Genetic context modulates aging and degeneration in the murine retina

Molecular Neurodegeneration, Journal Year: 2025, Volume and Issue: 20(1)

Published: Jan. 20, 2025

Abstract Background Age is the principal risk factor for neurodegeneration in both retina and brain. The brain share many biological properties; thus, insights into retinal aging degeneration may shed light onto similar processes Genetic makeup strongly influences susceptibility to age-related disease. However, studies investigating have not sufficiently accounted genetic diversity. Therefore, examining molecular across different backgrounds will enhance our understanding of human-relevant brain—potentially improving therapeutic approaches these debilitating conditions. Methods Transcriptomics proteomics were employed elucidate signatures nine genetically diverse mouse strains (C57BL/6J, 129S1/SvlmJ, NZO/HlLtJ, WSB/EiJ, CAST/EiJ, PWK/PhK, NOD/ShiLtJ, A/J, BALB/cJ) lifespan. These data predicted human disease-relevant changes WSB NZO strains. Accordingly, B6, WSB, mice subjected vivo examinations at 4, 8, 12, and/or 18M, including: slit lamp, fundus imaging, optical coherence tomography, fluorescein angiography, pattern/full-field electroretinography. Retinal morphology, vascular structure, cell counts assessed ex . Results We identified common strains, which included genes associated with photoreceptor function immune activation. background modulated signatures. Analysis type-specific marker loss photoreceptors ganglion cells (RGCs) NZO, respectively. Fundus exams revealed retinitis pigmentosa-relevant pigmentary abnormalities retinas diabetic retinopathy (DR)-relevant cotton wool spots exudates retinas. Profound dysfunction confirmed WSB. Molecular analyses indicated photoreceptor-specific proteins prior loss, suggesting photoreceptor-intrinsic In addition, age-associated RGC dysfunction, concomitant microvascular observed mice. Proteomic an early reduction protective antioxidant processes, underlie increased DR-relevant pathology NZO. Conclusions context a strong determinant aging, multi-omics resource can aid diseases eye Our investigations validated as improved preclinical models relevant neurodegenerative diseases.

Language: Английский

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Non-Invasive Retinal Biomarkers for Early Diagnosis of Alzheimer’s Disease

Biomedicines, Journal Year: 2025, Volume and Issue: 13(2), P. 283 - 283

Published: Jan. 24, 2025

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder of the brain associated with ageing and most prevalent form dementia, affecting an estimated 55 million people worldwide, projections suggesting this number will exceed 150 by 2050. With its increasing prevalence, AD represents significant global health challenge potentially serious social economic consequences. Diagnosing particularly challenging as it requires timely recognition. Currently, there no effective therapy for AD; however, certain medications may help slow progression. Existing diagnostic methods such magnetic resonance imaging (MRI), computed tomography (CT), positron emission (PET), biomarker analysis in cerebrospinal fluid tend to be expensive invasive, making them impractical widespread use. Consequently, research into non-invasive biomarkers that enable early detection screening crucial area contemporary clinical investigation. One promising approach diagnosis retinal imaging. As extension central nervous system, retina offers distinctive opportunity structure function assessment. Considering their shared embryological origins vascular immunological similarities between eye brain, alterations indicate pathological changes including those specifically related AD. Studies suggest structural retina, within neuronal network blood vessels, act markers cerebral caused These have potential diagnosis. Since typically diagnosed only after loss has occurred, identifying could intervention prevent Non-invasive techniques, optical coherence (OCT) OCT angiography, provide accessible linked This review article focuses on Investigating connections processes significantly enhance diagnosis, monitoring, treatment AD, paving way new therapeutic approaches.

Language: Английский

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Understanding retinal tau pathology through functional 2D and 3D iPSC-derived in vitro retinal models

Acta Neuropathologica Communications, Journal Year: 2025, Volume and Issue: 13(1)

Published: Jan. 29, 2025

The generation of retinal models from human induced pluripotent stem cells holds significant potential for advancing our understanding development, neurodegeneration, and the in vitro modeling neurodegenerative disorders. retina, as an accessible part central nervous system, offers a unique window into these processes, making it invaluable both study early diagnosis. This investigates impact Frontotemporal Dementia-linked IVS 10 + 16 MAPT mutation on development function using 2D 3D derived cells. Our findings reveal that leads to delayed cell differentiation maturation, with tau-mutant disease exhibiting sustained higher expression progenitor markers reduced presence post-mitotic neurons. Both demonstrated imbalance tau isoforms, favoring 4R tau, along increased phosphorylation, altered neurite morphology, impaired cytoskeletal maturation. These changes are associated synaptic neuronal connectivity, enhanced cellular stress responses, including formation granules, apoptosis autophagy, intracellular toxic aggregates. highlights value exploring mechanisms underlying pathology mutations. offer essential insights therapeutic strategies diseases characterized by aggregation.

Language: Английский

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Measures of retinal health successfully capture risk for Alzheimer's disease and related dementias at midlife

Journal of Alzheimer s Disease, Journal Year: 2025, Volume and Issue: unknown

Published: March 3, 2025

Background Identification of at-risk individuals who would benefit from early intervention for Alzheimer's disease and related dementias (ADRD) is critical as new treatments are developed. Measures retinal health could offer accessible low-cost indication pre-morbid risk, but their association with ADRD risk unknown. Objective To determine whether midlife neuronal microvascular measures associated risk-index scores individual domains risk. Methods Data were the Dunedin Multidisciplinary Health Development Study, a population-representative longitudinal New Zealand-based birth cohort study. 94.1% (N = 938) living Study members seen at age 45 (2017–2019). Retinal (retinal nerve fiber layer (RNFL) ganglion cell–inner plexiform (GC-IPL)) (arterioles venules) used predictors. Outcome four top indexes (CAIDE, LIBRA, Lancet, ADU-ADRI), comprehensive index, DunedinARB. Results Poorer (narrower arterioles wider was greater (βs 0.16–0.31; ps < 0.001). Thinner RNFL modestly higher 0.05–0.08; 0.02–0.13). Follow-up tests distinct indicated that while associations reflected cardiometabolic only, diverse factors. Conclusions health, particularly measures, successfully capture across several known factors, even young years. imaging may be an accessible, scalable, relatively method assessing among middle-aged adults.

Language: Английский

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Association between retinal layer thickness and postoperative delirium in older patients

General Psychiatry, Journal Year: 2025, Volume and Issue: 38(2), P. e101740 - e101740

Published: April 1, 2025

Background Postoperative delirium is one of the most common complications in older surgical population, but its pathogenesis and biomarkers are largely undetermined. Retinal layer thickness has been demonstrated to be associated with cognitive function mild impairment patients Alzheimer’s disease. However, relatively little known about possible retinal among postoperative delirium. Aims We aimed investigate relationship between this cross-sectional study. Methods The participants (≥65 years old) having elective surgery under general anaesthesia were screened via medical records from Shanghai 10th People’s Hospital. Preoperative macular peripapillary nerve fibre (RNFL) measured using optical coherence tomography (OCT). Confusion Assessment Method (CAM) algorithm CAM-Severity (CAM-S) used assess incidence severity on first, second third days after surgery. Results Among 169 (mean (standard deviation (SD) 71.15 (4.36) years), 40 (24%) developed Notably, individuals who exhibited thicker preoperative right eye compared those did not 283.35 (27.97) µm vs 273.84 (20.14) µm, p=0.013). Furthermore, was a higher (adjusted odds ratio 1.593, 95% confidence interval (CI) 1.093 2.322, p=0.015) greater mean difference ( β )=0.256, CI 0.037 0.476, p=0.022) adjustment for age, sex Mini-Mental State Examination (MMSE) scores. such or association appear left bilateral RNFL thicknesses. Conclusions Current findings that might serve as potential non-invasive marker vulnerability developing patients. Further large-scale validation studies should performed confirm these results.

Language: Английский

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Altered tear fluid protein expression in persons with mild Alzheimer's disease in proteins involved in oxidative stress, protein synthesis, and energy metabolism

Journal of Alzheimer s Disease, Journal Year: 2025, Volume and Issue: unknown

Published: April 4, 2025

Background Tear fluid (TF) is a protein-rich solution that reflects pathophysiological changes in Alzheimer's disease (AD). Objective In this study, we examined whether TF proteins were differently expressed persons with mild AD dementia compared to cognitively healthy controls (CO). Methods We analyzed data from 53 study participants including 34 CO (mean age, 71 years; Mini-Mental State Examination [MMSE] score, 28.9 ± 1.4), and 19 patients (Clinical Dementia Rating, 0.5–1; mean 72 MMSE 23.8 2.8). All underwent cognitive testing, as well neurological ophthalmological examinations. was collected using Schirmer strips, protein content evaluated mass spectrometry-based proteomics label-free quantification. Results found 16 exhibited significantly upregulated expression the group ( p ≤ 0.05). These NP1L4, BBOX1, CYTC, RNAS4, PCD, RNT2, AL1A3, SYSC, TPIS, CLH1, PGAM1, EIF3L, 5NTC, HNRNPA2B1, PYGL, ERO1α. No downregulated group. Conclusions Our results support hypothesis potential source of biomarkers for AD. Part those altered have previously linked increased oxidative stress, changed synthesis, disturbed regulation energy metabolism related or neurodegenerative disease. The present indicate value continued investigation

Language: Английский

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Exploring Retinal Neurodegeneration in Alzheimer’s Disease: A Molecular and Cellular Perspective

Neurotoxicity Research, Journal Year: 2025, Volume and Issue: 43(2)

Published: April 1, 2025

Language: Английский

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Lancao decoction in the treatment of alzheimer's disease via activating PI3K/AKT signaling to promote ERK involving in enhancing neuronal activities in the hippocampus

Journal of Ethnopharmacology, Journal Year: 2024, Volume and Issue: 338, P. 119017 - 119017

Published: Nov. 9, 2024

Language: Английский

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Targeting complement C3a receptor resolves mitochondrial hyperfusion and subretinal microglial activation in progranulin-deficient frontotemporal dementia

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 1, 2024

Mutations in progranulin (

Language: Английский

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Rationale and design of the BeyeOMARKER study: prospective evaluation of blood- and eye-based biomarkers for early detection of Alzheimer’s disease pathology in the eye clinic

Alzheimer s Research & Therapy, Journal Year: 2024, Volume and Issue: 16(1)

Published: Aug. 21, 2024

Abstract Background Alzheimer’s disease (AD) is a common, complex and multifactorial that may require screening across multiple routes of referral to enable early detection subsequent future implementation tailored interventions. Blood- eye-based biomarkers show promise as low-cost, scalable patient-friendly tools for AD given their ability provide information on pathophysiological changes manifestations in the retina, respectively. Eye clinics an intriguing real-world proof-of-concept setting evaluate performance these potential intricate connections between eye brain, presumed enrichment pathology aging population with disorders, accelerated diagnostic pathway under-recognized patient groups. Methods The BeyeOMARKER study prospective, observational, longitudinal cohort aiming include individuals visiting eye-clinic. Inclusion criteria entail being ≥ 50 years old having no prior dementia diagnosis. Excluded eye-conditions traumatic insults, superficial inflammation, conditions surrounding structures are not engaged vision. ( n = 700) will undergo blood collection assess plasma p-tau217 levels brief cognitive at clinic. All participants subsequently be invited annual follow-up including remotely administered questionnaires. + 150), consisting 100 positive matched negative controls selected from cohort, additionally Aβ-PET tau-PET, MRI, retinal imaging hyperspectral (primary), widefield imaging, optical coherence tomography (OCT) OCT-Angiography (secondary), cortical vision assessments. Results We aim implement current protocol April 2024 until March 2027. Primary outcomes detect (using Aβ- tau-PET visual read reference standard) decline. Initial ~ 2 but extended additional funding. Conclusions envision demonstrate feasibility based blood- alternative settings, improve our understanding eye-brain connection. Trial registration (Eudamed CIV ID: CIV-NL-23–09-044086; date: 19th 2024) approved by ethical review board Amsterdam UMC.

Language: Английский

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