Search Results (2,151)

Alzheimer’s disease (AD) presents a public health challenge due to its progressive neurodegeneration, cognitive decline, and memory loss. The amyloid cascade hypothesis, which postulates that the accumulation of amyloid-beta (Aβ) peptides initiates a cascade leading to AD, has dominated research and therapeutic strategies. The failure of recent Aβ-targeted therapies to yield conclusive benefits necessitates further exploration of AD pathology. This review proposes the Mitochondrial–Neurovascular–Metabolic (MNM) hypothesis, which integrates mitochondrial dysfunction, impaired neurovascular regulation, and systemic metabolic disturbances as interrelated contributors to AD pathogenesis. Mitochondrial dysfunction, a hallmark of AD, leads to oxidative stress and bioenergetic failure. Concurrently, the breakdown of the blood–brain barrier (BBB) and impaired cerebral blood flow, which characterize neurovascular dysregulation, accelerate neurodegeneration. Metabolic disturbances such as glucose hypometabolism and insulin resistance further impair neuronal function and survival. This hypothesis highlights the interconnectedness of these pathways and suggests that therapeutic strategies targeting mitochondrial health, neurovascular integrity, and metabolic regulation may offer more effective interventions. The MNM hypothesis addresses these multifaceted aspects of AD, providing a comprehensive framework for understanding disease progression and developing novel therapeutic approaches. This approach paves the way for developing innovative therapeutic strategies that could significantly improve outcomes for millions affected worldwide. Full article

Background: The senescence-accelerated mouse 8 (SAMP8) represents a model for Alzheimer’s disease (AD) research because it exhibits age-related learning and memory impairments consistent with early onset and rapid progression of senescence. To identify transcriptional changes during AD progression, in this study, we analyzed and compared the gene expression profiles involved in molecular pathways of neurodegeneration and cognitive impairment in senescence-accelerated resistant 1 (SAMR1) and SAMP8 mice. Methods: In total, 48 female SAMR1 and SAMP8 mice were randomly divided into six groups (SAMR1 and SAMP8 at 3, 7, and 9 months of age). Microarray analysis of 22,000 genes was performed, followed by functional analysis using Gene Ontology (NCBI) and examination of altered molecular pathways using the KEGG (Kyoto Encyclopedia of Genes and Genomes). Results: SAMP8 mice had 2516 dysregulated transcripts at 3 months, 2549 transcripts at 7 months, and 2453 genes at 9 months compared to SAMR1 mice of the same age. These accounted for 11.3% of the total number. This showed that with age, the gene expression of downregulated transcripts increases, and that of over-expressed transcripts decreases. Most of these genes were involved in neurodegenerative metabolic pathways associated with Alzheimer’s disease: apoptosis, inflammatory response, oxidative stress, and mitochondria. The qPCR results indicated that Ndufs4, TST/Rhodanese, Wnt3, and Sema6a expression was differentially expressed during aging. Conclusions: These results further revealed significant differences in gene expression profiles at different ages between SAMR1 and SAMP8 and showed alteration in genes involved in age-related cognitive decline and mitochondrial processes, demonstrating the relevance of the SAMP8 model as a model for sporadic AD. Full article

Lack of sleep, whether acute or chronic, is quite common and negatively affects an individual’s memory and cognitive function. The question of whether chronic sleep deprivation (CSD) causes cognitive impairment to arise and progress is not well studied. To investigate the effects of CSD on memory and cognition, this study began by establishing a CSD mouse model. Behavioral experiments on animals revealed that CSD induced cognitive behavioral abnormalities reminiscent of Alzheimer’s disease. Western blot experiments further demonstrated a considerable increase in amyloid-β (Aβ) expression in the mouse brain following CSD. Meanwhile, the hub gene Prkcg was searched for in the cerebellum using RNA-seq and bioinformatics analysis. PKCγ (Prkcg) expression was significantly reduced, as demonstrated by RT-qPCR and Western blot validations. Additionally, CSD was associated with downregulated CREB expression, decreased expression of the endothelin-converting enzyme (ECE1), and increased phosphorylation of ERK1/2 downstream of PKCγ. These findings suggested that CSD down-regulated PKCγ expression, decreased ECE1 expression, impaired Aβ degradation, and affected the PKCγ/ERK/CREB pathway and the synthesis of memory-related proteins. Overall, this study highlighted how CSD modulated PKCγ-related metabolism, impacting Aβ clearance and the production of memory-related proteins. Such insights are crucial for understanding and preventing sporadic Alzheimer’s disease (sAD) associated with CSD. Full article

Individual differences in responsiveness to environmental factors, including stress reactivity and anxiety levels, which differ between high (HR) and low (LR) responders to novelty, might be risk factors for development of memory and anxiety disorders in sporadic Alzheimer’s disease (sAD). In the present study, we investigated whether behavioral characteristics of the HR and LR rats, influence the progression of sAD (neuroinflammation, β-amyloid peptide, behavioral activity related to memory (Morris water maze) and anxiety (elevated plus maze, white and illuminated open field test) in streptozotocin (STZ)-induced neuroinflammation as a model of early pathophysiological alterations in sAD. Early (45 days) in disease progression, there was a more severe impairment of reference memory and higher levels of anxiety in HRs compared with LRs. Behavioral depression in HRs was associated with higher expression of β-amyloid deposits, particularly in the NAcS, and activation of microglia (CD68⁺ cells) in the hypothalamus, as opposed to less inflammation in the hippocampus, particularly in CA1, compared with LRs in late (90 days) sAD progression. Our findings suggest that rats with higher behavioral activity and increased responsivity to stressors show more rapid progression of disease and anxiety disorders compared with low responders to novelty in the STZ-induced sAD model. Full article

Background: Aortic valve stenosis (AVS) is a common valvular heart disease affecting millions of people worldwide. It leads to significant neurocognitive and neuropsychological impairments, impacting patients’ quality of life. Objective: The objective of this article is to identify and discuss the potential neurocognitive effects on patients with aortic stenosis before and after undergoing surgical aortic valve replacement (SAVR). Method: Our study involved the assessment of 64 patients undergoing aortic valve replacement (SAVR) using a neurocognitive evaluation comprising a battery of 11 different cognitive tests. These tests were designed to analyze the patients’ overall cognitive functioning, executive abilities, short- and long-term memory, and attentional performance. The tests were administered to patients before the aortic valve surgery (T0) and after the surgery (T1). From a statistical perspective, numerical variables are presented as means (±standard deviation) and medians (IQR), while categorical variables are presented as counts and percentages. Normality was assessed using the Shapiro–Wilk test. T0 and T1 scores were compared with the Wilcoxon signed rank test, with p < 0.05 considered significant. Analyses were performed using SAS version 9.4. Results: Conducted as part of a fully financed Italian Ministry of Health project (RF-2016-02361069), the study found that most patients showed normal cognitive functioning at baseline. Cognitive assessments showed that executive functions, attention, language, and semantic knowledge were within the normal range for the majority of participants. After SAVR, cognitive outcomes remained stable or improved, particularly in executive functions and language. Notably, verbal episodic memory demonstrated significant improvement, with the percentage of patients scoring within the normal range on the BSRT increasing from 73.4% at T0 to 92.2% at T1 (p < 0.0001). However, visuospatial and visuoconstructive abilities showed stability or slight decline, while attentional skills remained relatively stable. The Clock Drawing Test indicated the maintenance of cognitive functions. Conclusions: The findings of our study indicate a global stability in cognitive status among patients after undergoing SAVR, with significant improvement noted in verbal episodic memory. While other cognitive domains did not demonstrate statistically significant changes, these insights are valuable for understanding the cognitive effects of SAVR and can guide future research and clinical practice in selecting the most effective surgical and rehabilitative options for patients. Monitoring cognitive outcomes in patients undergoing aortic valve replacement surgery remains crucial. Full article

The increasing ubiquity of digital devices in childhood had outpaced the understanding of their effects on cognitive development, creating a significant research gap regarding their long-term impact. Objective: The present narrative overview explored the complex relationship between digital device usage and cognitive development in childhood. Methods: We conducted a comprehensive literature search across multiple databases, including PubMed, Embase, Scopus, and Web of Science, to critically assess cognitive domains such as attention, memory, executive functions, problem-solving skills, and social cognition. Incorporating over 157 peer-reviewed studies published between 2001 and 2024, we used strict inclusion and exclusion criteria to ensure scientific rigor. Results: The review integrated empirical findings with established theoretical frameworks, particularly from cognitive development and media psychology, to highlight both the advantages and risks of early, frequent exposure to technology. The potential for digital devices to enhance cognitive skills, such as multitasking and information processing, was weighed against risks such as cognitive overload, diminished attention spans, and impaired social skills. We also examined psychological and behavioral outcomes, including identity formation, emotional regulation, and maladaptive behaviors associated with excessive screen time. Additionally, we identified strategies to mitigate negative effects, emphasizing structured digital engagement and parental involvement to support healthy cognitive and psychological growth. Our findings provided actionable recommendations for parents, educators, and policymakers, promoting optimal digital practices that enhanced cognitive development while safeguarding against potential harms. Conclusions: The review offered essential insights for stakeholders in child development, education, and policy-making, highlighting the need for balanced integration of digital tools in childhood learning environments. Full article

Background: Anti-N-Methyl-d-aspartate receptor (NMDAR) autoimmune encephalitis (NMDAR AE) is an autoimmune disease characterized by severe psychiatric and neurological symptoms. While the pathogenic role of antibodies (Abs) directed against the GluN1 subunit of NMDAR is well described in this disease, the immune mechanisms involved in the generation of the autoimmune B cell response, especially the role of T helper cells, are poorly understood. Previously, we developed a B-cell-mediated mouse model of NMDAR AE by immunization with a GluN1_359–378 peptide that drives a series of symptoms that recapitulate AE such as anxiety behaviour and spatial memory impairment. Results: In this mouse model, we identified anti-GluN1-specific CD4⁺ but also CD8⁺ T cells in both spleen and meninges. T helper cells have a polyfunctional profile, arguing for a T and B cell crosstalk to generate anti-GluN1 pathogenic Abs. Interestingly, proteomic analysis of AE meninges showed enrichment of differentially expressed proteins in biological processes associated with B cell activation and cytokine signalling pathways. Conclusions: This study identified, for the first time, a potential contribution of T helper cells in the pathology of NMDAR AE and paved the way for the development of future tolerogenic approaches to treat relapses. Full article

Insecticides are widely used to boost crop yields, but their effects on non-target insects like Vespa magnifica are still poorly understood. Despite its ecological and economic significance, Vespa magnifica has been largely neglected in risk assessments. This study employed physiological, biochemical, and transcriptomic analyses to investigate the impact of sublethal concentrations of thiamethoxam, avermectin, chlorfenapyr, and β-cypermethrin on Vespa magnifica. Although larval survival rates remained unchanged, both pupation and fledge rates were significantly reduced. Enzymatic assays indicated an upregulation of superoxide dismutase and catalase activity alongside a suppression of peroxidase under insecticide stress. Transcriptomic analysis revealed increased adenosine triphosphate-related processes and mitochondrial electron transport activity, suggesting elevated energy expenditure to counter insecticide exposure, potentially impairing essential functions like flight, hunting, and immune response. The enrichment of pathways such as glycolysis, hypoxia-inducible factor signaling, and cholinergic synaptic metabolism under insecticide stress highlights the complexity of the molecular response with notable effects on learning, memory, and detoxification processes. These findings underscore the broader ecological risks of insecticide exposure to non-target insects and highlight the need for further research into the long-term effects of newer insecticides along with the development of strategies to safeguard beneficial insect populations. Full article

Alzheimer’s disease (AD), the most prevalent neurodegenerative disorder and the leading cause of dementia worldwide, profoundly impacts health and quality of life. While cognitive impairments—such as memory loss, attention deficits, and disorientation—predominate in AD, motor symptoms, though common, remain underexplored. These motor symptoms, including gait disturbances, reduced cardiorespiratory fitness, muscle weakness, sarcopenia, and impaired balance, are often associated with advanced stages of AD and contribute to increased mortality. Emerging evidence, however, suggests that motor symptoms may be present in earlier stages and can serve as predictive markers for AD in older adults. Despite a limited understanding of the underlying mechanisms driving these motor symptoms, several key pathways have been identified, offering avenues for further investigation. This review provides an in-depth analysis of motor symptoms in AD, discussing its progression, potential mechanisms, and therapeutic strategies. Addressing motor symptoms alongside cognitive decline may enhance patient functionality, improve quality of life, and support more comprehensive disease management strategies. Full article

Background: Due to the rising prevalence of cognitive impairment in the middle-aged and elderly population, combined with consumer demand for functional foods to improve health and well-being. Objective: This study aimed to formulate a functional cone mushroom (Termitomyces fuliginosus) (FCM) protein snack bar and evaluate its amino acid profile, phytochemical contents, biological activity and impact on cognitive function. Methods: A total of 26 middle-aged male and female participants were randomized and divided into placebo, FCM1 and FCM2 groups. Continuous consumption was performed for 6 weeks. Demographic data, body composition, cognitive function and memory were evaluated at baseline and at the end of the study period (6 weeks). Results: The event-related potential (ERP) analysis results showed a significant increase in N100 and P300 amplitude at the Fz location in participants who consumed the functional cone mushroom protein snack bar at a dose of 1 g compared to the placebo group (p = 0.015). Additionally, subjects who consumed the functional cone mushroom protein snack bar at a dose of 2 g showed a significantly increased P300 amplitude and percent accuracy of numeric working memory (p = 0.048) compared to those in the placebo group (p = 0.044). The possible underlying mechanism may involve AChE and MAO suppression activity alongside antioxidant activity. Conclusions: These data suggest that FCM can improve cognitive function and memory and may be considered for use in natural supplementation products with possible health benefits. Full article

Alzheimer’s disease (AD) is a representative neurodegenerative disease characterized by the structural and functional degeneration of neurons. The present study investigated the neuroprotective effect of Ixeris dentata (ID) extract on trimethyltin (TMT)-induced memory deficit in the rat. Cognitive improving effect and neuronal activity of ID were assessed by using Morris water maze (MWM) test and choline acetyltransferase (ChAT), cAMP-response element-binding protein (CREB) immunohistochemistry. Seven days after TMT injection (8.0 mg/kg, i.p.), each group of rats was administered saline, water extract of ID (WID, 400 or 800 mg/kg, p.o.), ethanol extract of ID (EID, 400 or 800 mg/kg, p.o.), or caffeic acid (CAF, 30 mg/kg, i.p.) daily for fourteen days. Results: Treatment with EID and CAF produced a significant improvement in escape latency time of the acquisition, and retention time in the target area of the MWM task. Additionally, administration of EID or CAF markedly alleviated TMT-induced loss of ChAT- and CREB-immunoreactive cells in the hippocampus. The results demonstrated that EID has a protective effect against TMT-induced memory deficit, partly through increasing the CREB and cholinergic signaling pathway in the hippocampus. These results suggest that ethanol extracts of ID might be useful for improving cognitive functions in neurodegenerative diseases such as Alzheimer’s disease. Full article

Background: Leptin, an adipokine essential for regulating energy balance, exerts important effects on brain function, notably within the hippocampus, a region integral to learning and memory. Leptin resistance, characterized by diminished responsiveness to elevated leptin levels, disrupts hippocampal function and exacerbates both obesity and cognitive impairments. Scope: This review critically examines how leptin resistance impairs hippocampal synaptic plasticity processes, specifically affecting long-term potentiation (LTP) and long-term depression (LTD), which are crucial for cognitive performance. Findings: Recent research highlights that leptin resistance disrupts N-methyl-D-aspartate (NMDA) receptor dynamics and hippocampal structure, leading to deficits in spatial learning and memory. Additionally, high-fat diets (HFDs), which contribute to leptin resistance, further deteriorate hippocampal function. Potential therapeutic strategies, including leptin sensitizers, show promise in mitigating brain disorders associated with leptin resistance. Complementary interventions such as caloric restriction and physical exercise also enhance leptin sensitivity and offer potential benefits to alleviating cognitive impairments. Aims of the review: This review synthesizes recent findings on the molecular pathways underlying leptin resistance and its impact on synaptic transmission and plasticity in the hippocampus. By identifying potential therapeutic targets, this work aims to provide an integrated approach for addressing cognitive deficits in obesity, ultimately improving the quality of life for affected individuals. Full article

Alzheimer’s disease (AD) is a progressive, degenerative brain disorder that impairs memory and thinking skills, leading to significant economic and humanistic burdens. It is associated with various neuropsychiatric symptoms (NPS) such as anxiety, agitation, depression, aggression, apathy, and psychosis. NPSs are common in patients with AD, affecting up to 97% of individuals diagnosed with AD. The severity of NPS is linked to disease progression and cognitive decline. NPS in Alzheimer’s disease leads to increased morbidity, mortality, caregiver burden, earlier nursing home placement, and higher healthcare costs. Despite their significant impact, clinical research on NPS in AD is limited. In clinical settings, accurately distinguishing and diagnosing NPS related to AD remains a challenge. Additionally, conventional treatments for NPS in AD are often ineffective, highlighting the need for new therapies that target these specific symptoms. Understanding these comorbidities can aid in early diagnosis and better management of AD. In this review, we provide a summary of the various neurological and psychiatric symptoms (NPS) associated with AD and new candidates under development for the treatment of NPS based on their therapeutic targets and mechanisms. On top of the conventional NPS studied so far, this review adds recent advancements in the understanding of social functional impairment in AD. This review also provides information that can contribute to the advancement of studies and translational research in this field by emphasizing therapeutic targets and mechanisms of action focused on AD-related NPS rather than conventional mechanisms targeted in AD drug development. Above all, considering the relative lack of research in this new field despite the importance of clinical, medical, and translational research, it may increase interest in NPS in AD, its pathophysiological mechanisms, and potential therapeutic candidates such as molecules with antioxidant potential. Full article

Mood disorders mainly affect the patient’s daily life, lead to suffering and disability, increase the incidence rate of many medical illnesses, and even cause a trend of suicide. The glucocorticoid (GC)-mediated hypothalamus–pituitary–adrenal (HPA) negative feedback regulation plays a key role in neuropsychiatric disorders. The balance of the mineralocorticoid receptor (MR)/glucocorticoid receptor (GR) level contributes to maintaining the homeostasis of the neuroendocrine system. Consistently, a chronic excess of GC can also lead to HPA axis dysfunction, triggering anxiety, depression, memory loss, and cognitive impairment. The animal model induced by chronic corticosterone (CORT) administration has been widely adopted because of its simple replication and strong stability. This review summarizes the behavioral changes and underlying mechanisms of chronic CORT administration-induced animal models, including neuroinflammatory response, pyroptosis, oxidative stress, neuroplasticity, and apoptosis. Notably, CORT administration at different doses and cycles can destroy the balance of the MR/GR ratio to make dose-dependent effects of CORT on the central nervous system (CNS). This work aims to offer an overview of the topic and recommendations for future cognitive function research. Full article

Within the central nervous system, synaptic plasticity, fundamental to processes like learning and memory, is largely driven by activity-dependent changes in synaptic strength. This plasticity often manifests as long-term potentiation (LTP) and long-term depression (LTD), which are bidirectional modulations of synaptic efficacy. Strong epidemiological and experimental evidence show that the heart–brain axis could be severely compromised by both neurological and cardiovascular disorders. Particularly, cardiovascular disorders, such as heart failure, hypertension, obesity, diabetes and insulin resistance, and arrhythmias, may lead to cognitive impairment, a condition known as cardiogenic dementia. Herein, we review the available knowledge on the synaptic and molecular mechanisms by which cardiogenic dementia may arise and describe how LTP and/or LTD induction and maintenance may be compromised in the CA1 region of the hippocampus by heart failure, metabolic syndrome, and arrhythmias. We also discuss the emerging evidence that endothelial dysfunction may contribute to directly altering hippocampal LTP by impairing the synaptically induced activation of the endothelial nitric oxide synthase. A better understanding of how CV disorders impact on the proper function of central synapses will shed novel light on the molecular underpinnings of cardiogenic dementia, thereby providing a new perspective for more specific pharmacological treatments. Full article