Anti-malaria drug artesunate prevents development of amyloid-β pathology in mice by upregulating PICALM at the blood-brain barrier

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

Published: Jan. 27, 2023

PICALM is one of the most significant susceptibility factors for Alzheimer's disease (AD). In humans and mice, highly expressed in brain endothelium. endothelial levels are reduced AD brains. controls several steps Aβ transcytosis across blood-brain barrier (BBB). Its loss from endothelium mice diminishes clearance at BBB, which worsens pathology, but reversible by re-expression. Thus, increasing BBB holds potential to slow down development pathology.To identify a drug that could increase expression, we screened library 2007 FDA-approved drugs HEK293t cells expressing luciferase driven human promoter, followed secondary mRNA screen Eahy926 cell line. vivo studies with lead hit were carried out Picalm-deficient (Picalm+/-) Picalm+/-; 5XFAD Picalmlox/lox; Cdh5-Cre; endothelial-specific Picalm knockout. We studied expression pathology blood, cerebral blood flow (CBF) responses, integrity behavior.Our identified anti-malaria artesunate as hit. Artesunate elevated protein capillaries Picalm+/- 2-3-fold. treatment (32 mg/kg/day 2 months) 3-month old compared vehicle increased capillary 2-fold, Aβ42 Aβ40 thioflavin S-load cortex hippocampus, vascular load 34-51%. also circulating 2-fold confirming accelerated blood. Consistent improved CBF behavior on novel object location recognition, burrowing nesting. Endothelial-specific knockout abolished all beneficial effects indicating required its therapeutic effects.Artesunate increases prevents functional deficits translation AD.

Language: Английский

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White matter injury, cholesterol dysmetabolism, and APP/Abeta dysmetabolism interact to produce Alzheimer’s disease (AD) neuropathology: A hypothesis and review

Frontiers in Aging Neuroscience, Journal Year: 2023, Volume and Issue: 15

Published: Feb. 10, 2023

We postulate that myelin injury contributes to cholesterol release from and dysmetabolism which Abeta dysmetabolism, combined with genetic AD risk factors, leads increased amyloid plaques. Increased damages form a vicious cycle. Thus, white matter injury, interact produce or worsen neuropathology. The cascade is the leading hypothesis for cause of Alzheimer’s disease (AD). failure clinical trials based on this has raised other possibilities. Even possible new success (Lecanemab), it not clear whether result disease. With discovery in 1993 apolipoprotein E type 4 allele (APOE4) was major factor sporadic, late-onset (LOAD), there been increasing interest since APOE transporter. Recent studies show metabolism intricately involved (Aβ)/amyloid transport metabolism, down-regulating Aβ LRP1 transporter upregulating RAGE receptor, both would increase brain Aβ. Moreover, manipulating rodent models can ameliorate pathology cognitive deficits, them depending upon manipulation. Though (WM) noted initial observations, recent have shown abnormal every brain. age-related WM normal individuals occurs earlier worse APOE4 genotype. precedes formation plaques tangles human Familial (FAD) plaque models. Restoring improves cognition without affecting pathology. we cascade, and/or further primary initiating event could be related any three, age diet genes FAD dysmetabolism.

Language: Английский

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Blood–brain barrier transporters: a translational consideration for CNS delivery of neurotherapeutics

Expert Opinion on Drug Delivery, Journal Year: 2024, Volume and Issue: 21(1), P. 71 - 89

Published: Jan. 2, 2024

Introduction Successful neuropharmacology requires optimization of CNS drug delivery and, by extension, free concentrations at brain molecular targets. Detailed assessment blood-brain barrier (BBB) physiological characteristics is necessary to achieve this goal. The 'next frontier' in targeting BBB uptake transporters, an approach that evaluation endothelial cell transport processes so effective accumulation and improved therapeutic efficacy can occur.

Language: Английский

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The impact of neuroinflammation on neuronal integrity

Immunological Reviews, Journal Year: 2024, Volume and Issue: 327(1), P. 8 - 32

Published: Oct. 1, 2024

Neuroinflammation, characterized by a complex interplay among innate and adaptive immune responses within the central nervous system (CNS), is crucial in responding to infections, injuries, disease pathologies. However, dysregulation of neuroinflammatory response could significantly affect neurons terms function structure, leading profound health implications. Although tremendous progress has been made understanding relationship between processes alterations neuronal integrity, specific implications concerning both structure have not extensively covered, with exception perspectives on glial activation neurodegeneration. Thus, this review aims provide comprehensive overview multifaceted interactions key inflammatory players, exploring mechanisms through which inflammation influences functionality structural integrity CNS. Further, it will discuss how these lead impairment functions architecture highlight consequences caused dysregulated functions, such as cognitive dysfunction mood disorders. By integrating insights from recent research findings, enhance our landscape set stage for future interventions that transform current approaches preserve CNS-related conditions.

Language: Английский

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VEGF Paradoxically Reduces Cerebral Blood Flow in Alzheimer’s Disease Mice

Neuroscience Insights, Journal Year: 2022, Volume and Issue: 17

Published: Jan. 1, 2022

Vascular dysfunction plays a critical role in the development of Alzheimer's disease. Cerebral blood flow reductions 10% to 25% present early disease pathogenesis. Endothelial Growth Factor-A (VEGF-A) drives angiogenesis, which typically addresses and global hypoxia. However, recent evidence suggests aberrant VEGF-A signaling may undermine its physiological angiogenic function. Instead improving cerebral flow, contributes brain capillary stalls reductions, likely accelerating cognitive decline. In this commentary, we explore for pathological VEGF disease, discuss implications therapy.

Language: Английский

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