The Biology and Pathobiology of Glutamatergic, Cholinergic, and Dopaminergic Signaling in the Aging Brain

Frontiers in Aging Neuroscience, Год журнала: 2021, Номер 13

Опубликована: Июль 13, 2021

The elderly population is growing worldwide, with important health and socioeconomic implications. Clinical experimental studies on aging have uncovered numerous changes in the brain, such as decreased neurogenesis, increased synaptic defects, greater metabolic stress, enhanced inflammation. These are associated cognitive decline neurobehavioral deficits. Although not a disease, it significant risk factor for functional worsening, affective impairment, disease exaggeration, dementia, general susceptibility. Conversely, life events related to mental stress trauma can also lead accelerated age-associated disorders dementia. Here, we review human mice rats, those modeling neurodegenerative diseases, that helped elucidate (1) dynamics mechanisms underlying biological pathological of main projecting systems brain (glutamatergic, cholinergic, dopaminergic) (2) effect defective glutamatergic, dopaminergic projection disabilities disorders, Alzheimer’s Parkinson’s diseases. Detailed knowledge age-related diseases be an element development effective ways treatment. In this context, briefly analyze which adverse glutaminergic could targeted by therapeutic strategies developed result our better understanding these damaging mechanisms.

Язык: Английский

---

Brain-derived neurotrophic factor and inflammation in depression: Pathogenic partners in crime?

World Journal of Psychiatry, Год журнала: 2022, Номер 12(1), С. 77 - 97

Опубликована: Янв. 17, 2022

Major depressive disorder is a debilitating affecting millions of people each year. Brain-derived neurotrophic factor (BDNF) and inflammation are two prominent biologic risk factors in the pathogenesis depression that have received considerable attention. Many clinical animal studies highlighted associations between low levels BDNF or high inflammatory markers development behavioral symptoms depression. However, less known about potential interaction inflammation, particularly within central nervous system. Emerging evidence suggests there bidirectional regulation these with important implications for anti-depressant response. Elevated mediators been shown to reduce expression BDNF, may play an negative regulatory role on brain. Understanding this more fully context neuropsychiatric disease both developing fuller understanding biological identifying novel therapeutic opportunities. Here we review particular focus pathogenic their interaction.

Язык: Английский

---

Mitochondria, energy, and metabolism in neuronal health and disease

FEBS Letters, Год журнала: 2022, Номер 596(9), С. 1095 - 1110

Опубликована: Янв. 28, 2022

Mitochondria are associated with various cellular activities critical to homeostasis, particularly in the nervous system. The plastic architecture of mitochondrial network and its dynamic structure play crucial roles ensuring that varying energetic demands rapidly met maintain neuronal axonal energy homeostasis. Recent evidence associates aging neurodegeneration anomalous metabolism as age‐dependent alterations now believed occur prior neurodegeneration. brain has a high demand, which makes it sensitive dysfunction. Distinct events causing oxidative stress or disruption homeostasis can trigger neuropathology. This review explores bioenergetic hypothesis for neurodegenerative pathomechanisms, discussing factors leading age‐related hypometabolism contribution cognitive decline. research on healthy system cells, response stress, how is affected by pathology, well current contributions novel therapeutic approaches will be highlighted.

Язык: Английский

---

Copper Induces Cognitive Impairment in Mice via Modulation of Cuproptosis and CREB Signaling

Nutrients, Год журнала: 2023, Номер 15(4), С. 972 - 972

Опубликована: Фев. 15, 2023

It has been reported that disordered Cu metabolism is associated with several neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's (PD). However, the underlying mechanism still unclear. In this study, 4-week-old male mice were exposed to by free-drinking water for three months. Then, effects of on cognitive functions in tested Morris maze tests, potential mechanisms investigated ELISA, immunochemistry, TUNEL, Western blot tests. was found exacerbates learning memory impairment, leads Cu-overload brain urine mice. The results showed induces neuronal degeneration oxidative damage, promotes expression apoptosis-related protein Bax, cuproptosis-related proteins FDX1 DLAT proteotoxic stress marker HSP70, decreases Fe-S cluster proteins. addition, affects pre-synaptic post-synaptic regulatory through inhibiting PSD-95 SYP. also suppresses phosphorylation levels CREB BDNF TrkB mouse hippocampus. conclusion, might mediate cuproptosis, damage synaptic plasticity inhibit CREB/BDNF pathway cause dysfunction

Язык: Английский

---

Incretin and insulin signaling as novel therapeutic targets for Alzheimer’s and Parkinson’s disease

Molecular Psychiatry, Год журнала: 2022, Номер 28(1), С. 217 - 229

Опубликована: Окт. 18, 2022

Abstract Despite an ever-growing prevalence and increasing economic burden of Alzheimer’s disease (AD) Parkinson’s (PD), recent advances in drug development have only resulted minimally effective treatment. In AD, along with amyloid tau phosphorylation, there is associated increase inflammation/glial activation, a decrease synaptic function, astrocyte state insulin resistance. PD, α-synuclein accumulation, inflammation, dysfunction, dopaminergic neuronal loss, some data to suggest Therapeutic strategies for neurodegenerative disorders commonly targeted individual pathological processes. An treatment might require either utilization multiple drugs which target the processes underlie or use single agent could influence Insulin incretins are compounds effects on Preclinical studies demonstrated that GLP-1 receptor agonists reduce neuroinflammation, deposition, improve memory formation. Incretin mimetics may act through restoration signaling pathways, inducing further neuroprotective effects. Currently, phase 2 3 trials underway AD PD populations. Here, we provide comprehensive review therapeutic potential incretin PD.

Язык: Английский

---

Beneficial effects of physical exercise on cognitive-behavioral impairments and brain-derived neurotrophic factor alteration in the limbic system induced by neurodegeneration

Experimental Gerontology, Год журнала: 2024, Номер 195, С. 112539 - 112539

Опубликована: Авг. 8, 2024

Neurodegenerative diseases (NDDs) are a class of neurological disorders marked by the progressive loss neurons that afflict millions people worldwide. These illnesses affect brain connection, impairing memory, cognition, behavior, sensory perception, and motor function. Alzheimer's, Parkinson's, Huntington's examples common NDDs, which frequently include buildup misfolded proteins. Cognitive-behavioral impairments early markers neurodevelopmental disorders, emphasizing importance detection intervention. Neurotrophins such as brain-derived neurotrophic factor (BDNF) critical for neuron survival synaptic plasticity, is required learning memory. NDDs have been associated with decreased BDNF levels. Physical exercise, non-pharmacological intervention, benefits health increasing levels, lowering cognitive deficits, slowing degradation. Exercise advantages increased well-being, reduced depression, improved skills, neuroprotection amyloid accumulation, oxidative stress, neuroinflammation. This study examines effects physical exercise on cognitive-behavioral deficits levels in limbic system impacted neurodegeneration. The findings highlight necessity including into NDD treatment to improve structure, function, total As research advances, becoming increasingly acknowledged an important technique treating decline neurodegenerative disorders.

Язык: Английский

---

BDNF/TrkB activators in Parkinson's disease: A new therapeutic strategy

Journal of Cellular and Molecular Medicine, Год журнала: 2024, Номер 28(10)

Опубликована: Май 1, 2024

Parkinson's disease (PD) is a neurodegenerative disorder of the brain and manifested by motor non-motor symptoms because degenerative changes in dopaminergic neurons substantia nigra. PD neuropathology associated with mitochondrial dysfunction, oxidative damage apoptosis. Thus, modulation apoptosis growth factors could be novel boulevard management PD. Brain-derived neurotrophic factor (BDNF) its receptor tropomyosin kinase type B (TrkB) are chiefly involved neuropathology. BDNF promotes survival nigra enhances functional activity striatal neurons. Deficiency TrkB triggers degeneration accumulation α-Syn As well, BDNF/TrkB signalling reduced early phase Targeting specific activators may attenuate this review aimed to discuss potential role against In conclusion, decreased linked severity long-term complications. Activation

Язык: Английский

---

TrkB transmembrane domain: bridging structural understanding with therapeutic strategy

Trends in Biochemical Sciences, Год журнала: 2024, Номер 49(5), С. 445 - 456

Опубликована: Март 2, 2024

TrkB (neuronal receptor tyrosine kinase-2, NTRK2) is the for brain-derived neurotrophic factor (BDNF) and a critical regulator of activity-dependent neuronal plasticity. The past few years have witnessed an increasing understanding structure function TrkB, including its transmembrane domain (TMD). interacts with membrane cholesterol, which bidirectionally regulates signaling. Additionally, has recently been recognized as binding target antidepressant drugs. A variety different antidepressants, typical rapid-acting well psychedelic compounds, act allosteric potentiators BDNF signaling through TrkB. This suggests that common compounds. Although more research needed, current knowledge promising further drug development.

Язык: Английский

---

Sleep disorders cause Parkinson's disease or the reverse is true: Good GABA good night

CNS Neuroscience & Therapeutics, Год журнала: 2024, Номер 30(3)

Опубликована: Март 1, 2024

Parkinson's disease (PD) is a progressive neurodegenerative brain due to degeneration of dopaminergic neurons (DNs) presented with motor and non-motor symptoms. PD symptoms are developed in response the disturbance diverse neurotransmitters including γ-aminobutyric acid (GABA). GABA has neuroprotective effect against neuropathology by protecting DNs substantia nigra pars compacta (SNpc). It been shown that GABAergic linked progression neurotransmission necessary pathway for normal sleep patterns, thus deregulation could be potential cause disorders PD.

Язык: Английский

---

Targeting uric acid: a promising intervention against oxidative stress and neuroinflammation in neurodegenerative diseases

Cell Communication and Signaling, Год журнала: 2025, Номер 23(1)

Опубликована: Янв. 3, 2025

Oxidative stress and neuroinflammation are recognized as key factors in the development of neurodegenerative diseases, yet effective interventions biomarkers to address oxidative these conditions limited. Uric acid (UA), traditionally associated with gout, is now gaining prominence a potential target diseases. Soluble UA stands out one most vital antioxidant compounds produced by human body, accounting for up 55% extracellular capacity neutralize free radicals. While there increasing evidence supporting neuroprotective properties Parkinson's disease Alzheimer's disease, gaps knowledge still exist regarding underlying mechanisms how effectively translate benefits into clinical practice. Moreover, current elevation therapy exhibits unstable properties, individual variability, even adverse effects, limiting its applications. This review consolidates recent advancements understanding exerts effects on diseases emphasizes dual roles managing neuroinflammation. Additionally, elucidates through which confers neuroprotection. Based this, underscores significance biomarker aims provide comprehensive therapeutic target, while also addressing possible challenges implementation.

Язык: Английский

---