Implications of Phosphoinositide 3-Kinase-Akt (PI3K-Akt) Pathway in the Pathogenesis of Alzheimer’s Disease

Molecular Neurobiology, Год журнала: 2021, Номер 59(1), С. 354 - 385

Опубликована: Окт. 26, 2021

Язык: Английский

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Combined metabolic activators improve cognitive functions in Alzheimer’s disease patients: a randomised, double-blinded, placebo-controlled phase-II trial

Translational Neurodegeneration, Год журнала: 2023, Номер 12(1)

Опубликована: Янв. 26, 2023

Alzheimer's disease (AD) is associated with metabolic abnormalities linked to critical elements of neurodegeneration. We recently administered combined activators (CMA) the AD rat model and observed that CMA improves AD-associated histological parameters in animals. promotes mitochondrial fatty acid uptake from cytosol, facilitates oxidation mitochondria, alleviates oxidative stress.

Язык: Английский

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Mitochondria-Targeted Antioxidants, an Innovative Class of Antioxidant Compounds for Neurodegenerative Diseases: Perspectives and Limitations

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(4), С. 3739 - 3739

Опубликована: Фев. 13, 2023

Neurodegenerative diseases comprise a wide spectrum of pathologies characterized by progressive loss neuronal functions and structures. Despite having different genetic backgrounds etiology, in recent years, many studies have highlighted point convergence the mechanisms leading to neurodegeneration: mitochondrial dysfunction oxidative stress been observed pathologies, their detrimental effects on neurons contribute exacerbation pathological phenotype at various degrees. In this context, increasing relevance has acquired antioxidant therapies, with purpose restoring order revert damage. However, conventional antioxidants were not able specifically accumulate diseased mitochondria, often eliciting harmful whole body. last decades, novel, precise, mitochondria-targeted (MTA) compounds developed studied, both vitro vivo, address need counter mitochondria restore energy supply membrane potentials neurons. review, we focus activity therapeutic perspectives MitoQ, SkQ1, MitoVitE MitoTEMPO, most studied belonging class MTA conjugated lipophilic cations, reach compartment.

Язык: Английский

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Insights into the Pathogenesis of Neurodegenerative Diseases: Focus on Mitochondrial Dysfunction and Oxidative Stress

International Journal of Molecular Sciences, Год журнала: 2021, Номер 22(21), С. 11847 - 11847

Опубликована: Окт. 31, 2021

As the population ages, incidence of neurodegenerative diseases is increasing. Due to intensive research, important steps in elucidation pathogenetic cascades have been made and significantly implicated mitochondrial dysfunction oxidative stress. However, available treatment Alzheimer’s disease, Parkinson’s amyotrophic lateral sclerosis mainly symptomatic, providing minor benefits and, at most, slowing down progression disease. Although preclinical setting, drugs targeting stress yielded encouraging results, clinical trials failed or had inconclusive results. It likely that by time diagnosis, are full-blown significant numbers neurons already degenerated, making it impossible for mitochondria-targeted antioxidant molecules stop reverse process. Until further research will provide more efficient molecules, a healthy lifestyle, with plenty dietary antioxidants avoidance exogenous oxidants may postpone onset neurodegeneration, while familial cases benefit from genetic testing aggressive therapy started stage.

Язык: Английский

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Molecular Pathophysiological Mechanisms in Huntington’s Disease

Biomedicines, Год журнала: 2022, Номер 10(6), С. 1432 - 1432

Опубликована: Июнь 17, 2022

Huntington's disease is an inherited neurodegenerative described 150 years ago by George Huntington. The genetic defect was identified in 1993 to be expanded CAG repeat on exon 1 of the huntingtin gene located chromosome 4. In following almost 30 years, a considerable amount research, using mainly animal models or vitro experiments, has tried unravel complex molecular cascades through which transcription mutant protein leads neuronal loss, especially medium spiny neurons striatum, and excitotoxicity, transcriptional dysregulation, mitochondrial dysfunction, oxidative stress, impaired proteostasis, altered axonal trafficking reduced availability trophic factors crucial contributors. This review discusses pathogenic literature demise. However, due ubiquitous presence huntingtin, astrocytes are also dysfunctional, neuroinflammation may additionally contribute pathology. quest for therapies delay onset reduce rate progression ongoing, but based findings from basic research.

Язык: Английский

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The Link between Oxidative Stress, Mitochondrial Dysfunction and Neuroinflammation in the Pathophysiology of Alzheimer’s Disease: Therapeutic Implications and Future Perspectives

Antioxidants, Год журнала: 2022, Номер 11(11), С. 2167 - 2167

Опубликована: Окт. 31, 2022

Alzheimer’s disease (AD), the most common form of dementia, has increasing incidence, mortality rates, and poses a huge burden on healthcare. None currently approved drugs for treatment AD influence progression. Many clinical trials aiming at inhibiting amyloid plaque formation, beta clearance, or neurofibrillary tangle pathology yielded inconclusive results failed. Meanwhile, research identified many interlinked vicious cascades implicating oxidative stress, mitochondrial dysfunction, chronic neuroinflammation, pointed to novel therapeutic targets such as improving bioenergetics quality control, diminishing modulating neuroinflammatory pathways. molecules tested in vitro animal models have proven efficient, but their translation into clinic needs further regarding appropriate doses, delivery routes, possible side effects. Cell-based therapies extracellular vesicle-mediated messenger RNAs microRNAs seem also promising strategies allowing target specific signaling pathways, need harvesting culture methods well control tumorigenic The rapidly developing area nanotechnology could improve drug be used early diagnosis.

Язык: Английский

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Pathogenesis of Dementia

International Journal of Molecular Sciences, Год журнала: 2022, Номер 24(1), С. 543 - 543

Опубликована: Дек. 29, 2022

According to Alzheimer’s Disease International, 55 million people worldwide are living with dementia. Dementia is a disorder that manifests as set of related symptoms, which usually result from the brain being damaged by injury or disease. The symptoms involve progressive impairments in memory, thinking, and behavior, accompanied emotional problems, difficulties language, decreased motivation. most common variant dementia disease dominated cognitive disorders, particularly memory loss, impaired personality, judgmental disorders. So far, all attempts treat dementias removing their rather than causes have failed. Therefore, presented narrative review, I will attempt explain etiology perspective energy metabolism dysfunction an aging brain. hope this perspective, though perhaps too simplified, bring us closer essence aging-related neurodegenerative disorders soon allow develop new preventive/therapeutic strategies our struggle dementia, disease, Parkinson’s

Язык: Английский

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Insulin and Its Key Role for Mitochondrial Function/Dysfunction and Quality Control: A Shared Link between Dysmetabolism and Neurodegeneration

Biology, Год журнала: 2022, Номер 11(6), С. 943 - 943

Опубликована: Июнь 20, 2022

Insulin was discovered and isolated from the beta cells of pancreatic islets dogs is associated with regulation peripheral glucose homeostasis. produced in brain related to synaptic plasticity memory. Defective insulin signaling plays a role dysfunction, such as neurodegenerative disease. Growing evidence suggests link between metabolic disorders, diabetes obesity, diseases, especially Alzheimer’s disease (AD). This association due common state resistance (IR) mitochondrial dysfunction. review takes journey into past summarize what known about physiological pathological tissues brain. Then, it will land present analyze on health effects diseases that are IR-dependent. Specifically, we focus our attention quality control mitochondria (MQC), dynamics, biogenesis, selective autophagy (mitophagy), healthy altered cases. Finally, this be projected toward future by examining most promising treatments target cure disorders.

Язык: Английский

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Ageing in the brain: mechanisms and rejuvenating strategies

Cellular and Molecular Life Sciences, Год журнала: 2023, Номер 80(7)

Опубликована: Июнь 24, 2023

Abstract Ageing is characterized by the progressive loss of cellular homeostasis, leading to an overall decline organism’s fitness. In brain, ageing highly associated with cognitive and neurodegenerative diseases. With rise in life expectancy, characterizing brain process becomes fundamental for developing therapeutic interventions against increased incidence age-related diseases aim increase human span and, more importantly, health span. this review, we start introducing molecular/cellular hallmarks their impact on cell populations. Subsequently, assess emerging evidence how systemic translates into ageing. Finally, revisit mainstream novel rejuvenating strategies, discussing most successful ones delaying related

Язык: Английский

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Homeostatic regulation of neuronal function: importance of degeneracy and pleiotropy

Frontiers in Cellular Neuroscience, Год журнала: 2023, Номер 17

Опубликована: Июнь 2, 2023

Neurons maintain their average firing rate and other properties within narrow bounds despite changing conditions. This homeostatic regulation is achieved using negative feedback to adjust ion channel expression levels. To understand how of excitability normally works it goes awry, one must consider the various channels involved as well regulated impacted by adjusting those when regulating excitability. raises issues degeneracy pleiotropy. Degeneracy refers disparate solutions conveying equivalent function (e.g., different combinations yielding excitability). many-to-one mapping contrasts one-to-many described pleiotropy affecting multiple properties). facilitates enabling a disturbance be offset compensatory changes in any several or thereof. Pleiotropy complicates because intended regulate property may inadvertently disrupt properties. Co-regulating pleiotropic requires greater than isolation and, extension, can fail for additional reasons such each being incompatible with another. Problems also arise if perturbation too strong and/or weak, set point disturbed. Delineating loops interactions provides valuable insight into might fail. Insofar failure modes require distinct interventions restore homeostasis, deeper understanding its pathological disruption reveal more effective treatments chronic neurological disorders like neuropathic pain epilepsy.

Язык: Английский

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