Endothelial dysfunction in neurodegenerative disease: Is endothelial inflammation an overlooked druggable target?

Journal of Neuroimmunology, Journal Year: 2024, Volume and Issue: 391, P. 578363 - 578363

Published: May 3, 2024

Neurological diseases with a neurodegenerative component have been associated alterations in the cerebrovasculature. At anatomical level, these are centred around changes cerebral blood flow and vessel organisation. molecular there is extensive expression of cellular adhesion molecules increased release pro-inflammatory mediators. Together, has found to negatively impact blood-brain barrier integrity. Systemic inflammation accelerate exacerbate endothelial dysfunction, neuroinflammation degeneration. Here, we review role cerebrovasculature dysfunction disease discuss potential contribution intermittent systemic causing pathology, highlighting possible mechanism that may allow broad-spectrum therapeutic targeting future.

Language: Английский

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Marine Sources of DHA-Rich Phospholipids with Anti-Alzheimer Effect

Marine Drugs, Journal Year: 2022, Volume and Issue: 20(11), P. 662 - 662

Published: Oct. 25, 2022

Alzheimer’s disease (AD) is a complex and progressive disease, which affects millions of people around the world. Despite many efforts over years to find efficient therapeutics, there no cure yet. Nonetheless, compounds have been proven decrease symptoms. After short overview hypotheses considered in AD drug development drugs approved for treatment, lead symptom release, we focus on valorization natural marine sources that symptoms, particularly docosahexaenoic acid (DHA), an important component membrane phospholipids most abundant n−3 polyunsaturated fatty acids (PUFA) found gray matter brain retina DHA-containing (DHA-PLs) present sources, namely fish, krill, mollusks fisheries aquaculture by-products. DHA-PLs’ bioactivities are presented, their properties anti-neurodegeneration, neuroinflammation, as anticancer agents, well benefits obesity visual problems. Fisheries by-products also highlighted they high content DHA DHA-rich phospholipids, can be extracted by green methodologies should circular economy healthy sustainable future.

Language: Английский

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Astrocytes display ultrastructural alterations and heterogeneity in the hippocampus of aged APP-PS1 mice and human post-mortem brain samples

Journal of Neuroinflammation, Journal Year: 2023, Volume and Issue: 20(1)

Published: March 14, 2023

The past decade has witnessed increasing evidence for a crucial role played by glial cells, notably astrocytes, in Alzheimer's disease (AD). To provide novel insights into the roles of astrocytes pathophysiology AD, we performed quantitative ultrastructural characterization their intracellular contents and parenchymal interactions an aged mouse model AD pathology, as aging is considered main risk factor developing AD. We compared 20-month-old APP-PS1 age-matched C57BL/6J male mice, among ventral hippocampus CA1 strata lacunosum-moleculare radiatum, two hippocampal layers severely affected pathology. Astrocytes both interacted more with synaptic elements displayed markers increased phagolysosomal activity versus C57BL6/J mice. In addition, investigated heterogeneity describing examined dark astrocytic state that characterized terms distribution, hallmarks, contents. This electron-dense state, termed was observed throughout parenchyma, closely associated vasculature, possessed several cellular stress. A case study exploring head human post-mortem brain sample also revealed presence similar electron-dense, state. Overall, our provides first analysis well thorough conserved from to human.

Language: Английский

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NOX-induced oxidative stress is a primary trigger of major neurodegenerative disorders

Progress in Neurobiology, Journal Year: 2023, Volume and Issue: 231, P. 102539 - 102539

Published: Oct. 12, 2023

Neurodegenerative diseases (NDDs) causing cognitive impairment and dementia are difficult to treat due the lack of understanding primary initiating factors. Meanwhile, major sporadic NDDs share many risk factors exhibit similar pathologies in their early stages, indicating existence common initiation pathways. Glucose hypometabolism associated with oxidative stress is one such primary, shared pathology, a likely cause detrimental disease-associated cascades; targeting this pathology may therefore be an effective preventative strategy for most NDDs. However, its exact trigger remain unclear. Recent research suggests that caused by NADPH oxidase (NOX) activation mechanism among could prove long-sought ubiquitous NDD trigger. We focus on two - Alzheimer's disease (AD) Parkinson's (PD), as well acquired epilepsy which increasingly recognized comorbidity also discuss available data suggesting relevance proposed mechanisms other delve into commonalities these neuroinflammation NOX involvement identify potential therapeutic targets gain deeper underlying causes

Language: Английский

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Precise Modulation of Pericyte Dysfunction by a Multifunctional Nanoprodrug to Ameliorate Alzheimer’s Disease

ACS Nano, Journal Year: 2024, Volume and Issue: 18(22), P. 14348 - 14366

Published: May 20, 2024

Pericyte dysfunction severely undermines cerebrovascular integrity and exacerbates neurodegeneration in Alzheimer's disease (AD). However, pericyte-targeted therapy is a yet-untapped frontier for AD. Inspired by the elevation of vascular cell adhesion molecule-1 (VCAM-1) reactive oxygen species (ROS) levels pericyte lesions, we fabricated multifunctional nanoprodrug conjugating hybrid peptide VLC, fusion VCAM-1 high-affinity VHS neuroprotective apolipoprotein mimetic COG1410, to curcumin (Cur) through phenylboronic ester bond (VLC@Cur-NPs) alleviate complex pericyte-related pathological changes. Importantly, VLC@Cur-NPs effectively homed lesions via VLC released their contents upon ROS stimulation maximize regulatory effects. Consequently, markedly increased regeneration form positive feedback loop thus improved neurovascular function ultimately alleviated memory defects APP/PS1 transgenic mice. We present promising therapeutic strategy AD that can precisely modulate pericytes has potential treat other diseases.

Language: Английский

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Retinal peri-arteriolar versus peri-venular amyloidosis, hippocampal atrophy, and cognitive impairment: exploratory trial

Acta Neuropathologica Communications, Journal Year: 2024, Volume and Issue: 12(1)

Published: June 28, 2024

The relationship between amyloidosis and vasculature in cognitive impairment Alzheimer's disease (AD) pathogenesis is increasingly acknowledged. We conducted a quantitative topographic assessment of retinal perivascular amyloid plaque (AP) distribution individuals with both normal impaired cognition. Using retrospective dataset scanning laser ophthalmoscopy fluorescence images from twenty-eight subjects varying states, we developed novel image processing method to examine peri-arteriolar peri-venular curcumin-positive AP burden. further correlated neuroimaging measures neurocognitive scores. Our study unveiled that counts surpassed throughout the entire cohort (P < 0.0001), irrespective primary, secondary, or tertiary vascular branch location, notable increase among cognitively individuals. Moreover, secondary count was elevated 0.01). Significantly, count, particularly venules, exhibited strong correlation clinical dementia rating, Montreal score, hippocampal volume, white matter hyperintensity count. In conclusion, our exploratory analysis detected greater versus marked elevation deposition regions subjects. These findings underscore potential feasibility imaging predicting decline AD progression. Larger longitudinal studies encompassing diverse populations AD-biomarker confirmation are warranted delineate temporal-spatial dynamics continuum.

Language: Английский

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From BBB to PPP: Bioenergetic requirements and challenges for oligodendrocytes in health and disease

Journal of Neurochemistry, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 10, 2024

Abstract Mature myelinating oligodendrocytes, the cells that produce myelin sheath insulates axons in central nervous system, have distinct energetic and metabolic requirements compared to neurons. Neurons require substantial energy execute action potentials, while needs of oligodendrocytes are directed toward building lipid‐rich components supporting neuronal metabolism by transferring glycolytic products as additional fuel. The utilization metabolites brain parenchyma is tightly regulated meet different cell types. Disruption supply can lead stress oligodendrocyte injury, contributing various neurological disorders, including some demyelinating diseases. Understanding physiological properties, structures, mechanisms involved metabolism, well relationship between neighboring cells, crucial investigate underlying pathophysiology caused impairment these disorders. In this review, we describe particular properties response stress. We delineate other context neurovascular unit, regulation metabolite according needs. focus on specific bioenergetic address disruption encourage further studies increase understanding significance support development novel therapeutic approaches for treatment image

Language: Английский

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Advancing Alzheimer’s Therapeutics: Exploring the Impact of Physical Exercise in Animal Models and Patients

Cells, Journal Year: 2023, Volume and Issue: 12(21), P. 2531 - 2531

Published: Oct. 27, 2023

Alzheimer’s disease (AD) is the main neurodegenerative disorder characterized by several pathophysiological features, including misfolding of tau protein and amyloid beta (Aβ) peptide, neuroinflammation, oxidative stress, synaptic dysfunction, metabolic alterations, cognitive impairment. These mechanisms collectively contribute to neurodegeneration, necessitating exploration therapeutic approaches with multiple targets. Physical exercise has emerged as a promising non-pharmacological intervention for AD, demonstrated effects on promoting neurogenesis, activating neurotrophic factors, reducing Aβ aggregates, minimizing formation neurofibrillary tangles (NFTs), dampening inflammatory processes, mitigating improving functionality neurovascular unit (NVU). Overall, neuroprotective are not singular, but multi-targets. Numerous studies have investigated physical exercise’s potential in both AD patients animal models, employing various protocols elucidate underlying neurobiological effects. The objective this review analyze neurological these models compare them conducted patients. By translating findings from different approaches, aims identify opportune, specific, personalized windows, thus advancing research use

Language: Английский

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CD163-Mediated Small-Vessel Injury in Alzheimer’s Disease: An Exploration from Neuroimaging to Transcriptomics

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(4), P. 2293 - 2293

Published: Feb. 14, 2024

Patients with Alzheimer’s disease (AD) often present imaging features indicative of small-vessel injury, among which, white-matter hyperintensities (WMHs) are the most prevalent. However, underlying mechanism association between AD and injury is still obscure. The aim this study to investigate in AD. Differential gene expression analyses were conducted identify genes related WMHs separately mild cognitive impairment (MCI) cognitively normal (CN) subjects from ADNI database. WMH-related identified patients MCI considered be associated early Functional enrichment a protein–protein interaction (PPI) network performed explore pathway hub MCI. Subsequently, Boruta algorithm support vector machine recursive feature elimination (SVM-RFE) feature-selection genes. Finally, was analyzed immunological perspectives; relationship various immune cells neuroimaging indices also explored. Furthermore, 5×FAD mice used demonstrate injury. results logistic regression suggested that significantly contributed MCI, stage A total 276 determined as while 203 obtained CN patients. Among them, only 15 overlapped thus crosstalk By employing SVM-RFE algorithms, CD163, ALDH3B1, MIR22HG, DTX2, FOLR2, ALDH2, ZNF23 recognized linked After considering PPI network, CD163 finally critical correlated fractional anisotropy (FA) values regions vulnerable immunostaining RT-qPCR verifying experiments demonstrated indicators presented cortical tissue upregulation expression. may pivotal candidates

Language: Английский

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Therapeutic potential of plant-derived natural compounds in Alzheimer’s disease: Targeting microglia-mediated neuroinflammation

Biomedicine & Pharmacotherapy, Journal Year: 2024, Volume and Issue: 178, P. 117235 - 117235

Published: Aug. 1, 2024

Language: Английский

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