Cardiometabolic risk factors and neurodegeneration: a review of the mechanisms underlying diabetes, obesity and hypertension in Alzheimer’s disease

Journal of Neurology Neurosurgery & Psychiatry, Год журнала: 2024, Номер 95(6), С. 581 - 589

Опубликована: Янв. 30, 2024

A growing body of evidence suggests that cardiometabolic risk factors play a significant role in Alzheimer’s disease (AD). Diabetes, obesity and hypertension are highly prevalent can accelerate neurodegeneration perpetuate the burden AD. Insulin resistance enzymes including insulin degrading implicated AD where breakdown is prioritised over amyloid-β. Leptin inflammation demonstrated by higher plasma central nervous system levels interleukin-6 (IL-6), IL-1β tumour necrosis factor-α, mechanisms connecting diabetes with has been shown to ameliorate pathology enhance long-term potentiation hippocampal-dependent cognitive function. The renin-aldosterone angiotensin system, involved hypertension, associated neurotoxic reactive oxygen species, binds specific angiotensin-1 receptors hippocampus cerebral cortex. This review aims consolidate behind putative processes stimulated obesity, which leads increased risk. We focus on how novel knowledge be applied clinically facilitate recognition efficacious treatment strategies for

Язык: Английский

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Re-Routing Drugs to Blood Brain Barrier: A Comprehensive Analysis of Machine Learning Approaches With Fingerprint Amalgamation and Data Balancing

IEEE Access, Год журнала: 2022, Номер 11, С. 9890 - 9906

Опубликована: Дек. 29, 2022

Computational drug repurposing is an efficient method to utilize existing knowledge for understanding and predicting their effect on neurological diseases. The ability of a molecule cross the blood-brain barrier primary criteria effective therapy. Thus, accurate predictions by employing Machine learning models can effectively identify candidates that could be repurposed conditions. This study comprehensively analyzes performance well-known machine two different datasets overcome dataset-related biases. We found random forest extratrees (i.e., tree-based ensembled models) have highest accuracy with mol2vec fingerprint BBB permeability prediction, attaining AUC_ROC 0.9453 0.9601 B3DB dataset, respectively. Additionally, we analyzed impact data balancing technique SMOTE) improve specificity models. Finally, explored combinations accuracy. By SMOTE combination, SVC attains 0.9511 dataset. used best-performing dataset evaluate drugs intended repurposing. Model validation predicted non-passage most antihypertensive passage CYP17A1 cancer drugs.

Язык: Английский

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The COVID-19 pandemic and Alzheimer’s disease: mutual risks and mechanisms

Translational Neurodegeneration, Год журнала: 2022, Номер 11(1)

Опубликована: Сен. 11, 2022

Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a life-threatening disease, especially in elderly individuals and those with comorbidities. The predominant clinical manifestation of COVID-19 dysfunction, while neurological presentations are increasingly being recognized. SARS-CoV-2 invades host cells primarily via attachment the spike protein to angiotensin-converting enzyme (ACE2) receptor expressed on cell membranes. Patients Alzheimer's (AD) more susceptible infection prone outcomes. Recent studies have revealed some common risk factors for AD COVID-19. An understanding association between potential related mechanisms may lead development novel approaches treating both diseases. In present review, we first summarize central nervous system (CNS) then discuss associations shared key AD, focus ACE2 receptor, apolipoprotein E (APOE) genotype, age, neuroinflammation.

Язык: Английский

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The GLP-1 Agonist Semaglutide Ameliorates Cognitive Regression in P301S Tauopathy Mice Model via Autophagy/ACE2/SIRT1/FOXO1-Mediated Microglia Polarization

European Journal of Pharmacology, Год журнала: 2025, Номер unknown, С. 177305 - 177305

Опубликована: Янв. 1, 2025

Язык: Английский

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The Renin Angiotensin System as a Therapeutic Target in Traumatic Brain Injury

Neurotherapeutics, Год журнала: 2023, Номер 20(6), С. 1565 - 1591

Опубликована: Сен. 27, 2023

Язык: Английский

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Intranasal irbesartan reverts cognitive decline and activates the PI3K/AKT pathway in an LPS-induced neuroinflammation mice model

International Immunopharmacology, Год журнала: 2024, Номер 128, С. 111471 - 111471

Опубликована: Янв. 9, 2024

New strategies are urgently needed to manage and delay the development of Alzheimer's disease (AD). Neuroinflammation is a significant contributor cognitive decline in neurodegenerative diseases, including AD. Angiotensin receptor blockers (ARBs) angiotensin converting enzyme inhibitors (ACEIs) protect hypertensive patients against AD, but cellular molecular mechanisms underlying these effects remain unknown. In light this, protective three ARBs ACEIs neuroinflammation were investigated through comprehensive pharmacologicalin vitro/in vivoscreening.

Язык: Английский

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Angiotensin-(1-7) protective effects in neurocognitive disorders: molecular mechanisms to therapeutic implications

Frontiers in Physiology, Год журнала: 2025, Номер 16

Опубликована: Март 27, 2025

Cognition broadly refers to the ability perform mental processes such as learning and memory, attention, emotional awareness, higher-order thinking. Cognitive deficits can result from normal aging process or other factors disease progression injury. While exact etiology is not fully understood, emerging evidence suggests that enhanced inflammatory oxidative stress during dramatically decrease cognitive function in older adults, well contribute onset of neurocognitive disorders. Current treatments for disorders have limited efficacy typically focus on symptom attenuation rather than targeting intrinsic pathophysiology. With rising population, there a critical need identify novel treatment approaches target underlying mechanisms contributing In this regard, renin-angiotensin system (RAS) may provide an ideal target, hormonal has been implicated regulation responses impact functions. most research date focused deleterious role angiotensin (Ang) II pathways age-related decline disorders, more recent examined potential Ang-(1-7), protective hormone RAS, counteract these effects. This review highlights showing activation Ang-(1-7) reduces inflammation improve elicit neuroprotection, context both

Язык: Английский

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Under the umbrella of depression and Alzheimer’s disease physiopathology: Can cannabinoids be a dual-pleiotropic therapy?

Ageing Research Reviews, Год журнала: 2023, Номер 90, С. 101998 - 101998

Опубликована: Июль 5, 2023

Depression and Alzheimer´s disease (AD) are two disorders highly prevalent worldwide. affects more than 300 million people worldwide while AD 60% to 80% of the 55 cases dementia. Both diseases affected by aging with high prevalence in elderly share not only main brain areas but also several physiopathological mechanisms. is already ascribed as a risk factor development AD. Despite wide diversity pharmacological treatments currently available clinical practice for depression management, they remain associated slow recovery process treatment-resistant depression. On other hand, treatment essentially based symptomatology relieve. Thus, need new multi-target arises. Herein, we discuss current state-of-art regarding contribution endocannabinoid system (ECS) synaptic transmission processes, synapses plasticity neurogenesis consequently use exogenous cannabinoids on delaying progression Besides well-known imbalance neurotransmitter levels, including serotonin, noradrenaline, dopamine glutamate, recent scientific evidence highlights aberrant spine density, neuroinflammation, dysregulation neurotrophic levels formation amyloid beta (Aβ) peptides, mechanisms compromised The ECS these herein specified well pleiotropic effects phytocannabinoids. At end, it became evident that Cannabinol, Cannabidiol, Cannabigerol, Cannabidivarin Cannabichromene may act novel therapeutic targets, presenting potential pharmacotherapy both diseases.

Язык: Английский

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Renin–angiotensin system inhibitors positively impact on multiple aging regulatory pathways: Could they be used to protect against human aging?

Physiological Reports, Год журнала: 2024, Номер 12(12)

Опубликована: Июнь 1, 2024

The renin-angiotensin system (RAS)-a classical blood pressure regulator-largely contributes to healthy organ development and function. Besides, RAS activation promotes age-related changes age-associated diseases, which are attenuated/abolished by RAS-blockade in several mammalian species. RAS-blockers also increase rodent lifespan. In previous work, we discussed how downregulates mTOR growth hormone/IGF-1 signaling, stimulates AMPK activity (together with klotho, sirtuin, vitamin D-receptor upregulation), proposed that at least some of RAS-blockade's aging benefits mediated through regulation these intermediaries their signaling mitochondria. Here, included impact on other regulatory pathways, is, TGF-ß, NF-kB, PI3K, MAPK, PKC, Notch, Wnt, all affect No direct evidence is available RAS/RAS-blockade-aging pathway-mitochondria interactions. However, existing results allow conjecture neutralize mitochondrial dysfunction acting the pathways. reviewed led us propose foundation laid for conducting clinical trials aimed testing whether angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB)-even subclinical doses-offer possibility live longer better health. As ACEi ARB low cost well-tolerated anti-hypertension therapies use over 35 years, investigating administration attenuate/prevent effects seems simple implement.

Язык: Английский

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Acute Myocardial Infarction and Risk of Cognitive Impairment and Dementia: A Review

Biology, Год журнала: 2023, Номер 12(8), С. 1154 - 1154

Опубликована: Авг. 21, 2023

Cognitive impairment (CI) shares common cardiovascular risk factors with acute myocardial infarction (AMI), and is increasingly prevalent in our ageing population. Whilst AMI associated increased rates of CI, CI remains underreported infrequently identified patients AMI. In this review, we discuss the evidence surrounding its links to dementia including pathophysiology, factors, management interventions. Vascular dysregulation plays a major role atherosclerosis, platelet activation, microinfarcts perivascular inflammation resulting neurovascular unit dysfunction, disordered homeostasis dysfunctional neurohormonal response. This subsequently affects perfusion pressure, enlarged periventricular spaces hippocampal sclerosis. The activation seen coronary artery disease (CAD) can also result amyloid-β protein deposition which Alzheimer’s Dementia. Post-AMI, reduced blood pressure left ventricular ejection fraction cause chronic cerebral hypoperfusion, failure normal circulatory autoregulatory mechanisms. Patients who undergo revascularization (percutaneous intervention or bypass surgery) are at for post-procedure cognitive impairment, though whether related itself underlying debated. Mortality higher AMI, post-AMI more elderly heart failure. Medical (antiplatelet, statin, renin-angiotensin system inhibitors, cardiac rehabilitation) reduce CI; however, beta-blockers may be functional decline existing CI. early identification those present important, as subsequent tailoring strategies potentially improve outcomes well guide prognosis.

Язык: Английский

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