The Cholinergic System, the Adrenergic System and the Neuropathology of Alzheimer’s Disease

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(3), P. 1273 - 1273

Published: Jan. 28, 2021

Neurodegenerative diseases are a major public health problem worldwide with wide spectrum of symptoms and physiological effects. It has been long reported that the dysregulation cholinergic system adrenergic linked to etiology Alzheimer's disease. Cholinergic neurons widely distributed in brain regions play role cognitive functions normal signaling related learning memory is dependent on acetylcholine. The Locus Coeruleus norepinephrine (LC-NE) main noradrenergic nucleus projects supplies different regions. Norepinephrine shown be neuroprotective against neurodegeneration plays behavior cognition. dysregulated degeneration basalis Meynert basal forebrain LC-NE were aim this review describe current literature pathology disease potential therapeutic implications.

Language: Английский

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G protein-coupled receptors in neurodegenerative diseases and psychiatric disorders

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: May 3, 2023

Neuropsychiatric disorders are multifactorial with diverse aetiological factors. Identifying treatment targets is challenging because the diseases resulting from heterogeneous biological, genetic, and environmental Nevertheless, increasing understanding of G protein-coupled receptor (GPCR) opens a new possibility in drug discovery. Harnessing our knowledge molecular mechanisms structural information GPCRs will be advantageous for developing effective drugs. This review provides an overview role various neurodegenerative psychiatric diseases. Besides, we highlight emerging opportunities novel GPCR address recent progress development.

Language: Английский

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The Locus Coeruleus in Aging and Alzheimer’s Disease: A Postmortem and Brain Imaging Review

Journal of Alzheimer s Disease, Journal Year: 2021, Volume and Issue: 83(1), P. 5 - 22

Published: July 3, 2021

The locus coeruleus (LC), a tiny nucleus in the brainstem and principal site of noradrenaline synthesis, has major role regulating autonomic function, arousal, attention, neuroinflammation. LC dysfunction been linked to range disorders; however particular interest is given it plays Alzheimer’s disease (AD). undergoes significant neuronal loss AD, thought occur early process. While also suggested aging, this relationship less clear as findings have contradictory. density be indicative cognitive reserve evidence for these claims will discussed. Recent imaging techniques allowing visualization vivo using neuromelanin-sensitive MRI are developing our understanding aging AD. Tau pathology within evident at an age most individuals; however, between tau accumulation why some individuals then develop AD not understood. Neuromelanin pigment accumulates cells with proposed toxic inflammatory when released into extracellular environment. This review explore current knowledge changes both from postmortem, imaging, experimental studies. We discuss reasons behind susceptibility loss, focus on neuromelanin neuroinflammation caused by LC-noradrenaline pathway.

Language: Английский

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Inflaming the Brain with Iron

Antioxidants, Journal Year: 2021, Volume and Issue: 10(1), P. 61 - 61

Published: Jan. 6, 2021

Iron accumulation and neuroinflammation are pathological conditions found in several neurodegenerative diseases, including Alzheimer’s disease (AD) Parkinson’s (PD). inflammation intertwined a bidirectional relationship, where iron modifies the inflammatory phenotype of microglia infiltrating macrophages, turn, these cells secrete diffusible mediators that reshape neuronal homeostasis regulate entry into brain. Secreted include cytokines reactive oxygen/nitrogen species (ROS/RNS), notably hepcidin nitric oxide (·NO). Hepcidin is small cationic peptide with central role regulating systemic homeostasis. Also present cerebrospinal fluid (CSF), can reduce export from neurons decreases through blood–brain barrier (BBB) by binding to exporter ferroportin 1 (Fpn1). Likewise, ·NO selectively converts cytosolic aconitase (c-aconitase) regulatory protein (IRP1), which regulates cellular its response elements (IRE) located mRNAs iron-related proteins. Nitric oxide-activated IRP1 impair during neuroinflammation, triggering accumulation, especially mitochondria, leading death. In this review, we will summarize findings connect support their causal association processes observed AD PD.

Language: Английский

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Effects of β-Blockers on the Sympathetic and Cytokines Storms in Covid-19

Frontiers in Immunology, Journal Year: 2021, Volume and Issue: 12

Published: Nov. 11, 2021

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a causative virus in the development of disease 2019 (Covid-19) pandemic. Respiratory manifestations SARS-CoV-2 infection such as lung injury (ALI) and distress (ARDS) leads to hypoxia, oxidative stress, sympatho-activation severe cases sympathetic storm (SS). On other hand, an exaggerated immune response invasion may lead uncontrolled release pro-inflammatory cytokine (CS). In Covid-19, there are interactive interactions between CS SS multi-organ failure (MOF). Interestingly, cutting bridge by anti-inflammatory anti-adrenergic agents mitigate complications that induced severely affected Covid-19 patients. The potential mechanisms through different pathways which activate central center carotid bodies chemosensory input cytokines, cross blood-brain barrier activation center. β2-receptors signaling pathway play crucial role production macrophage activation, B-cells for antibodies with inflammation exacerbation. β-blockers have effects reduction cytokines inhibition NF-κB. conclusion, interrupt this interaction several mediators prevention neural-cytokine loop infection. Evidence from study triggers idea future prospective studies confirm management Covid-19.

Language: Английский

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Blood–brain barrier permeable β-blockers linked to lower risk of Alzheimer’s disease in hypertension

Brain, Journal Year: 2022, Volume and Issue: 146(3), P. 1141 - 1151

Published: Feb. 21, 2022

Alzheimer's disease is a neurodegenerative disorder in which the pathological accumulation of amyloid-β and tau begins years before symptom onset. Emerging evidence suggests that β-blockers (β-adrenergic antagonists) increase brain clearance these metabolites by enhancing CSF flow. Our objective was to determine whether β-blocker treatments easily cross blood-brain barrier reduce risk compared less permeable β-blockers. Data from Danish national registers were used identify retrospective cohort individuals with hypertension, those treated included analysis. People indications for use other than hypertension (e.g. heart failure) only retained sensitivity divided into three permeability groups: low, moderate high. We multivariable cause-specific Cox regression model effect on time dementia outcomes, adjusting baseline comorbidities, demographics socioeconomic variables. Death modelled as competing risk. The 10-year standardized absolute estimated averaged person-specific risks per treatment. In 69 081 (median age = 64.4 years, 64.8% female) people highly barrier-permeable associated reduced versus low (-0.45%, P < 0.036). This specific diagnoses did not extend general. Propensity score analysis matching high patients also detected decreased (-0.92%, 0.001) group 1-year landmark (-0.57%, 0.029) events within first year follow-up ignored likely unrelated results suggest amongst taking treatment reduces drugs. findings support hypothesis protect against promoting waste metabolite clearance.

Language: Английский

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Hypertension and hyperhomocysteinemia as modifiable risk factors for Alzheimer's disease and dementia: New evidence, potential therapeutic strategies, and biomarkers

Alzheimer s & Dementia, Journal Year: 2022, Volume and Issue: 19(2), P. 671 - 695

Published: Nov. 19, 2022

Abstract This review summarizes recent evidence on how mid‐life hypertension, hyperhomocysteinemia (HHcy) and blood pressure variability, as well late‐life hypotension, exacerbate Alzheimer's disease (AD) dementia risk. Intriguingly, HHcy also increases the risk for revealing importance of understanding relationship between comorbid cardiovascular factors. Hypertension‐induced presents more evidently in women, highlighting relevance sex differences impact We summarize each major antihypertensive drug class's effects cognitive impairment AD pathology, carbonic anhydrase inhibitors, diuretics modulating cerebral flow, have recently gained preclinical promising treatment against AD. report novel vascular biomarkers risk, those associated with hypertension HHcy. Importantly, we propose that future studies should consider potential contributors to impairment, uncovering underlying molecular mechanisms would aid identification preventive strategies.

Language: Английский

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Unveiling the impact of aging on BBB and Alzheimer's disease: Factors and therapeutic implications

Ageing Research Reviews, Journal Year: 2024, Volume and Issue: 98, P. 102224 - 102224

Published: Feb. 10, 2024

Language: Английский

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Unveiling the Interplay: Neurovascular Coupling, Astrocytes and G Protein-Coupled Receptors in Alzheimer’s Disease

ACS Pharmacology & Translational Science, Journal Year: 2025, Volume and Issue: 8(2), P. 271 - 285

Published: Jan. 8, 2025

Astrocytes are a type of glial cell that involved in actively modulating synaptic plasticity, neurotransmitter homeostasis, and neuroinflammatory responses. More importantly, they coordinate neuronal activity cerebral blood flow (CBF) what is known as neurovascular coupling (NVC). NVC an essential mechanism maintains the high energy demand brain requires by supplying continuous rapid supply oxygen nutrients through CBF. Impairment one key events triggers spiral occurrences lead to clinical advancement Alzheimer's disease (AD). It yet be determined molecular manifestations impairment relate to; nonetheless, it believed alterations G protein-coupled receptors (GPCRs) responsible for exacerbating these effects. In this review, we summarize current evidence supporting involvement GPCRs on astrocytes pathophysiology AD. Additionally, propose potential research directions further elucidate underlying mechanisms evaluate feasibility targeting specific therapeutic strategy correct memory impairments associated with

Language: Английский

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Commonly prescribed multi‐medication therapies exert sex‐specific effects on Alzheimer's disease pathology and metabolomic profiles in App^NL‐G‐F mice: Implications for personalized therapeutics in aging

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

Published: March 1, 2025

Abstract INTRODUCTION Polypharmacy is common among older adults and people with dementia. Multi‐medication therapy poses risks of harm but also targets comorbidities risk factors associated dementia, offering therapeutic potential. METHODS We evaluated the effects two polypharmacy regimens monotherapies on male female App NL‐G‐F knock‐in mice. assessed functional, emotional, cognitive outcomes;amyloid pathology; serum metabolomics profiles. RESULTS A combination metoprolol, simvastatin, aspirin, paracetamol, citalopram improved memory, reduced amyloid burden neuroinflammation, modulated AD‐associated metabolomic signatures in mice, negligible Substituting cardiovascular drugs impacted emotional domains worsened predominantly In males, could not explain effects, suggesting drug synergy, whereas certain monotherapy were lost when combined. DISCUSSION This study uncovers sex‐specific an AD model, identifying mechanisms biomarkers that can guide gender‐specific use medicines dementia prevention management. Highlights Two combinations show pathology Metoprolol+simvastatin+aspirin+paracetamol+citalopram improves memory Replacing metoprolol simvastatin enalapril atorvastatin eliminates benefits mice impairs Selected produce only partially outcomes combinations. Metabolomic pathways indicate possible for evaluating effectiveness safety personalized therapies aging

Language: Английский

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