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1.
    
For decades, numerous seminal studies have built our understanding of the locus coeruleus (LC), the vertebrate brain’s principal noradrenergic system. Containing a numerically small but broadly efferent cell population, the LC provides brain-wide noradrenergic modulation that optimizes network function in the context of attentive and flexible interaction with the sensory environment. This review turns attention to the LC’s roles during sleep. We show that these roles go beyond down-scaled versions of the ones in wakefulness. Novel dynamic assessments of noradrenaline signaling and LC activity uncover a rich diversity of activity patterns that establish the LC as an integral portion of sleep regulation and function. The LC could be involved in beneficial functions for the sleeping brain, and even minute alterations in its functionality may prove quintessential in sleep disorders.  相似文献   

2.
    
The most common cause of dementia, especially in elderly people, is Alzheimer’s disease (AD), with aging as its main risk factor. AD is a multifactorial neurodegenerative disease. There are several factors increasing the risk of AD development. One of the main features of Alzheimer’s disease is impairment of brain energy. Hypometabolism caused by decreased glucose uptake is observed in specific areas of the AD-affected brain. Therefore, glucose hypometabolism and energy deficit are hallmarks of AD. There are several hypotheses that explain the role of glucose hypometabolism in AD, but data available on this subject are poor. Reduced transport of glucose into neurons may be related to decreased expression of glucose transporters in neurons and glia. On the other hand, glucose transporters may play a role as potential targets for the treatment of AD. Compounds such as antidiabetic drugs, agonists of SGLT1, insulin, siRNA and liposomes are suggested as therapeutics. Nevertheless, the suggested targets of therapy need further investigations.  相似文献   

3.
    
Neurodegenerative diseases affect millions of people worldwide and are characterized by the chronic and progressive deterioration of neural function. Neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD), represent a huge social and economic burden due to increasing prevalence in our aging society, severity of symptoms, and lack of effective disease-modifying therapies. This lack of effective treatments is partly due to a lack of reliable models. Modeling neurodegenerative diseases is difficult because of poor access to human samples (restricted in general to postmortem tissue) and limited knowledge of disease mechanisms in a human context. Animal models play an instrumental role in understanding these diseases but fail to comprehensively represent the full extent of disease due to critical differences between humans and other mammals. The advent of human-induced pluripotent stem cell (hiPSC) technology presents an advantageous system that complements animal models of neurodegenerative diseases. Coupled with advances in gene-editing technologies, hiPSC-derived neural cells from patients and healthy donors now allow disease modeling using human samples that can be used for drug discovery.  相似文献   

4.
    
Alzheimer’s disease (AD) is the leading cause of dementia and cognitive function impairment. The multi-faced character of AD requires new drug solutions based on substances that incorporate a wide range of activities. Antioxidants, AChE/BChE inhibitors, BACE1, or anti-amyloid platelet aggregation substances are most desirable because they improve cognition with minimal side effects. Plant secondary metabolites, used in traditional medicine and pharmacy, are promising. Among these are the monoterpenes—low-molecular compounds with anti-inflammatory, antioxidant, enzyme inhibitory, analgesic, sedative, as well as other biological properties. The presented review focuses on the pathophysiology of AD and a selected group of anti-neurodegenerative monoterpenes and monoterpenoids for which possible mechanisms of action have been explained. The main body of the article focuses on monoterpenes that have shown improved memory and learning, anxiolytic and sleep-regulating effects as determined by in vitro and in silico tests—followed by validation in in vivo models.  相似文献   

5.
Brain is one of the richest organs in lipid content. Phospholipids (glycerophospholipids and sphingolipids) are important building blocks of cell membranes, which provide an optimal environment for protein interactions, trafficking and function. Because of that, alterations in their cellular levels could lead to different pathogenic processes in the brain, such as in Alzheimer’s disease (AD), the most common type of dementia among older populations. There is increasing evidence that phospholipid changes occur during pathogenic processes in AD. It is known that lipids are tightly connected with metabolism of the Amyloid Precursor Protein (APP), which produces Amyloid-beta peptide (Aβ), the main component of senile plaques, which represent the main pathological hallmark of AD. However, the mechanism(s) of the lipid-effect on Aβ metabolism and AD pathogenesis is still not completely understood. This review summarizes the current knowledge on phospholipid changes occurring during normal aging and discusses phospholipid changes in the human brain associated with different stages of AD, as well changes in the cerebrospinal fluid and blood/plasma, which are interesting potential biomarkers for AD diagnosis and disease monitoring. At the end, we have discussed future perspectives of phospholipid changes as potential biomarkers and as targets for development of novel treatment strategies against AD.  相似文献   

6.
    
There is a huge need for novel therapeutic and preventative approaches to Alzheimer’s disease (AD) and neuroinflammation seems to be one of the most fascinating solutions. The primary cell type that performs immunosurveillance and helps clear out unwanted chemicals from the brain is the microglia. Microglia work to reestablish efficiency and stop further degeneration in the early stages of AD but mainly fail in the illness’s later phases. This may be caused by a number of reasons, e.g., a protracted exposure to cytokines that induce inflammation and an inappropriate accumulation of amyloid beta (Aβ) peptide. Extracellular amyloid and/or intraneuronal phosphorylated tau in AD can both activate microglia. The activation of TLRs and scavenger receptors, inducing the activation of numerous inflammatory pathways, including the NF-kB, JAK-STAT, and NLRP3 inflammasome, facilitates microglial phagocytosis and activation in response to these mediators. Aβ/tau are taken up by microglia, and their removal from the extracellular space can also have protective effects, but if the illness worsens, an environment that is constantly inflamed and overexposed to an oxidative environment might encourage continuous microglial activation, which can lead to neuroinflammation, oxidative stress, iron overload, and neurotoxicity. The complexity and diversity of the roles that microglia play in health and disease necessitate the urgent development of new biomarkers that identify the activity of different microglia. It is imperative to comprehend the intricate mechanisms that result in microglial impairment to develop new immunomodulating therapies that primarily attempt to recover the physiological role of microglia, allowing them to carry out their core function of brain protection.  相似文献   

7.
    
Aging is associated with a decline in cognitive function, which can partly be explained by the accumulation of damage to the brain cells over time. Neurons and glia undergo morphological and ultrastructure changes during aging. Over the past several years, it has become evident that at the cellular level, various hallmarks of an aging brain are closely related to mitophagy. The importance of mitochondria quality and quantity control through mitophagy is highlighted by the contribution that defects in mitochondria–autophagy crosstalk make to aging and age-related diseases. In this review, we analyze some of the more recent findings regarding the study of brain aging and neurodegeneration in the context of mitophagy. We discuss the data on the dynamics of selective autophagy in neurons and glial cells during aging and in the course of neurodegeneration, focusing on three mechanisms of mitophagy: non-receptor-mediated mitophagy, receptor-mediated mitophagy, and transcellular mitophagy. We review the role of mitophagy in neuronal/glial homeostasis and in the molecular pathogenesis of neurodegenerative disorders, such as Parkinson’s disease, Alzheimer’s disease, and other disorders. Common mechanisms of aging and neurodegeneration that are related to different mitophagy pathways provide a number of promising targets for potential therapeutic agents.  相似文献   

8.
    
Alzheimer’s disease is a neurodegenerative disorder associated with age, and is characterized by pathological markers such as amyloid-beta plaques and neurofibrillary tangles. Symptoms of AD include cognitive impairments, anxiety and depression. It has also been shown that individuals with AD have impaired neurotransmission, which may result from the accumulation of amyloid plaques and neurofibrillary tangles. Preclinical studies showed that melatonin, a monoaminergic neurotransmitter released from the pineal gland, is able to ameliorate AD pathologies and restore cognitive impairments. Theoretically, inhibition of the pathological progression of AD by melatonin treatment should also restore the impaired neurotransmission. This review aims to explore the impact of AD on neurotransmission, and whether and how melatonin can enhance neurotransmission via improving AD pathology.  相似文献   

9.
    
Currently, more than 55 million people live with dementia worldwide, and there are nearly 10 million new cases every year. Alzheimer’s disease (AD) is the most common neurodegenerative disease resulting in personality changes, cognitive impairment, memory loss, and physical disability. Diagnosis of AD is often missed or delayed in clinical practice due to the fact that cognitive deterioration occurs already in the later stages of the disease. Thus, methods to improve early detection would provide opportunities for early treatment of disease. All FDA-approved PET imaging agents for Aβ plaques use short-lived radioisotopes such as 11C (t1/2 = 20.4 min) and 18F (t1/2 = 109.8 min), which limit their widespread use. Thus, a novel metal-based imaging agent for visualization of Aβ plaques is of interest, due to the simplicity of its synthesis and the longer lifetimes of its constituent isotopes. We have previously summarized a metal-containing drug for positron emission tomography (PET), magnetic resonance imaging (MRI), and single-photon emission computed tomography (SPECT) imaging of Alzheimer’s disease. In this review, we have summarized a recent advance in design of Aβ-targeting bifunctional chelators for potential therapeutic and PET imaging applications, reported after our previous review.  相似文献   

10.
    
Neurodegenerative disorders are a major public health issue. Despite decades of research efforts, we are still seeking an efficient cure for these pathologies. The initial paradigm of large aggregates of amyloid proteins (amyloid plaques, Lewis bodies) as the root cause of Alzheimer’s and Parkinson’s diseases has been mostly dismissed. Instead, membrane-bound oligomers forming Ca2+-permeable amyloid pores are now considered appropriate targets for these diseases. Over the last 20 years, our group deciphered the molecular mechanisms of amyloid pore formation, which appeared to involve a common pathway for all amyloid proteins, including Aβ (Alzheimer) and α-synuclein (Parkinson). We then designed a short peptide (AmyP53), which prevents amyloid pore formation by targeting gangliosides, the plasma membrane receptors of amyloid proteins. Herein, we show that aqueous solutions of AmyP53 are remarkably stable upon storage at temperatures up to 45 °C for several months. AmyP53 appeared to be more stable in whole blood than in plasma. Pharmacokinetics studies in rats demonstrated that the peptide can rapidly and safely reach the brain after intranasal administration. The data suggest both the direct transport of AmyP53 via the olfactory bulb (and/or the trigeminal nerve) and an indirect transport via the circulation and the blood–brain barrier. In vitro experiments confirmed that AmyP53 is as active as cargo peptides in crossing the blood–brain barrier, consistent with its amino acid sequence specificities and physicochemical properties. Overall, these data open a route for the use of a nasal spray formulation of AmyP53 for the prevention and/or treatment of Alzheimer’s and Parkinson’s diseases in future clinical trials in humans.  相似文献   

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12.
    
Recent clinical and epidemiological studies support the contention that diabetes mellitus (DM) is a strong risk factor for the development of Alzheimer’s disease (AD). The use of insulin cell toxin, streptozotocin (STZ), when injected into the lateral ventricles, develops an insulin resistant brain state (IRBS) and represents a non-transgenic, or sporadic AD model (SAD), with several AD-like neuropathological features. The present study explored the effects of an anti-diabetic drug, liraglutide (LIR), in reversing major pathological hallmarks in the prodromal disease stage of both the 5xFAD transgenic and SAD mouse models of AD. Three-month-old 5xFAD and age-matched wild type mice were given a single intracerebroventricular (i.c.v) injection of STZ or vehicle (saline) and were subsequently treated with LIR, intraperitoneally (IP), once a day for 30 days. The extent of neurodegeneration, Aβ plaque load, and key proteins associated with the insulin signaling pathways were measured using Western blot and neuroinflammation (via immunohistological assays) in the cortical and hippocampal regions of the brain were assessed following a series of behavioral tests used to measure cognitive function after LIR or vehicle treatments. Our results indicated that STZ significantly increased neuroinflammation, Aβ plaque deposition and disrupted insulin signaling pathway, while 25 nmol/kg LIR, when injected IP, significantly decreased neuroinflammatory responses in both SAD and 5xFAD mice before significant cognitive changes were observed, suggesting LIR can reduce early neuropathology markers prior to the emergence of overt memory deficits. Our results indicate that LIR has neuroprotective effects and has the potential to serve as an anti-inflammatory and anti-amyloid prophylactic therapy in the prodromal stages of AD.  相似文献   

13.
    
Biological material is one of the most important aspects that allow for the correct diagnosis of the disease, and tears are an interesting subject of research because of the simplicity of collection, as the well as the relation to the components similar to other body fluids. In this review, biomarkers for Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS) in tears are investigated and analyzed. Records were obtained from the PubMed and Google Scholar databases in a timeline of 2015–2022. The keywords were: tear film/tear biochemistry/tear biomarkers + diseases (AD, PD, or MS). The recent original studies were analyzed, discussed, and biomarkers present in tears that can be used for the diagnosis and management of AD, PD, and MS diseases were shown. α-synTotal and α-synOligo, lactoferrin, norepinephrine, adrenaline, epinephrine, dopamine, α-2-macroglobulin, proteins involved in immune response, lipid metabolism and oxidative stress, apolipoprotein superfamily, and others were shown to be biomarkers in PD. For AD as potential biomarkers, there are: lipocalin-1, lysozyme-C, and lacritin, amyloid proteins, t-Tau, p-Tau; for MS there are: oligoclonal bands, lipids containing choline, free carnitine, acylcarnitines, and some amino acids. Information systematized in this review provides interesting data and new insight to help improve clinical outcomes for patients with neurodegenerative disorders.  相似文献   

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15.
    
There is evidence indicating that a vegan diet could be beneficial in the prevention of neurodegenerative disorders, including Alzheimer’s disease (AD). The purpose of this review is to summarize the current knowledge on the positive and negative aspects of a vegan diet regarding the risk of AD. Regarding AD prevention, a vegan diet includes low levels of saturated fats and cholesterol, contributing to a healthy blood lipid profile. Furthermore, it is rich in phytonutrients, such as vitamins, antioxidants, and dietary fiber, that may help prevent cognitive decline. Moreover, a vegan diet contributes to the assumption of quercetin, a natural inhibitor of monoamine oxidase (MAO), which can contribute to maintaining mental health and reducing AD risk. Nonetheless, the data available do not allow an assessment of whether strict veganism is beneficial for AD prevention compared with vegetarianism or other diets. A vegan diet lacks specific vitamins and micronutrients and may result in nutritional deficiencies. Vegans not supplementing micronutrients are more prone to vitamin B12, vitamin D, and DHA deficiencies, which have been linked to AD. Thus, an evaluation of the net effect of a vegan diet on AD prevention and/or progression should be ascertained by taking into account all the positive and negative effects described here.  相似文献   

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17.
    
Sirtuin 2 (SIRT2) has been associated to aging and age-related pathologies. Specifically, an age-dependent accumulation of isoform 3 of SIRT2 in the CNS has been demonstrated; however, no study has addressed the behavioral or molecular consequences that this could have on aging. In the present study, we have designed an adeno-associated virus vector (AAV-CAG-Sirt2.3-eGFP) for the overexpression of SIRT2.3 in the hippocampus of 2 month-old SAMR1 and SAMP8 mice. Our results show that the specific overexpression of this isoform does not induce significant behavioral or molecular effects at short or long term in the control strain. Only a tendency towards a worsening in the performance in acquisition phase of the Morris Water Maze was found in SAMP8 mice, together with a significant increase in the pro-inflammatory cytokine Il-1β. These results suggest that the age-related increase of SIRT2.3 found in the brain is not responsible for induction or prevention of senescence. Nevertheless, in combination with other risk factors, it could contribute to the progression of age-related processes. Understanding the specific role of SIRT2 on aging and the underlying molecular mechanisms is essential to design new and more successful therapies for the treatment of age-related diseases.  相似文献   

18.
    
The aim of this study was to assess the potency of selected antipsychotic drugs (haloperidol (HAL), bromperidol (BRMP), benperidol (BNP), penfluridol (PNF), pimozide (PIM), quetiapine (QUET) and promazine (PROM)) on the main pathological hallmarks of Alzheimer’s disease (AD). Binary mixtures of donepezil and antipsychotics produce an anti-BuChE effect, which was greater than either compound alone. The combination of rivastigmine and antipsychotic drugs (apart from PNF) enhanced AChE inhibition. The tested antipsychotics (excluding HAL and PNF) significantly reduce the early stage of Aβ aggregation. BRMP, PIM, QUET and PROM were found to substantially inhibit Aβ aggregation after a longer incubation time. A test of human erythrocytes hemolysis showed that short-term incubation of red blood cells (RBCs) with QUET resulted in decreased hemolysis. The antioxidative properties of antipsychotics were also proved in human umbilical vein endothelial cells (HUVEC); all tested drugs were found to significantly increase cell viability. In the case of astrocytes, BNP, PNF, PIM and PROM showed antioxidant potential.  相似文献   

19.
    
Mitochondrial dysfunction is now recognized as a contributing factor to neurodegenerative diseases, including Alzheimer’s disease (AD). Mitochondria are signaling organelles with a variety of functions ranging from energy production to the regulation of cellular metabolism, energy homeostasis, and response to stress. The successful functioning of these complex processes is critically dependent on the accuracy of mitochondrial dynamics, which includes the ability of mitochondria to change shape and position in the cell, which is necessary to maintain proper function and quality control, especially in polarized cells such as neurons. There has been much evidence to suggest that the disruption of mitochondrial dynamics may play a critical role in the pathogenesis of AD. This review highlights aspects of altered mitochondrial dynamics in AD that may contribute to the etiology of this debilitating condition. We also discuss therapeutic strategies to improve mitochondrial dynamics and function that may provide an alternative treatment approach.  相似文献   

20.
    
ADAM10 is the main α-secretase that participates in the non-amyloidogenic cleavage of amyloid precursor protein (APP) in neurons, inhibiting the production of β-amyloid peptide (Aβ) in Alzheimer’s disease (AD). Strong recent evidence indicates the importance of the localization of ADAM10 for its activity as a protease. In this study, we investigated ADAM10 activity in plasma and CSF samples of patients with amnestic mild cognitive impairment (aMCI) and mild AD compared with cognitively healthy controls. Our results indicated that plasma levels of soluble ADAM10 were significantly increased in the mild AD group, and that in these samples the protease was inactive, as determined by activity assays. The same results were observed in CSF samples, indicating that the increased plasma ADAM10 levels reflect the levels found in the central nervous system. In SH-SY5Y neuroblastoma cells, ADAM10 achieves its major protease activity in the fraction obtained from plasma membrane lysis, where the mature form of the enzyme is detected, confirming the importance of ADAM10 localization for its activity. Taken together, our results demonstrate the potential of plasma ADAM10 to act as a biomarker for AD, highlighting its advantages as a less invasive, easier, faster, and lower-cost processing procedure, compared to existing biomarkers.  相似文献   

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