Inhibition of Aβ Aggregation and Tau Phosphorylation with Functionalized Biomimetic Nanoparticles for Synergic Alzheimer’s Disease Therapy DOI

Yunfei Tang,

Xiaolei Song, Mengmeng Xiao

et al.

ACS Applied Materials & Interfaces, Journal Year: 2024, Volume and Issue: 16(45), P. 61774 - 61786

Published: Nov. 4, 2024

The main pathological mechanisms of Alzheimer's Disease (AD) are extracellular senile plaques caused by β-amyloid (Aβ) deposition and intracellular neurofibrillary tangles derived from hyperphosphorylated Tau protein (p-Tau). However, it is difficult to obtain a good curative effect because the poor brain bioavailability drugs, which attributed blood-brain barrier (BBB) restriction complicated conditions. Herein, HM-DK was proposed for synergistic therapy AD using hollow mesoporous manganese dioxide (HM) as carrier deliver an Aβ-inhibiting peptide Dp-peptide inhibitor Tau-related fibril formation synergistically. Inspired 4T1 cancer cells promoting BBB penetration during metastasis, prospective biomimetic nanocarrier (HM-DK@CM) encapsulated cell membranes designed. After crossing BBB, HM-DK@CM inhibited Aβ aggregation prevented phosphorylation simultaneously. Moreover, taking advantage catalase-like activity HM, relieved oxidative stress altered microenvironment associated with development AD. Compared single therapeutic drug, restored nerve damage improved mice's learning memory abilities decreasing oligomer, p-Tau protein, inflammation through various pathways therapy, has broad prospects effective treatment

Language: Английский

Perivascular brain clearance as a therapeutic target in cerebral amyloid angiopathy and Alzheimer's disease DOI Creative Commons
Orla Bonnar, Beth Eyre, Susanne J. van Veluw

et al.

Neurotherapeutics, Journal Year: 2025, Volume and Issue: unknown, P. e00535 - e00535

Published: Jan. 1, 2025

Language: Английский

Citations

2
Molecular profiling of frontal and occipital subcortical white matter hyperintensities in Alzheimer’s disease DOI Creative Commons
Sulochan Malla, Annie G. Bryant,

Rojashree Jayakumar

et al.

Frontiers in Neurology, Journal Year: 2025, Volume and Issue: 15

Published: Jan. 7, 2025

White matter hyperintensities (WMHs) are commonly detected on T2-weighted magnetic resonance imaging (MRI) scans, occurring in both typical aging and Alzheimer's disease (AD). Despite their frequent appearance association with cognitive decline AD, the molecular factors contributing to WMHs remain unclear. In this study, we investigated transcriptomic profiles of two affected brain regions coincident AD pathology-frontal subcortical white (frontal-WM) occipital (occipital-WM)-and compared age-matched cognitively intact controls. Through RNA-sequencing frontal- occipital-WM bulk tissues, identified an upregulation genes associated vasculature function matter. To further elucidate vasculature-specific features, performed RNA-seq analysis blood vessels isolated from these regions, which revealed related protein folding pathways. Finally, comparing gene expression between individuals high- versus low-WMH burden showed increased pathways immune function. Taken together, our study characterizes diverse changes provides mechanistic insights into processes underlying AD-related WMHs.

Language: Английский

Citations

0
Fibrillar tau alters cerebral endothelial cell metabolism, vascular inflammatory activation, and barrier function in vitro and in vivo DOI Creative Commons
Roberto Guzmán‐Hernández, Silvia Fossati

Alzheimer s & Dementia, Journal Year: 2025, Volume and Issue: 21(3)

Published: March 1, 2025

Abstract INTRODUCTION The presence of tau aggregates in and around the brain vasculature Alzheimer's disease (AD) tauopathies suggests its possible pathogenicity to cerebral endothelial cells (ECs). METHODS We used an vitro model blood–brain barrier (BBB) understand mechanisms fibrillar tau–mediated EC BBB pathology, confirming our findings 3‐month‐old P301S mice brains extracted microvessels. RESULTS Protofibrillar species induce permeability through increase glycolysis, which activates ECs toward a pro‐inflammatory phenotype, inducing loss junction protein expression localization. Warburg‐like metabolic shift glycolysis increased vascular pathological phenotypes are also present young mice. DISCUSSION In sum, work reveals that species, by enhancing glycolytic metabolism, promote inflammatory function, highlighting importance addressing targeting early tau‐mediated neurovascular damage AD tauopathies. Highlights improve understanding pathology Fibrillar mediates changes, inflammation, dysfunction. These events replicated at stages tauopathy mouse model. Inhibiting altered reduces activation.

Language: Английский

Citations

0
Dissection of blood–brain barrier dysfunction through CSF PDGFRβ and amyloid, tau, neuroinflammation, and synaptic CSF biomarkers in neurodegenerative disorders DOI
Agathe Vrillon,

Nicholas J. Ashton,

Elodie Bouaziz‐Amar

et al.

EBioMedicine, Journal Year: 2025, Volume and Issue: 115, P. 105694 - 105694

Published: April 15, 2025

Language: Английский

Citations

0
Tau depletion diminishes vascular amyloid‐related deficits in a mouse model of cerebral amyloid angiopathy DOI Creative Commons
Nur Jury, Enrique Chimal‐Juárez, Henika Patel

et al.

Alzheimer s & Dementia, Journal Year: 2025, Volume and Issue: 21(5)

Published: May 1, 2025

Abstract INTRODUCTION Tau is essential for amyloid beta (Aβ)–induced synaptic and cognitive deficits in Alzheimer's disease (AD), making its downregulation a therapeutic target. Cerebral angiopathy (CAA), major vascular contributor to decline, affects over 90% of patients with AD. This study explores the impact tau on CAA pathogenesis. METHODS We crossed Familial Danish Dementia mouse model (Tg‐FDD), which develops amyloid, tau‐null (mTau −/− ) mice generate lacking endogenous (Tg‐FDD/mTau ). Behavioral, electrophysiological, histological, transcriptomic analyses were performed. RESULTS depletion ameliorated motor impairments, reduced deposition, prevented damage. ablation also mitigated astrocytic reactivity neuroinflammation associated accumulation. CONCLUSION These findings provide first vivo evidence beneficial effects model, supporting reduction as potential strategy parenchymal deposition. Highlights improves function impair, reduces cerebrovascular deposits, prevents damage cerebral (CAA). decreases reactivity, alters neuroinflammatory gene expression, enhances oligodendrocyte function, suggesting protective role against CAA. highlight mitigate CAA‐induced pathogenesis, implications treating both

Language: Английский

Citations

0
The influences of ApoE isoforms on endothelial adherens junctions and actin cytoskeleton responding to mCRP DOI Creative Commons
Zhengrong Zhang,

Weiwei Lin,

Qini Gan

et al.

Angiogenesis, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 14, 2024

Language: Английский

Citations

3
Molecular profiling of frontal and occipital subcortical white matter hyperintensities in Alzheimer’s disease DOI Creative Commons
Sulochan Malla, Annie G. Bryant,

Rojashree Jayakumar

et al.

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

Published: June 13, 2024

Abstract White matter hyperintensities (WMHs) are commonly detected on T2-weighted magnetic resonance imaging (MRI) scans, occurring in both typical aging and Alzheimer’s disease. Despite their frequent appearance association with cognitive decline, the molecular factors contributing to WMHs remain unclear. In this study, we investigated transcriptomic profiles of two affected brain regions coincident AD pathology—frontal subcortical white (frontal-WM) occipital (occipital-WM)—and compared age-matched healthy controls. Through RNA-sequencing frontal- occipital-WM bulk tissues, identified an upregulation genes associated vasculature function matter. To further elucidate vasculature-specific features, performed RNA-seq analysis blood vessels isolated from these regions, which revealed related protein folding pathways. Finally, comparing gene expression between individuals high-versus low-WMH burden showed increased pathways immune function. Taken together, our study characterizes diverse changes normal provides new mechanistic insights processes underlying AD-related WMHs.

Language: Английский

Citations

1
Inhibition of Aβ Aggregation and Tau Phosphorylation with Functionalized Biomimetic Nanoparticles for Synergic Alzheimer’s Disease Therapy DOI

Yunfei Tang,

Xiaolei Song, Mengmeng Xiao

et al.

ACS Applied Materials & Interfaces, Journal Year: 2024, Volume and Issue: 16(45), P. 61774 - 61786

Published: Nov. 4, 2024

The main pathological mechanisms of Alzheimer's Disease (AD) are extracellular senile plaques caused by β-amyloid (Aβ) deposition and intracellular neurofibrillary tangles derived from hyperphosphorylated Tau protein (p-Tau). However, it is difficult to obtain a good curative effect because the poor brain bioavailability drugs, which attributed blood-brain barrier (BBB) restriction complicated conditions. Herein, HM-DK was proposed for synergistic therapy AD using hollow mesoporous manganese dioxide (HM) as carrier deliver an Aβ-inhibiting peptide Dp-peptide inhibitor Tau-related fibril formation synergistically. Inspired 4T1 cancer cells promoting BBB penetration during metastasis, prospective biomimetic nanocarrier (HM-DK@CM) encapsulated cell membranes designed. After crossing BBB, HM-DK@CM inhibited Aβ aggregation prevented phosphorylation simultaneously. Moreover, taking advantage catalase-like activity HM, relieved oxidative stress altered microenvironment associated with development AD. Compared single therapeutic drug, restored nerve damage improved mice's learning memory abilities decreasing oligomer, p-Tau protein, inflammation through various pathways therapy, has broad prospects effective treatment

Language: Английский

Citations

1