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Frontiers in Immunology 2023The pathogenesis of Alzheimer's disease (AD) is complex and multi-factorial. Increasing evidence has shown the important role of immune infiltration in AD. Thus the...
BACKGROUND
The pathogenesis of Alzheimer's disease (AD) is complex and multi-factorial. Increasing evidence has shown the important role of immune infiltration in AD. Thus the current study was designed to identify immune infiltration-related genes and to explore their diagnostic value in AD.
METHODS
The expression data of AD patients were downloaded from the GEO database. The limma R package identified differentially expressed genes (DEGs) between AD and controls. The CIBERSORT algorithm identified differentially infiltrated immune cells (DIICs) between AD and controls. DIIC-correlated DEGs were obtained by Pearson correlation analysis. WGCNA was employed to identify DIIC-related modules. Next, LASSO, RFE, and RF machine learning methods were applied to screen robust DIIC-related gene signatures in AD, followed by the construction and validation of a diagnostic nomogram. Detection of the expression of related genes in the peripheral blood of Alzheimer's disease and healthy volunteers by RT-PCR. In addition, the CTD database predicted chemicals targeting DIIC-related gene signatures in the treatment of AD.
RESULTS
NK cells, M0 macrophages, activated myeloid dendritic cells, resting mast cells, CD8+ T cells, resting memory CD4+ T cells, gamma delta T cells, and M2 macrophages were differentially infiltrated between AD and controls. Pearson analysis identified a total of 277 DIIC-correlated DEGs between AD and controls. Thereafter, 177 DIIC-related genes were further obtained by WGCNA analysis. By LASSO, RFE and RF algorithms, CMTM2, DDIT4, LDHB, NDUFA1, NDUFB2, NDUFS5, RPL17, RPL21, RPL26 and NDUFAF2 were identified as robust gene signature in AD. The results of RT-PCR detection of peripheral blood samples from Alzheimer's disease and healthy volunteers showed that the expression trend of ten genes screened was consistent with the detection results; among them, the expression levels of CMTM2, DDIT4, LDHB, NDUFS5, and RPL21 are significantly different among groups. Thus, a diagnostic nomogram based on a DIIC-related signature was constructed and validated. Moreover, candidate chemicals targeting those biomarkers in the treatment of AD, such as 4-hydroxy-2-nonenal, rosiglitazone, and resveratrol, were identified in the CTD database.
CONCLUSION
For the first time, we identified 10 immune infiltration-related biomarkers in AD, which may be helpful for the diagnosis of AD and provide guidance in the treatment of AD.
Topics: Humans; Alzheimer Disease; Ribosomal Proteins; Algorithms; CD8-Positive T-Lymphocytes; Computational Biology
PubMed: 37545529
DOI: 10.3389/fimmu.2023.1147501 -
International Journal of Molecular... Oct 2023Glaucoma is the leading cause of blindness worldwide. It is classically associated with structural and functional changes in the optic nerve head and retinal nerve fiber... (Review)
Review
Glaucoma is the leading cause of blindness worldwide. It is classically associated with structural and functional changes in the optic nerve head and retinal nerve fiber layer, but the damage is not limited to the eye. The involvement of the central visual pathways and disruption of brain network organization have been reported using advanced neuroimaging techniques. The brain structural changes at the level of the areas implied in processing visual information could justify the discrepancy between signs and symptoms and underlie the analogy of this disease with neurodegenerative dementias, such as Alzheimer's disease, and with the complex group of pathologies commonly referred to as "disconnection syndromes." This review aims to summarize the current state of the art on the use of advanced neuroimaging techniques in glaucoma and Alzheimer's disease, highlighting the emerging biomarkers shared by both diseases.
Topics: Humans; Alzheimer Disease; Magnetic Resonance Imaging; Glaucoma; Neuroimaging; Brain; Biomarkers
PubMed: 37834380
DOI: 10.3390/ijms241914932 -
European Heart Journal Jul 2023Dementia is a major global challenge for health and social care in the 21st century. A third of individuals >65 years of age die with dementia, and worldwide incidence...
Dementia is a major global challenge for health and social care in the 21st century. A third of individuals >65 years of age die with dementia, and worldwide incidence numbers are projected to be higher than 150 million by 2050. Dementia is, however, not an inevitable consequence of old age; 40% of dementia may theoretically be preventable. Alzheimer's disease (AD) accounts for approximately two-thirds of dementia cases and the major pathological hallmark of AD is accumulation of amyloid-β. Nevertheless, the exact pathological mechanisms of AD remain unknown. Cardiovascular disease and dementia share several risk factors and dementia often coexists with cerebrovascular disease. In a public health perspective, prevention is crucial, and it is suggested that a 10% reduction in prevalence of cardiovascular risk factors could prevent more than nine million dementia cases worldwide by 2050. Yet this assumes causality between cardiovascular risk factors and dementia and adherence to the interventions over decades for a large number of individuals. Using genome-wide association studies, the entire genome can be scanned for disease/trait associated loci in a hypothesis-free manner, and the compiled genetic information is not only useful for pinpointing novel pathogenic pathways but also for risk assessments. This enables identification of individuals at high risk, who likely will benefit the most from a targeted intervention. Further optimization of the risk stratification can be done by adding cardiovascular risk factors. Additional studies are, however, highly needed to elucidate dementia pathogenesis and potential shared causal risk factors between cardiovascular disease and dementia.
Topics: Humans; Cardiovascular Diseases; Genome-Wide Association Study; Risk Factors; Alzheimer Disease; Heart Disease Risk Factors
PubMed: 37224508
DOI: 10.1093/eurheartj/ehad293 -
Journal of Enzyme Inhibition and... Dec 2023Alzheimer's disease (AD), a persistent neurological dysfunction, has an increasing prevalence with the aging of the world and seriously threatens the health of the... (Review)
Review
Alzheimer's disease (AD), a persistent neurological dysfunction, has an increasing prevalence with the aging of the world and seriously threatens the health of the elderly. Although there is currently no effective treatment for AD, researchers have not given up, and are committed to exploring the pathogenesis of AD and possible therapeutic drugs. Natural products have attracted considerable attention owing to their unique advantages. One molecule can interact with multiple AD-related targets, thus having the potential to be developed in a multi-target drug. In addition, they are amenable to structural modifications to increase interaction and decrease toxicity. Therefore, natural products and their derivatives that ameliorate pathological changes in AD should be intensively and extensively studied. This review mainly presents research on natural products and their derivatives for the treatment of AD.
Topics: Humans; Aged; Alzheimer Disease; Biological Products; Aging; Drug Delivery Systems
PubMed: 36803484
DOI: 10.1080/14756366.2023.2171026 -
Nature Communications Nov 2023Many aging individuals accumulate the pathology of Alzheimer's disease (AD) without evidence of cognitive decline. Here we describe an integrated neurodegeneration...
Many aging individuals accumulate the pathology of Alzheimer's disease (AD) without evidence of cognitive decline. Here we describe an integrated neurodegeneration checkpoint response to early pathological changes that restricts further disease progression and preserves cognitive function. Checkpoint activation is mediated by the REST transcriptional repressor, which is induced in cognitively-intact aging humans and AD mouse models at the onset of amyloid β-protein (Aβ) deposition and tau accumulation. REST induction is mediated by the unfolded protein response together with β-catenin signaling. A consequence of this response is the targeting of REST to genes involved in key pathogenic pathways, resulting in downregulation of gamma secretase, tau kinases, and pro-apoptotic proteins. Deletion of REST in the 3xTg and J20 AD mouse models accelerates Aβ deposition and the accumulation of misfolded and phosphorylated tau, leading to neurodegeneration and cognitive decline. Conversely, viral-mediated overexpression of REST in the hippocampus suppresses Aβ and tau pathology. Thus, REST mediates a neurodegeneration checkpoint response with multiple molecular targets that may protect against the onset of AD.
Topics: Animals; Humans; Mice; Aging; Alzheimer Disease; Amyloid beta-Peptides; Cognitive Dysfunction; Disease Models, Animal; Mice, Transgenic; tau Proteins
PubMed: 37919281
DOI: 10.1038/s41467-023-42704-6 -
International Journal of Molecular... May 2024The neuroimmune system is a collection of immune cells, cytokines, and the glymphatic system that plays a pivotal role in the pathogenesis and progression of Alzheimer's... (Review)
Review
The neuroimmune system is a collection of immune cells, cytokines, and the glymphatic system that plays a pivotal role in the pathogenesis and progression of Alzheimer's disease (AD). Of particular focus are cytokines, a group of immune signaling molecules that facilitate communication among immune cells and contribute to inflammation in AD. Extensive research has shown that the dysregulated secretion of certain cytokines (IL-1β, IL-17, IL-12, IL-23, IL-6, and TNF-α) promotes neuroinflammation and exacerbates neuronal damage in AD. However, anti-inflammatory cytokines (IL-2, IL-3, IL-33, and IL-35) are also secreted during AD onset and progression, thereby preventing neuroinflammation. This review summarizes the involvement of pro- and anti-inflammatory cytokines in AD pathology and discusses their therapeutic potential.
Topics: Alzheimer Disease; Humans; Cytokines; Animals; Neuroinflammatory Diseases; Inflammation
PubMed: 38891990
DOI: 10.3390/ijms25115803 -
Cells Oct 2023Alzheimer's disease (AD)-the most common cause of dementia in the elderly-is characterized by progressive memory loss and β-amyloid protein (Aβ) accumulation in the... (Review)
Review
Alzheimer's disease (AD)-the most common cause of dementia in the elderly-is characterized by progressive memory loss and β-amyloid protein (Aβ) accumulation in the brain. Recently, loneliness was found to be a high risk factor for AD, and social isolation has become a major cause of AD. AD. Oxytocin (OXT), the main hormone involved in social bonding, has been implicated in social interactions, notably in building trust and relationships. Moreover, social isolation or social enrichment modulates the activation of neurons related to OXT. Recently, we reported that OXT reverses learning and memory impairment in AD animal models. Based on the limited number of studies currently available, OXT might be a therapeutic target for AD. Further studies are necessary in order to better understand the role of oxytocin in AD. In this review, we described the relationships between OXT, AD, and social interaction.
Topics: Animals; Humans; Aged; Alzheimer Disease; Oxytocin; Social Interaction; Amyloid beta-Peptides; Brain
PubMed: 37887270
DOI: 10.3390/cells12202426 -
Journal of Integrative Neuroscience Apr 2024Alzheimer's disease (AD) is the leading cause of dementia worldwide and significantly impacts the essential functions of daily life and social activities. Research on AD... (Review)
Review
Alzheimer's disease (AD) is the leading cause of dementia worldwide and significantly impacts the essential functions of daily life and social activities. Research on AD has found that its pathogenesis is related to the extracellular accumulation of amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles in the cortical and limbic areas of the human brain, as well as cerebrovascular factors. The detection of Aβ or tau can be performed using various probes and methodologies. However, these modalities are expensive to implement and often require invasive procedures, limiting accessibility on a large scale. While magnetic resonance imaging (MRI) and computed tomography (CT) are generally used for morphological and structural brain imaging, they show wide variability in their accuracy for the clinical diagnosis of AD. Several novel imaging modalities have emerged as alternatives that can accurately and vividly display the changes in blood flow and metabolism in each brain area and enable physicians and researchers to gain insights into the generation and progression of the cerebro-microvascular pathologies of AD. In this review, we summarize the current knowledge on microvascular perfusion imaging modalities and their application in AD, including MRI (dynamic susceptibility contrast-MRI, arterial spin labeling-MRI), CT (cerebral CT perfusion imaging), emission computed tomography (positron emission tomography (PET), single-photon emission computed tomography (SPECT)), transcranial doppler ultrasonography (TCD), and retinal microvascular imaging (optical coherence tomography imaging, computer-assisted methods for evaluating retinal vasculature).
Topics: Humans; Alzheimer Disease; Perfusion Imaging; Cerebrovascular Circulation; Microvessels; Brain
PubMed: 38682213
DOI: 10.31083/j.jin2304070 -
Biomolecules Jul 2023This review examines the potential of fasting-mimicking diets (FMDs) in preventing and treating Alzheimer's disease (AD). FMDs are low-calorie diets that mimic the... (Review)
Review
This review examines the potential of fasting-mimicking diets (FMDs) in preventing and treating Alzheimer's disease (AD). FMDs are low-calorie diets that mimic the physiological and metabolic effects of fasting, including the activation of cellular stress response pathways and autophagy. Recent studies have shown that FMDs can reduce amyloid-beta accumulation, tau phosphorylation, and inflammation, as well as improve cognitive function in animal models of AD. Human studies have also reported improvements in AD biomarkers, cognitive functions, and subjective well-being measures following FMDs. However, the optimal duration and frequency of FMDs and their long-term safety and efficacy remain to be determined. Despite these uncertainties, FMDs hold promise as a non-pharmacological approach to AD prevention and treatment, and further research in this area is warranted.
Topics: Animals; Humans; Alzheimer Disease; Fasting; Diet; Amyloid beta-Peptides; Caloric Restriction; tau Proteins
PubMed: 37509169
DOI: 10.3390/biom13071133 -
CNS Neuroscience & Therapeutics Feb 2024Transcranial pulse stimulation (TPS) is a novel noninvasive ultrasonic brain stimulation that can increase cortical and corticospinal excitability, induce...
BACKGROUND
Transcranial pulse stimulation (TPS) is a novel noninvasive ultrasonic brain stimulation that can increase cortical and corticospinal excitability, induce neuroplasticity, and increase functional connectivity within the brain. Several trials have confirmed its potential in treating Alzheimer's disease (AD).
OBJECTIVE
To investigate the effect and safety of TPS on AD.
DESIGN
A systematic review.
METHODS
PubMed, Embase via Ovid, Web of Science, Cochrane Library, CNKI (China National Knowledge Infrastructure), VIP (China Science and Technology Journal Database), and WanFang were searched from inception to April 1, 2023. Study selection, data extraction, and quality evaluation of the studies were conducted by two reviewers independently, with any controversy resolved by consensus. The Methodological Index for Nonrandomized Studies was used to assess the risk of bias.
RESULTS
Five studies were included in this review, with a total of 99 patients with AD. For cognitive performance, TPS significantly improved the scores of the CERAD (Consortium to Establish a Registry for Alzheimer's Disease) test battery, Alzheimer's Disease Assessment Scale (cognitive), Montreal Cognitive Assessment, and Mini-Mental Status Examination. For depressive symptoms, TPS significantly reduced the scores of the Alzheimer's Disease Assessment Scale (affective), Geriatric Depression Score, and Beck Depression Inventory. By functional magnetic resonance imaging, studies have shown that TPS improved cognitive performance in AD patients by increasing functional connectivity in the hippocampus, parahippocampal cortex, precuneus, and parietal cortex, and activating cortical activity in the bilateral hippocampus. TPS alleviated depressive symptoms in AD patients by decreasing functional connectivity between the ventromedial network (left frontal orbital cortex) and the salience network (right anterior insula). Adverse events in this review, including headache, worsening mood, jaw pain, nausea, and drowsiness, were reversible and lasted no longer than 1 day. No serious adverse events or complications were observed.
CONCLUSIONS
TPS is promising in improving cognitive performance and reducing depressive symptoms in patients with AD. TPS may be a safe adjunct therapy in the treatment of AD. However, these findings lacked a sham control and were limited by the small sample size of the included studies. Further research may be needed to better explore the potential of TPS.
PATIENT AND PUBLIC INVOLVEMENT
Patients and the public were not involved in this study.
Topics: Humans; Aged; Alzheimer Disease; Brain; Magnetic Resonance Imaging; Hippocampus; Mental Status and Dementia Tests; Transcranial Magnetic Stimulation
PubMed: 37469252
DOI: 10.1111/cns.14372