Border-associated macrophages promote cerebral amyloid angiopathy and cognitive impairment through vascular oxidative stress

Molecular Neurodegeneration, Journal Year: 2023, Volume and Issue: 18(1)

Published: Oct. 3, 2023

Abstract Background Cerebral amyloid angiopathy (CAA) is a devastating condition common in patients with Alzheimer’s disease but also observed the general population. Vascular oxidative stress and neurovascular dysfunction have been implicated CAA cellular source of reactive oxygen species (ROS) related signaling mechanisms remain unclear. We tested hypothesis that brain border-associated macrophages (BAM), yolk sac-derived myeloid cells closely apposed to parenchymal leptomeningeal blood vessels, are radicals through Aβ-binding innate immunity receptor CD36, leading dysfunction, CAA, cognitive impairment. Methods Tg2576 mice WT littermates were transplanted CD36 −/− or +/+ bone marrow at 12-month age 15 months. This approach enables repopulation perivascular compartments BAM. Neurovascular function was anesthetized equipped cranial window which cerebral flow monitored by laser-Doppler flowmetry. Amyloid pathology examined. Results The increase evoked whisker stimulation (functional hyperemia) endothelial smooth muscle vasoactivity markedly attenuated → chimeras fully restored chimeras, BAM ROS production suppressed. CAA-associated Aβ 1-40 , not 1-42 reduced chimeras. Similarly, plaques, These beneficial vascular effects associated improvement. Finally, able more efficiently clear exogenous injected into neocortex striatum. Conclusions deletion suppresses rescues damage induced Aβ. ameliorated without affecting parenchyma plaques. Lack enhanced clearance Restoration attenuation resulted near complete rescue function. Collectively, these data implicate pathogenesis raise possibility targeting other conditions deposition damage. Graphical

Language: Английский

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Advancements in APOE and dementia research: Highlights from the 2023 AAIC Advancements: APOE conference

Alzheimer s & Dementia, Journal Year: 2024, Volume and Issue: 20(9), P. 6590 - 6605

Published: July 19, 2024

Abstract INTRODUCTION The apolipoprotein E gene ( APOE ) is an established central player in the pathogenesis of Alzheimer's disease (AD), with distinct apoE isoforms exerting diverse effects. influences not only amyloid‐beta and tau pathologies but also lipid energy metabolism, neuroinflammation, cerebral vascular health, sex‐dependent manifestations. Furthermore, ancestral background may significantly impact link between AD, underscoring need for more inclusive research. METHODS In 2023, Association convened multidisciplinary researchers at “AAIC Advancements: APOE” conference to discuss various topics, including their roles AD pathogenesis, progress apoE‐targeted therapeutic strategies, updates on models interventions that modulate expression function. RESULTS This manuscript presents highlights from provides overview opportunities further research field. DISCUSSION Understanding apoE's multifaceted will help develop targeted advance field precision medicine. Highlights a disease. exerts numerous effects throughout brain amyloid‐beta, tau, other pathways. AAIC encouraged discussions collaborations understanding role APOE.

Language: Английский

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Mechanisms and environmental factors shaping the ecosystem of brain macrophages

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: Jan. 24, 2025

Brain macrophages encompass two major populations: microglia in the parenchyma and border-associated (BAMs) extra-parenchymal compartments. These cells play crucial roles maintaining brain homeostasis immune surveillance. Microglia BAMs are phenotypically epigenetically distinct exhibit highly specialized functions tailored to their environmental niches. Intriguingly, recent studies have shown that both originate from same myeloid progenitor during yolk sac hematopoiesis, but developmental fates diverge within brain. Several works partially unveiled mechanisms orchestrating development of mice humans; however, many questions remain unanswered. Defining molecular underpinnings controlling transcriptional epigenetic programs is one upcoming challenges for field. In this review, we outline current knowledge on ontogeny, phenotypic diversity, factors shaping ecosystem macrophages. We discuss insights garnered human studies, highlighting similarities differences compared mice. Lastly, address research gaps potential future directions Understanding how communicate with local environment tissue instructs trajectories functional features essential fully comprehend physiology disease.

Language: Английский

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Molecular and cellular characteristics of cerebrovascular cell types and their contribution to neurodegenerative diseases

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

Published: Jan. 29, 2025

Language: Английский

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Repetitive head trauma and apoE4 induce chronic cerebrovascular alterations that impair tau elimination from the brain

Experimental Neurology, Journal Year: 2024, Volume and Issue: 374, P. 114702 - 114702

Published: Jan. 30, 2024

Language: Английский

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The immunology of stroke and dementia

Immunity, Journal Year: 2025, Volume and Issue: 58(1), P. 18 - 39

Published: Jan. 1, 2025

Language: Английский

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Potential therapeutic effects of SIRT1 targeting APOE4-induced microvascular endothelial dysfunction

EBioMedicine, Journal Year: 2025, Volume and Issue: 113, P. 105594 - 105594

Published: Feb. 7, 2025

Language: Английский

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Cerebral Hemodynamic Impairment and Cognitive Dysfunction in APOE4 Carriers With Asymptomatic Carotid Artery Stenosis/Occlusion

Journal of the American Heart Association, Journal Year: 2025, Volume and Issue: unknown

Published: March 13, 2025

Background Our previous preclinical study demonstrated that APOE4 ‐targeted replacement mice exhibit more severe cerebral hypoperfusion and cognitive impairment than APOE3 with carotid artery stenosis due to neurovascular dysfunction. Therefore, we clinically investigate whether contributes hemodynamic in subjects asymptomatic or occlusion. Methods Results A cross‐sectional observational was conducted between January 2017 March 2022. In a primary analysis, 91 (114 affected hemispheres) occlusion who underwent neuropsychological examinations 15 O‐gas positron emission tomography were included examine associations of impairment. sensitivity analysis performed 161 (201 scan. the 20 (22.0%) carriers. an independent risk factor lower blood flow anterior circulation territory (β=−0.058 [95% CI, −0.098 −0.018], P =0.005) short‐term memory Alzheimer's Disease Assessment Scale‐Cognitive Subscale 13 (β=1.16 0.009–2.30], =0.048) multivariable linear regression analysis. 31 (19.3%) carried , which (β=−0.048 −0.079 −0.012], =0.003) territory. Conclusions may confer increased decreased accompanied by consistent our experimental study. APOE genotyping such be useful for early detection disease severity.

Language: Английский

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Ginkgo biloba Extract GBE50 ameliorates cerebrovascular dysfunction and cognitive impairment in a mouse model of Alzheimer's disease

Phytomedicine, Journal Year: 2025, Volume and Issue: unknown, P. 156646 - 156646

Published: March 1, 2025

Language: Английский

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Blood–brain barrier disruption: a pervasive driver and mechanistic link between traumatic brain injury and Alzheimer's disease

Translational Neurodegeneration, Journal Year: 2025, Volume and Issue: 14(1)

Published: March 26, 2025

Abstract Traumatic brain injury (TBI) has emerged as a significant risk factor for Alzheimer’s disease (AD), complex and devastating neurodegenerative disorder characterized by progressive cognitive decline memory loss. Both conditions share common feature: blood‒brain barrier (BBB) dysfunction, which is believed to play pivotal role in linking TBI the development of AD. This review delves into intricate relationship between AD, with focus on BBB dysfunction its critical mechanisms therapeutic development. We first present recent evidence from epidemiological studies highlighting increased incidence AD among individuals history TBI, well pathological animal model that demonstrate how can accelerate AD-like pathology. Next, we explore may mediate TBI-induced Finally, investigate shared molecular pathways associated both discuss latest findings targeting these employing regenerative approaches, such stem cell therapy pharmacological interventions, enhance function mitigate neurodegeneration.

Language: Английский

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