (ADNC) (56%), followed by primary age-related tauopathy (PART) 26% subjects. In 16% HPτ limited locus coeruleus. 14 subjects (<1%), no altered proteins observed. 3 only Aβ observed, 17, distribution other than seen ADNC/PART. transactive DNA-binding protein 43 (TDP43) associated with limbic-predominant TDP encephalopathy (LATE) 565 (35%) α-synuclein (αS) pathology, i.e., Lewy body (LBD) or multi system atrophy (MSA) 21% A total 39% ADNC, 59% PART, 81% coeruleus lacked concomitant pathologies, LATE-NC LBD-NC. Of 293 (18% subjects) dementia, exhibited high intermediate level ADNC. 84% individuals various degrees alterations observed; MIXED-NC cause dementia. PART 10 dementia (3%), tangle-predominant No vascular NC (VNC), but 17 severe VNC might have contributed cognitive decline. Age-related tau astrogliopathy (ARTAG) 37% 53% those

Язык: Английский

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Analysis of Cerebrospinal Fluid, Plasma β-Amyloid Biomarkers, and Cognition from a 2-Year Phase 2 Trial Evaluating Oral ALZ-801/Valiltramiprosate in APOE4 Carriers with Early Alzheimer’s Disease Using Quantitative Systems Pharmacology Model

Drugs, Год журнала: 2024, Номер 84(7), С. 825 - 839

Опубликована: Июнь 20, 2024

ALZ-801/valiltramiprosate is an oral, small-molecule inhibitor of beta-amyloid (Aβ) aggregation and oligomer formation in late-stage development as a disease-modifying therapy for early Alzheimer's disease (AD). The present investigation provides quantitative systems pharmacology (QSP) analysis amyloid fluid biomarkers cognitive results from 2-year ALZ-801 Phase 2 trial APOE4 carriers with AD.

Язык: Английский

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A nasally administrated reactive oxygen species-responsive carrier-free gene delivery nanosystem for Alzheimer's disease combination therapy

Journal of Controlled Release, Год журнала: 2025, Номер unknown, С. 113604 - 113604

Опубликована: Март 1, 2025

Язык: Английский

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Oligomer sensitive in-situ detection and characterization of gold colloid aggregate formations observed within the hippocampus of the Alzheimer’s disease rat

Neuroscience Letters, Год журнала: 2025, Номер unknown, С. 138218 - 138218

Опубликована: Март 1, 2025

Язык: Английский

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Study of multifunctional anti-AD ligands: design, synthesis, X-ray crystal structure and biological evaluation of diosmetin derivatives

Molecular Diversity, Год журнала: 2024, Номер unknown

Опубликована: Июнь 27, 2024

Язык: Английский

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sAPPα Peptide Promotes Damaged Microglia to Clear Alzheimer’s Amyloid‐β via Restoring Mitochondrial Function

Chemistry - A European Journal, Год журнала: 2024, Номер 30(40)

Опубликована: Май 13, 2024

Alzheimer's disease (AD) is an age-related neurodegenerative with amyloid-β (Aβ) deposition as the main pathological feature. It's important challenge to find new ways clear Aβ from brain. The soluble amyloid precursor protein α (sAPPα) a neuroprotective and can attenuate neuronal damage, including toxic Aβ. However, regulatory role of sAPPα in non-neuronal cells, such microglia, less reported controversial. Here, we showed that promoted phagocytosis degradation both normal damaged microglia. Moreover, function microglia was improved by through normalizing mitochondrial function. Furthermore, results molecular docking simulation had good affinity We preliminarily reveal similar antibodies participate regulation after binding expected be mild safe peptide drug or carrier for AD.

Язык: Английский

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Application of engineered antibodies (scFvs and nanobodies) targeting pathological protein aggregates in Alzheimer’s disease

Expert Opinion on Investigational Drugs, Год журнала: 2024, Номер 33(10), С. 1047 - 1062

Опубликована: Авг. 23, 2024

The misfolding and aggregation of proteins are associated with various neurodegenerative diseases, such as Alzheimer's disease (AD). small-molecule engineered antibodies, single-chain fragment variable (scFv) antibodies nanobodies (Nbs), have gained attention in recent years due to their strong conformational specificity, ability cross the blood-brain barrier (BBB), low immunogenicity, enhanced proximity active sites within aggregates.

Язык: Английский

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Usnic Acid Derivatives as Multi‐Target Anti‐Alzheimer's Disease Agents: Design, Synthesis, X‐Ray Single Crystal Structure of Zn(II) Complex and Biological Activities

Chemistry & Biodiversity, Год журнала: 2024, Номер unknown

Опубликована: Окт. 30, 2024

Abstract Alzheimer's disease (AD) is multifactorial, which makes the design of multi‐target‐directed ligands an attractive strategy for development anti‐AD drugs. In order to enhance effects and reduce toxicity, two usnic acid (UA) derivatives ( 1–2 ) were designed, synthesized fully characterized by introducing dimethylamine Schiff base moiety into toxic “triketone” portion. Ellman's method molecular docking used test cholinesterase inhibitory activities. Antioxidant activities studied with Fenton reaction, cyclic voltammetry C. elegans . The results showed that compared UA, had stronger anti‐cholinesterase similar antioxidant Notably, solvent evaporation 2 ZnCl formed a single crystal, was revealed be Zn(II) complex UA tertiary amine as mixed X‐ray diffraction. hydrolysis thus furtherly HPLC. Furthermore, crystal structure supported replacement in chelation process, playing detoxifying role at same time regulating metal homeostasis. silico prediction also low hepatotoxicity acceptable drug‐likeness Overall, this work provided useful insights multi‐target candidates natural product lead compound.

Язык: Английский

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