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Activation of cell-cycle machinery in Alzheimer's disease (AD) brain was reported by Mark Smith and colleagues and by other researchers. Among other biochemical processes underlying this activation, the notion that AD brain, under the onslaught of oxidative and nitrosative damage leading to neuronal loss, neurons would attempt to replenish their numbers by entering the cell cycle. However, being post-mitotic, neurons entering the cell cycle would become trapped therein, ultimately leading to death of these neurons. Yang and co-workers and the Butterfield laboratory first reported that similar activation of the cell cycle was present in the brains of individuals with amnestic mild cognitive impairment (MCI), arguably the earliest clinical stage of AD, but who demonstrate normal activities of daily living and no dementia. Activation of the cell cycle in MCI brain is consonant with the concept that this process is an early aspect in the progression of AD. This brief review article discusses these findings and recognizes the contribution of Dr. Mark Smith to the investigation of cell-cycle activation in AD brain and other aspects of AD neuropathology. [ABSTRACT FROM AUTHOR]

Oxidative stress is implicated in the pathogenesis and progression of Alzheimer's disease (AD) and its earlier stage, amnestic mild cognitive impairment (aMCI). One source of oxidative stress in AD and aMCI brains is that associated with amyloid-β peptide, Aβ1-42 oligomers. Our laboratory first showed in AD elevated oxidative stress occurred in brain regions rich in Aβ1-42, but not in Aβ1-42-poor regions, and was among the first to demonstrate Aβ peptides led to lipid peroxidation (indexed by HNE) in AD and aMCI brains. Oxidatively modified proteins have decreased function and contribute to damaged key biochemical and metabolic pathways in which these proteins normally play a role. Identification of oxidatively modified brain proteins by the methods of redox proteomics was pioneered in the Butterfield laboratory. Four recurring altered pathways secondary to oxidative damage in brain from persons with AD, aMCI, or Down syndrome with AD are interrelated and contribute to neuronal death. This "Quadrilateral of Neuronal Death" includes altered: glucose metabolism, mTOR activation, proteostasis network, and protein phosphorylation. Some of these pathways are altered even in brains of persons with preclinical AD. We opine that targeting these pathways pharmacologically and with lifestyle changes potentially may provide strategies to slow or perhaps one day, prevent, progression or development of this devastating dementing disorder. This invited review outlines both in vitro and in vivo studies from the Butterfield laboratory related to Aβ1-42 and AD and discusses the importance and implications of some of the major achievements of the Butterfield laboratory in AD research. [ABSTRACT FROM AUTHOR]

Oxidative stress, an overproduction of free radicals or a diminution of free radical scavenging ability relative to those of cognitively aged-matched controls, is widely recognized as a critical component of the pathogenesis and progression of Alzheimer's disease (AD). This recognition arose in significant part from the work in the author's laboratory, complemented by research from others' laboratories. The Butterfield laboratory discovered the oxidative stress associated with oligomeric amyloid-β peptide manifested primarily as elevated oxidative modification of proteins and peroxidation of lipids. Such oxidative damage caused neuronal death, which undoubtedly underlies the progressive loss of cognition in AD. Identification of specific oxidatively modified brain proteins in subjects with AD or amnestic mild cognitive impairment was achieved by the methods of redox proteomics, pioneered in the author's laboratory. The importance and significance of the research emanating from the Butterfield laboratory rest on the paradigm shift of thinking regarding the roles of oxidative stress and resulting damage to key proteins and biochemical pathways in the pathogenesis and progression of AD. Predictions of future research directions also are presented. Given the enormous financial and personal burden placed upon citizens (and governments) of the US from AD, and the surety that the number of AD patients will greatly increase over the next 20-30 years, greater understanding of the molecular basis of pathogenesis and progression of AD is essential. Our laboratory is privileged to have contributed to better understanding of AD and provided rationales to identify effective therapeutic targets for this devastating dementing disorder. [ABSTRACT FROM AUTHOR]

Aging is the major risk factor associated with neurodegenerative diseases, including Alzheimer's disease (AD). Until now no clear understanding of the mechanisms of initiation and progression of this dementing disorder exists. Based on the studies that have been conducted so far amyloid β-peptide (Aβ), a protein found in senile plaques, one of the key pathological hallmarks of AD, has been reported to be critical in the pathogenesis of AD. Studies from our laboratory and others showed that Aβ can induce oxidative stress, which leads to oxidative modification of biomolecules, thereby diminishing the normal functions of neuronal cells and eventually leading to loss of neurons and AD. In this review paper, we summarize evidence of oxidative stress in brains of AD and mild cognitive impairment patients, as well as the results from redox proteomics studies. The investigations have provided insights into the downstream effects of oxidative modification of key brain proteins in the pathogenesis of AD. Based on these redox proteomics results, we suggest future areas of research that could be considered to better understand this devastating dementing disorder. [ABSTRACT FROM AUTHOR]

Several studies showed increased oxidative and nitrosative stress in plasma from patients with Alzheimer's disease (AD), however, little and controversial knowledge has emerged about the antioxidant functionality of the heme oxygenase-1/biliverdin reductase-A (HO-1/BVR-A) system in blood. The current study reports increased levels of both HO-1 and BVR-A in plasma from probable AD patients, as a result of the increased oxidative environment. However, the increase of oxidative stress in plasma result also in the increase of BVR-A 3-nitrotyrosine levels and the decrease of BVR-A phosphotyrosine levels and reductase activity, suggesting that nitrosative stress play the prominent oxidative role in plasma during AD. Our data on HO-1/BVR-A status in plasma closely correlate with recent reports in hippocampus of subjects with AD and arguably its early form, mild cognitive impairment. Moreover, we show that alterations on HO-1/BVR-A system are tightly connected with cognitive decline indexed by Mini-Mental Status Exam scores. We hypothesize that the HO-1/BVR-A system status in plasma might reflect the ongoing situation in the brain, offering an important biochemical tool for the potential prediction of AD at the earliest stages of the disease. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a central nervous system disorder pathologically characterized by senile plaques, neurofibrillary tangles, and synapse loss. A small percentage of individuals with normal antemortem psychometric scores, after adjustments for age and education, meet the neuropathological criteria for amnestic mild cognitive impairment (MCI) or AD; these individuals have been termed 'preclinical' or 'asymptomatic' AD (PCAD). In this study, we employed the immunochemical slot-blot method and two-dimensional gel-based redox proteomics to observe differences in protein levels and oxidative modifications between groups with equal levels of AD pathology who differ in regards to clinical symptoms of memory impairment. Results of global oxidative stress measurements revealed significantly higher levels of protein carbonyls in the MCI inferior parietal lobule (IPL) relative to PCAD (and controls), despite equal levels of neuropathology. Proteomics analysis of the IPL revealed differences in protein levels and specific carbonylation that are consistent with preservation of memory in PCAD and apparent memory decline in MCI. Our data suggest that marked changes occur at the protein level in MCI that may cause or reflect memory loss and other AD symptoms. [ABSTRACT FROM AUTHOR]

Biliverdin reductase-A (BVR-A) is a pleiotropic enzyme and plays pivotal role in the antioxidant defense against free radicals as well as in cell homeostasis. Together with heme oxygenase, BVR-A forms a powerful system involved in the cell stress response during neurodegenerative disorders including Alzheimer's disease (AD), whereas due to the serine/threonine/tyrosine kinase activity the enzyme regulates glucose metabolism and cell proliferation. In this paper, we report results that demonstrate BVR-A undergoes post-translational oxidative and nitrosative modifications in the hippocampus, but not cerebellum, of subjects with AD and amnestic mild cognitive impairment (MCI). A significant increase of nitrated BVR-A was demonstrated only in AD and MCI hippocampi, whereas no significant modifications were found in cerebellar tissue. In addition, a significant reduction in protein carbonyl-derivatives of BVR-A was found in both AD and MCI hippocampi (15% and 18%, respectively). Biliverdin reductase-bound 4-hydroxynonenals were not modified in hippocampi and cerebella from AD and MCI subjects. These results supported the hypothesis of a prevalence of nitrosative stress-induced modifications on BVR-A structure, and this evidence was confirmed by a significant upregulation of inducible nitric oxide synthase in hippocampal tissue of subjects with AD and MCI that was not present in cerebellum. In conclusion, nitrosative stress-induced modifications on hippocampal BVR-A are an early event in the pathogenesis of AD since they appear also in MCI subjects and could contribute to the antioxidant and metabolic derangement characteristic of these neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurodegenerative disease with a long preclinical and prodromal stage near 20 years. The neuropathological hallmarks of AD include amyloid plaques, neurofibrillary tangles, and neuroinflammation, those lead to neuronal and synaptic loss. Important fact, oxidative stress participates in the AD development by promoting amyloid-β deposition, tau hyperphosphorylation. However, the inflammatory response and pyroptotic death are mediated by the aberrant expression of NLRP inflammasome activated caspase-1, which leads to cleavage pro-inflammatory cytokines such as pro-interleukin-1β and pro-IL-18. IL-1β, TNF-α, and IL-6 which amplify the neuroinflammation loop, are produce by activated microglia and astrocytes, that can serve as early diagnostic markers or therapeutic targets in AD. In this review, we summarize our current understanding of the role of inflammasome in the pathogenesis of AD, highlighting key issues that need to be addressed to improve the development of new therapies. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by gradual and progressive cognitive decline leading to dementia. At its core, the neuropathological features of AD include hallmark accumulations of amyloid-β and hyperphosphorylated tau proteins. Other harmful processes, such as oxidative stress and inflammation, contribute to the disease's neuropathological progression. This review evaluates the role of oxidative stress in AD, placing a spotlight on the disappointing outcomes of various antioxidant clinical trials. Several hypotheses are discussed that might elucidate the failures of these therapies in AD. Specifically: 1) The paradoxical and overlooked harmful implications of prooxidant intermediates, particularly stemming from conventional antioxidants like vitamins E and C; 2) The challenges and failure to appreciate the issue of bioavailability—epitomized by the dictum "no on-site protection, no protection"—and the preeminent, yet often ignored, role played by endogenous antioxidant enzymes in combating oxidative stress; 3) The influence of unrecognized etiologies, such as latent infectious agents and others, as foundational drivers of oxidative stress in AD; 4) The underestimation of the complexity of oxidative mechanisms and the necessity of multi-targeted therapeutic approaches, such as those provided by various diets; and 5) The limitations of clinical trial designs in fully capturing the effects of antioxidants on AD progression. This article also examines the outcomes of select clinical trials while highlighting the challenges and barriers these therapies pose, offering insights into potential mechanisms to overcome their marginal success. [ABSTRACT FROM AUTHOR]

Functional impairments in the brain's insulin and insulin-like growth factor (IGF) signal transduction networks are recognized mediators of dysregulated energy metabolism, a major driver of the Alzheimer's disease (AD) neurodegeneration cascade. AD-associated insulin-deficient and insulin-resistant states mimic those of diabetes mellitus and affect all cell types in the brain. Besides accounting for abundant amyloid-β and hyperphosphorylated tau lesions in AD, insulin/IGF pathway dysfunctions cause cortical atrophy, loss of synaptic plasticity, white matter myelin/oligodendrocyte degeneration, astrocyte and microglial neuroinflammation and oxidative stress, deficits in energy metabolism, mitochondrial dysfunction, and microvascular disease. These same neuropathological processes have been linked to cognitive impairment in type 2 diabetes mellitus, Parkinson's disease, and vascular dementia. Strategies to address metabolic mediators of cognitive impairment have been borrowed from diabetes and other insulin-resistant diseases and leveraged on preclinical AD model data. The repurposing of diabetes drugs led to clinical trials with intranasal insulin, followed by insulin sensitizers including metformin and peroxisome-proliferator-activated receptor agonists, and then incretin mimetics primarily targeting GLP-1 receptors. In addition, other glucose-lowering agents have been tested for their efficacy in preventing cognitive declines. The strengths and limitations of these approaches are discussed. The main conclusion of this review is that we have now arrived at a stage in which it is time to address long-term deficits in trophic factor availability and receptor responsiveness, signaling abnormalities that extend beyond insulin and include IGFs and interconnected pathways, and the need for multi-pronged rather than single-pronged therapeutic targeting to remediate AD and other forms of neurodegeneration. [ABSTRACT FROM AUTHOR]

There are currently no effective treatments to prevent, halt, or reverse Alzheimer's disease (AD), the most common cause of dementia in older adults. Melatonin, a relatively harmless over-the-counter supplement, may offer some benefits to patients with AD. Melatonin is known for its sleep-enhancing properties, but research shows that it may provide other advantages as well, such as antioxidant and anti-amyloidogenic properties. Clinical trials for melatonin use in AD have mixed results but, overall, show modest benefits. However, it is difficult to interpret clinical research in this area as there is little standardization to guide the administration and study of melatonin. This review covers basic biology and clinical research on melatonin in AD focusing on prominent hypotheses of pathophysiology of neurodegeneration and cognitive decline in AD (i.e., amyloid and tau hypotheses, antioxidant and anti-inflammation, insulin resistance and glucose homeostasis, the cholinergic hypothesis, sleep regulation, and the hypothalamic-pituitary-adrenal axis and cortisol). This is followed by a discussion on pending clinical trials, considerations for future research protocols, and open questions in the field. [ABSTRACT FROM AUTHOR]

Background: Tau aggregation demonstrates close associations with hypometabolism in Alzheimer's disease (AD), although differing pathophysiological processes may underlie their development. Objective: To establish whether tau deposition and glucose metabolism have different trajectories in AD progression and evaluate the utility of global measures of these pathological hallmarks in predicting cognitive deficits. Methods: 279 participants with amyloid-β (Aβ) status, and T1-weighted MRI scans, were selected from the Alzheimer's Disease Neuroimaging Initiative (). We created the standard uptake value ratio images using Statistical Parametric Mapping 12 for [18F]AV1451-PET (tau) and [18F]FDG-PET (glucose metabolism) scans. Voxel-wise group and single-subject level SPM analysis evaluated the relationship between global [18F]FDG-PET and [18F]AV1451-PET depending on the Aβ status. Linear models assessed whether tau deposition or glucose metabolism better predicted clinical progression. Results: There was a dissociation between global cerebral glucose hypometabolism and global tau load in amyloid-positive AD and amyloid-negative mild cognitive impairment (MCI) (p > 0.05). Global hypometabolism was only associated with global cortical tau in amyloid-positive MCI. Voxel-level single subject tau load better predicted neuropsychological performance, Alzheimer's disease assessment scale-cognitive (ADAS-Cog) 13 score, and one-year change compared with regional and global hypometabolism. Conclusions: A dissociation between tau pathology and glucose metabolism at a global level in AD could imply that other pathological processes influence glucose metabolism. Furthermore, as tau is a better predictor of clinical progression, these processes may have independent trajectories and require independent consideration in the context of therapeutic interventions. [ABSTRACT FROM AUTHOR]

Background: Ethylene oxide (EO) is a common organic compound associated with many adverse health outcomes. However, studies exploring the association between EO exposure and cognitive function are limited. Objective: This study aims to examine this relationship between EO exposure and cognition in older adults. Methods: This study enrolled 438 older adults from the National Health and Nutrition Examination Survey (NHANES) 2013-2014 cycle. EO exposure was quantified by the measurements of blood hemoglobin adducts of ethylene oxide (HbEO) concentrations. Cognitive function was measured by the Consortium to Establish a Registry for Alzheimer's Disease battery (CREAD), the Animal Fluency test (AFT), and the Digit Symbol Substitution Test (DSST). Linear regression model, generalized additive model, and smooth curve fitting were applied to examine the linear and nonlinear relationship between EO exposure and cognitive function. We used a two-piecewise linear regression model to detect the threshold effect of EO exposure on cognitive function. Results: Participants with higher HbEO levels had lower AFT and DSST scores than those with lower HbEO levels. After adjusting for all confounding factors, log2-transformed HbEO levels were negatively associated with AFT score. The smooth curve fitting demonstrated the nonlinear relationship between EO exposure and DSST scores. When log-2 transformed HbEO levels >4.34 pmol/g Hb, EO exposure was negatively associated with DSST score. Conclusions: This study indicated that high levels of HbEO were associated with cognitive decline in US older adults. Future cohort studies are needed to verify our findings. [ABSTRACT FROM AUTHOR]

Background: The connection between diabetes-associated cognitive dysfunction (DACD) and Alzheimer's disease (AD) has been shown in several observational studies. However, it remains controversial as to how the two related. Objective: To explore shared genes and pathways between DACD and AD using bioinformatics analysis combined with biological experiment. Methods: We analyzed GEO microarray data to identify DEGs in AD and type 2 diabetes mellitus (T2DM) induced-DACD datasets. Weighted gene co-expression network analysis was used to find modules, while R packages identified overlapping genes. A robust protein-protein interaction network was constructed, and hub genes were identified with Gene ontology enrichment and Kyoto Encyclopedia of Genome and Genome pathway analyses. HT22 cells were cultured under high glucose and amyloid-β 25–35 (Aβ25-35) conditions to establish DACD and AD models. Quantitative polymerase chain reaction with reverse transcription verification analysis was then performed on intersection genes. Results: Three modules each in AD and T2DM induced-DACD were identified as the most relevant and 10 hub genes were screened, with analysis revealing enrichment in pathways such as synaptic vesicle cycle and GABAergic synapse. Through biological experimentation verification, 6 key genes were identified. Conclusions: This study is the first to use bioinformatics tools to uncover the genetic link between AD and DACD. GAD1, UCHL1, GAP43, CARNS1, TAGLN3, and SH3GL2 were identified as key genes connecting AD and DACD. These findings offer new insights into the diseases' pathogenesis and potential diagnostic and therapeutic targets. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is one of the most common neurodegenerative disorders and is characterized by a decrease in learning capacity, memory loss and behavioral changes. In addition to the well-recognized amyloid-β cascade hypothesis and hyperphosphorylated Tau hypothesis, accumulating evidence has led to the proposal of the mitochondrial dysfunction hypothesis as the primary etiology of AD. However, the predominant molecular mechanisms underlying the development and progression of AD have not been fully elucidated. Mitochondrial dysfunction is not only considered an early event in AD pathogenesis but is also involved in the whole course of the disease, with numerous pathophysiological processes, including disordered energy metabolism, Ca2+ homeostasis dysfunction and hyperactive oxidative stress. In the current review, we have integrated emerging evidence to summarize the main mitochondrial alterations— bioenergetic metabolism, mitochondrial inheritance, mitobiogenesis, fission– fusion dynamics, mitochondrial degradation, and mitochondrial movement— underlying AD pathogenesis; precisely identified the mitochondrial regulators; discussed the potential mechanisms and primary processes; highlighted the leading players; and noted additional incidental signaling pathway changes. This review may help to stimulate research exploring mitochondrial metabolically-oriented neuroprotection strategies in AD therapies, leading to a better understanding of the link between the mitochondrial dysfunction hypothesis and AD pathogenesis. [ABSTRACT FROM AUTHOR]

Oxidative stress (OS) is a critical factor in the pathogenesis of Alzheimer's disease (AD). Elevated OS in AD lowers the level of glutathione (GSH), a brain antioxidant. Currently, GSH is under examination in the clinical population for understanding its association with oxidative load in AD research. Significant depletion in hippocampal GSH, as observed using in vivo magnetic resonance spectroscopy (MRS), reportedly correlates with cognitive impairment in AD. Alterations in cellular-energy metabolism and increased hippocampal pH have also been reported in AD. Hence, this combined molecular interplay between hippocampal GSH and pH must be studied longitudinally for advancing AD research. Herein, we propose a schematic model depicting the molecular events in AD pathogenesis and provide a possible link between OS, GSH depletion, and pH alterations in the hippocampus. The model would further potentiate the need for in vivo longitudinal studies to confirm the interlinked mechanism between OS, hippocampal GSH depletion, and pH increment in an AD patient brain. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) accounts for most dementia cases, but we lack a complete understanding of the mechanisms responsible for the core pathology associated with the disease (e.g., amyloid plaque and neurofibrillary tangles). Inflammation has been identified as a key contributor of AD pathology, with recent evidence pointing towards Reelin dysregulation as being associated with inflammation. Here we describe Reelin signaling and outline existing research involving Reelin signaling in AD and inflammation. Research is described pertaining to the inflammatory and immunological functions of Reelin before we propose a mechanism through which inflammation renders Reelin susceptible to dysregulation resulting in the induction and exacerbation of AD pathology. Based on this hypothesis, it is predicted that disorders of both inflammation (including peripheral inflammation and neuroinflammation) and Reelin dysregulation (including disorders associated with upregulated Reelin expression and disorders of Reelin downregulation) have elevated risk of developing AD. We conclude with a description of AD risk in various disorders involving Reelin dysregulation and inflammation. [ABSTRACT FROM AUTHOR]

Accumulating evidence suggests that gut inflammation is implicated in neuroinflammation in Alzheimer's and Parkinson's diseases. Despite the numerous connections it remains unclear how the gut and the brain communicate and whether gut dysbiosis is the cause or consequence of these pathologies. Importantly, several reports highlight the importance of mitochondria in the gut-brain axis, as well as in mechanisms like gut epithelium self-renewal, differentiation, and homeostasis. Herein we comprehensively address the important role of mitochondria as a cellular hub in infection and inflammation and as a link between inflammation and neurodegeneration in the gut-brain axis. The role of mitochondria in gut homeostasis and as well the crosstalk between mitochondria and gut microbiota is discussed. Significantly, we also review studies highlighting how gut microbiota can ultimately affect the central nervous system. Overall, this review summarizes novel findings regarding this cross-talk where the mitochondria has a main role in the pathophysiology of both Alzheimer's and Parkinson's disease strengthen by cellular, animal and clinical studies. [ABSTRACT FROM AUTHOR]

Amyloid protein-β (Aβ) concentrations are increased in the brain in both early onset and late onset Alzheimer's disease (AD). In early onset AD, cerebral Aβ production is increased and its clearance is decreased, while increased Aβ burden in late onset AD is due to impaired clearance. Aβ has been the focus of AD therapeutics since development of the amyloid hypothesis, but efforts to slow AD progression by lowering brain Aβ failed until phase 3 trials with the monoclonal antibodies lecanemab and donanemab. In addition to promoting phagocytic clearance of Aβ, antibodies lower cerebral Aβ by efflux of Aβ-antibody complexes across the capillary endothelia, dissolving Aβ aggregates, and a "peripheral sink" mechanism. Although the blood-brain barrier is the main route by which soluble Aβ leaves the brain (facilitated by low-density lipoprotein receptor-related protein-1 and ATP-binding cassette sub-family B member 1), Aβ can also be removed via the blood-cerebrospinal fluid barrier, glymphatic drainage, and intramural periarterial drainage. This review discusses experimental approaches to increase cerebral Aβ efflux via these mechanisms, clinical applications of these approaches, and findings in clinical trials with these approaches in patients with AD or mild cognitive impairment. Based on negative findings in clinical trials with previous approaches targeting monomeric Aβ, increasing the cerebral efflux of soluble Aβ is unlikely to slow AD progression if used as monotherapy. But if used as an adjunct to treatment with lecanemab or donanemab, this approach might allow greater slowing of AD progression than treatment with either antibody alone. [ABSTRACT FROM AUTHOR]

Background: With the aging of populations worldwide, Alzheimer's disease (AD) has become a concern due to its high prevalence and the continued lack of established treatments. Early diagnosis is required as a preventive intervention to modify the disease's progression. In our previous study, we performed peptidomic analysis of serum samples obtained from AD patients and age-matched healthy subjects to seek peptide biomarker candidates for AD by using BLOTCHIP-MS analysis, and identified four peptides as AD biomarker candidates. Objective: The objective was to validate the serum biomarker peptides to distinguish mild cognitive impairment (MCI) and AD in comparison to cognitively healthy controls using a new peptidome technology, the Dementia Risk Test. Methods: We enrolled 195 subjects with normal cognitive function (NC; n = 70), MCI (n = 55), and AD (n = 70), The concentrations of cognitive impairment marker peptides (Fibrinogen α chain (FAC), Fibrinogen β chain (FBC), Plasma protease C1 inhibitor (PPC1I), α2-HS-glycoprotein (AHSG)) were quantified by using a selected reaction monitoring assay based on liquid chromatography-MS/MS. Results: The present study confirmed that three peptides, FAC, FBC, and PPC1I, were significantly upregulated during the onset of AD. This three-peptide set was both highly sensitive in determining AD (sensitivity: 85.7%, specificity: 95.7%, AUC: 0.900) and useful in distinguishing MCI (sensitivity: 61.8%, specificity: 98.6%, AUC: 0.824) from NC. Conclusions: In this validation study, we confirmed the high diagnostic potential of the three peptides identified in our previous study as candidate serum biomarkers for AD. The Dementia Risk Test may be a powerful tool for detecting AD-related pathological changes. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized pathologically by the presence of senile plaques, neurofibrillary tangles, and synapse loss. Increasing evidence supports a role of amyloid β-peptide (Aβ)-induced oxidative stress in the progression and pathogenesis of AD. In this review, we summarize evidence for a role of oxidative stress in the progression of AD by comparing the appearance of the same oxidized brain proteins from subjects with mild cognitive impairment (MCI), early AD (EAD), and late-stage AD, and relating these findings to the reported AD pathology. The identification of oxidized brain proteins in common in MCI, EAD, and AD brain suggest that certain key pathways are triggered and may be involved in the progression of AD. Exploring these pathways in detail may provide clues for better understanding the pathogenesis and progression of AD and also for the development of effective therapies to treat or delay this dementing disorder. [ABSTRACT FROM AUTHOR]

Oxidative stress is associated with the progression of Alzheimer's disease (AD). Reactive oxygen species can modify lipids, DNA, RNA, and proteins in the brain. The products of their peroxidation and oxidation are readily detectable at incipient stages of disease. Based on these oxidation products, various biomarker-based strategies have been developed to identify oxidative stress levels in AD. Known oxidative stress-related biomarkers include lipid peroxidation products F2-isoprostanes, as well as malondialdehyde and 4-hydroxynonenal which both conjugate to specific amino acids to modify proteins, and DNA or RNA oxidation products 8-hydroxy-2'-deoxyguanosine (8-OHdG) and 8-hydroxyguanosine (8-OHG), respectively. The inducible enzyme heme oxygenase type 1 (HO-1) is found to be upregulated in response to oxidative stress-related events in the AD brain. While these global biomarkers for oxidative stress are associated with early-stage AD, they generally poorly differentiate from other neurodegenerative disorders that also coincide with oxidative stress. Redox proteomics approaches provided specificity of oxidative stress-associated biomarkers to AD pathology by the identification of oxidatively damaged pathology-specific proteins. In this review, we discuss the potential combined diagnostic value of these reported biomarkers in the context of AD and discuss eight oxidative stress-related mRNA biomarkers in AD that we newly identified using a transcriptomics approach. We review these genes in the context of their reported involvement in oxidative stress regulation and specificity for AD. Further research is warranted to establish the protein levels and their functionalities as well as the molecular mechanisms by which these potential biomarkers are involved in regulation of oxidative stress levels and their potential for determination of oxidative stress and disease status of AD patients. [ABSTRACT FROM AUTHOR]

Background: Late-onset Alzheimer's disease (LOAD) is the most common type of dementia, but its pathogenesis remains unclear, and there is a lack of simple and convenient early diagnostic markers to predict the occurrence. Objective: Our study aimed to identify diagnostic candidate genes to predict LOAD by machine learning methods. Methods: Three publicly available datasets from the Gene Expression Omnibus (GEO) database containing peripheral blood gene expression data for LOAD, mild cognitive impairment (MCI), and controls (CN) were downloaded. Differential expression analysis, the least absolute shrinkage and selection operator (LASSO), and support vector machine recursive feature elimination (SVM-RFE) were used to identify LOAD diagnostic candidate genes. These candidate genes were then validated in the validation group and clinical samples, and a LOAD prediction model was established. Results: LASSO and SVM-RFE analyses identified 3 mitochondria-related genes (MRGs) as candidate genes, including NDUFA1, NDUFS5, and NDUFB3. In the verification of 3 MRGs, the AUC values showed that NDUFA1, NDUFS5 had better predictability. We also verified the candidate MRGs in MCI groups, the AUC values showed good performance. We then used NDUFA1, NDUFS5 and age to build a LOAD diagnostic model and AUC was 0.723. Results of qRT-PCR experiments with clinical blood samples showed that the three candidate genes were expressed significantly lower in the LOAD and MCI groups when compared to CN. Conclusion: Two mitochondrial-related candidate genes, NDUFA1 and NDUFS5, were identified as diagnostic markers for LOAD and MCI. Combining these two candidate genes with age, a LOAD diagnostic prediction model was successfully constructed. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD), the most common form of dementia, remains long-term and challenging to diagnose. Furthermore, there is currently no medication to completely cure AD patients. Rapamycin has been clinically demonstrated to postpone the aging process in mice and improve learning and memory abilities in animal models of AD. Therefore, rapamycin has the potential to be significant in the discovery and development of drugs for AD patients. Objective: The main objective of this systematic review and meta-analysis was to investigate the effects and mechanisms of rapamycin on animal models of AD by examining behavioral indicators and pathological features. Methods: Six databases were searched and 4,277 articles were retrieved. In conclusion, 13 studies were included according to predefined criteria. Three authors independently judged the selected literature and methodological quality. Use of subgroup analyses to explore potential mechanistic effects of rapamycin interventions: animal models of AD, specific types of transgenic animal models, dosage, and periodicity of administration. Results: The results of Morris Water Maze (MWM) behavioral test showed that escape latency was shortened by 15.60 seconds with rapamycin therapy, indicating that learning ability was enhanced in AD mice; and the number of traversed platforms was increased by 1.53 times, indicating that the improved memory ability significantly corrected the memory deficits. CONCLUSIONS: Rapamycin therapy reduced age-related plaque deposition by decreasing AβPP production and down-regulating β-secretase and γ-secretase activities, furthermore increased amyloid-β clearance by promoting autophagy, as well as reduced tau hyperphosphorylation by up-regulating insulin-degrading enzyme levels. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common form of dementia and a public health problem. It exhibits significant oxidative stress and redox alterations. The antioxidant enzyme systems defend the cellular environment from oxidative stress. One of the redox systems is the thioredoxin system (TS), which exerts decisive control over the cellular redox environment. We aimed to review the protective effects of TS, which include thioredoxin (Trx), thioredoxin reductase (TrxR), and NADPH. In the following, we discussed the physiological functioning and the role of the TS in maintaining the cellular redox-homeostasis in the AD-damaged brain. Trx protects the cellular environment from oxidative stress, while TrxR is crucial for the cellular detoxification of reactive oxygen species in the brain. However, TS dysregulation increases the susceptibility to cellular death. The changes in Trx and TrxR levels are significantly associated with AD progression. Though the data from human, animal, and cellular models support the neuroprotective role of TS in the brain of AD patients, the translational potential of these findings to clinical settings is not yet applied. This review summarizes the current knowledge on the emerging role of the TrxR-Trx system in AD. [ABSTRACT FROM AUTHOR]

Animal models, particularly transgenic mice, are extensively used in Alzheimer's disease (AD) research to emulate key disease hallmarks, such as amyloid plaques and neurofibrillary tangles formation. Although these models have contributed to our understanding of AD pathogenesis and can be helpful in testing potential therapeutic interventions, their reliability is dubious. While preclinical studies have shown promise, clinical trials often yield disappointing results, highlighting a notable gap and disparity between animal models and human AD pathology. Existing models frequently overlook early-stage human pathologies and other key AD characteristics, thereby limiting their application in identifying optimal therapeutic interventions. Enhancing model reliability necessitates rigorous study design, comprehensive behavioral evaluations, and biomarker utilization. Overall, a nuanced understanding of each model's neuropathology, its fidelity to human AD, and its limitations is essential for accurate interpretation and successful translation of findings. This article analyzes the discrepancies between animal models and human AD pathology that complicate the translation of findings from preclinical studies to clinical applications. We also delve into AD pathogenesis and attributes to propose a new perspective on this pathology and deliberate over the primary limitations of key experimental models. Additionally, we discuss several fundamental problems that may explain the translational failures and suggest some possible directions for more effective preclinical studies. [ABSTRACT FROM AUTHOR]

A hypothesis of Alzheimer's disease etiology is proposed describing how cellular stress induces excessive polyamine synthesis and recycling which can disrupt nucleoli. Polyamines are essential in nucleolar functions, such as RNA folding and ribonucleoprotein assembly. Changes in the nucleolar pool of anionic RNA and cationic polyamines acting as counterions can cause significant nucleolar dynamics. Polyamine synthesis reduces S-adenosylmethionine which, at low levels, triggers tau phosphorylation. Also, polyamine recycling reduces acetyl-CoA needed for acetylcholine, which is low in Alzheimer's disease. Extraordinary nucleolar expansion and/or contraction can disrupt epigenetic control in peri-nucleolar chromatin, such as chromosome 14 with the presenilin-1 gene; chromosome 21 with the amyloid precursor protein gene; chromosome 17 with the tau gene; chromosome 19 with the APOE4 gene; and the inactive X chromosome (Xi; aka "nucleolar satellite") with normally silent spermine synthase (polyamine synthesis) and spermidine/spermine-N1-acetyltransferase (polyamine recycling) alleles. Chromosomes 17, 19 and the Xi have high concentrations of Alu elements which can be transcribed by RNA polymerase III if positioned nucleosomes are displaced from the Alu elements. A sudden flood of Alu RNA transcripts can competitively bind nucleolin which is usually bound to Alu sequences in structural RNAs that stabilize the nucleolar heterochromatic shell. This Alu competition leads to loss of nucleolar integrity with leaking of nucleolar polyamines that cause aggregation of phosphorylated tau. The hypothesis was developed with key word searches (e.g., PubMed) using relevant terms (e.g., Alzheimer's, lupus, nucleolin) based on a systems biology approach and exploring autoimmune disease tautology, gaining synergistic insights from other diseases. [ABSTRACT FROM AUTHOR]

High dietary intake of saturated fatty acids is a suspected risk factor for neurodegenerative diseases, including Alzheimer's disease (AD). To decipher the causal link behind these associations, high-fat diets (HFD) have been repeatedly investigated in animal models. Preclinical studies allow full control over dietary composition, avoiding ethical concerns in clinical trials. The goal of the present article is to provide a narrative review of reports on HFD in animal models of AD. Eligibility criteria included mouse models of AD fed a HFD defined as > 35% of fat/weight and western diets containing > 1% cholesterol or > 15% sugar. MEDLINE and Embase databases were searched from 1946 to August 2022, and 32 preclinical studies were included in the review. HFD-induced obesity and metabolic disturbances such as insulin resistance and glucose intolerance have been replicated in most studies, but with methodological variability. Most studies have found an aggravating effect of HFD on brain Aβ pathology, whereas tau pathology has been much less studied, and results are more equivocal. While most reports show HFD-induced impairment on cognitive behavior, confounding factors may blur their interpretation. In summary, despite conflicting results, exposing rodents to diets highly enriched in saturated fat induces not only metabolic defects, but also cognitive impairment often accompanied by aggravated neuropathological markers, most notably Aβ burden. Although there are important variations between methods, particularly the lack of diet characterization, these studies collectively suggest that excessive intake of saturated fat should be avoided in order to lower the incidence of AD. [ABSTRACT FROM AUTHOR]

Background: The taxus chinensis fruit (TCF) shows promises in treatment of aging-related diseases such as Alzheimer's disease (AD). However, its related constituents and targets against AD have not been deciphered. Objective: This study was to uncover constituents and targets of TCF extracts against AD. Methods: An integrated approach including ultrasound extractions and constituent identification of TCF by UPLC-QE-MS/MS, target identification of constituents and AD by R data-mining from Pubchem, Drugbank and GEO databases, network construction, molecular docking and the ROC curve analysis was carried out. Results: We identified 250 compounds in TCF extracts, and obtained 3,231 known constituent targets and 5,326 differential expression genes of AD, and 988 intersection genes. Through the network construction and KEGG pathway analysis, 19 chemicals, 31 targets, and 11 biological pathways were obtained as core compounds, targets and pathways of TCF extracts against AD. Among these constituents, luteolin, oleic acid, gallic acid, baicalein, naringenin, lovastatin and rutin had obvious anti-AD effect. Molecular docking results further confirmed above results. The ROC AUC values of about 87% of these core targets of TCF extracts was greater than 0.5 in the two GEO chips of AD, especially 10 targets with ROC AUC values greater than 0.7, such as BCL2, CASP7, NFKBIA, HMOX1, CDK2, LDLR, RELA, and CCL2, which mainly referred to neuron apoptosis, response to oxidative stress and inflammation, fibroblast proliferation, etc. Conclusions: The TCF extracts have diverse active compounds that can act on the diagnostic genes of AD, which deserve further in-depth study. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is a fatal and debilitating neurodegenerative disease. Sphingosine-1-phosphate receptor 2 (S1PR2), one of the receptors of S1P, is a key regulatory factor for various diseases. Objective: This study aimed to explore the role and possible mechanism of S1PR2 in AD. Methods: S1PR2 expression in the AD mice was detected, and after intervening S1PR2 expression with sh-S1PR2 in AD mice, the behavioral changes, pathological lesions of the hippocampus, autophagy level, and AKT/mTOR pathway activation were analyzed. Furthermore, SH-SY5Y cells were induced by Aβ25-35 to construct an AD cell model, and the effects of sh-S1PR2 on proliferation, apoptosis, autophagy, and AKT/mTOR pathway of AD cells were investigated. In addition, the effects of pathway inhibitor rapamycin on model cells were further analyzed. Results: The expression of S1PR2 was significantly increased in AD mice, the sh-S1PR2 significantly improved behavioral dysfunction, alleviated pathological injury of the hippocampus, increased the number of neurons, and inhibited Aβ production and p-tau expression, showing a positive effect on the AD pathology. In addition, silencing of S1PR2 expression significantly promoted the autophagy level and inhibited the activation of the AKT/mTOR pathway in AD model mice. In vitro experiments further confirmed that sh-S1PR2 promoted cell proliferation, inhibited apoptosis, relieved cytopathology, promoted autophagy, and inhibited the activation of the AKT/mTOR pathway in the cell model. The use of rapamycin further confirmed the role of AKT/mTOR pathway-mediated autophagy in the regulation of AD by S1PR2. Conclusion: S1PR2 promoted AD pathogenesis by inhibiting autophagy through the activation of AKT/mTOR pathway. [ABSTRACT FROM AUTHOR]

There are several implications of the surge in the incidence of pandemics and epidemics in the last decades. COVID-19 being the most remarkable one, showed the vulnerability of patients with neurodegenerative diseases like Alzheimer's disease (AD). This review studies the pathological interlinks and triggering factors between the two illnesses and proposes a multifactorial pathway of AD causation due to COVID-19. The article evaluates and describes all the postulated hypotheses which explain the etiology and possible pathogenesis of the disease in four domains: Inflammation & Neurobiochemical interactions, Oxidative Stress, Genetic Factors, and Social Isolation. We believe that a probable hypothesis of an underlying cause of AD after COVID-19 infection could be the interplay of all these factors. [ABSTRACT FROM AUTHOR]

Diet is an important nonpharmacological risk-modifying factor for Alzheimer's disease (AD). The approaches used here to assess diet's role in the risk of AD include multi-country ecological studies, prospective and cross-sectional observational studies, and laboratory studies. Ecological studies have identified fat, meat, and obesity from high-energy diets as important risk factors for AD and reported that AD rates peak about 15–20 years after national dietary changes. Observational studies have compared the Western dietary pattern with those of the Dietary Approaches to Stop Hypertension (DASH), Mediterranean (MedDi), and Mediterranean–DASH Intervention for Neurodegenerative Delay (MIND) diets. Those studies identified AD risk factors including higher consumption of saturated and total fats, meat, and ultraprocessed foods and a lower risk of AD with higher consumption of fruits, legumes, nuts, omega-3 fatty acids, vegetables, and whole grains. Diet-induced factors associated with a significant risk of AD include inflammation, insulin resistance, oxidative stress, elevated homocysteine, dietary advanced glycation end products, and trimethylamine N-oxide. The molecular mechanisms by which dietary bioactive components and specific foods affect risk of AD are discussed. Given most countries' entrenched food supply systems, the upward trends of AD rates would be hard to reverse. However, for people willing and able, a low–animal product diet with plenty of anti-inflammatory, low–glycemic load foods may be helpful. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the main cause of dementia in older age. The prevalence of AD is growing worldwide, causing a tremendous burden to societies and families. Due to the complexity of its pathogenesis, the current treatment of AD is not satisfactory, and drugs acting on a single target may not prevent AD progression. This review summarizes the multi-target pharmacological effects of thiazolidinediones (TZDs) on AD. TZDs act as peroxisome proliferator-activated receptor gamma (PPARγ) agonists and long-chain acyl-CoA synthetase family member 4 (ACSL4) inhibitors. TZDs ameliorated neuroinflammation and ferroptosis in preclinical models of AD. Here, we discussed recent findings from clinical trials of pioglitazone in the treatment of AD, ischemic stroke, and atherosclerosis. We also dissected the major limitations in the clinical application of pioglitazone and explained the potential benefit of pioglitazone in AD. We recommend the use of pioglitazone to prevent cognitive decline and lower AD risk in a specific group of patients. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is characterized by the progressive degeneration of neuronal cells. With the increase in aged population, there is a prevalence of irreversible neurodegenerative changes, causing a significant mental, social, and economic burden globally. The factors contributing to AD are multidimensional, highly complex, and not completely understood. However, it is widely known that aging, neuroinflammation, and excessive production of reactive oxygen species (ROS), along with other free radicals, substantially contribute to oxidative stress and cell death, which are inextricably linked. While oxidative stress is undeniably important in AD, limiting free radicals and ROS levels is an intriguing and potential strategy for deferring the process of neurodegeneration and alleviating associated symptoms. Therapeutic compounds from natural sources have recently become increasingly accepted and have been effectively studied for AD treatment. These phytocompounds are widely available and a multitude of holistic therapeutic efficiencies for treating AD owing to their antioxidant, anti-inflammatory, and biological activities. Some of these compounds also function by stimulating cholinergic neurotransmission, facilitating the suppression of beta-site amyloid precursor protein-cleaving enzyme 1, α-synuclein, and monoamine oxidase proteins, and deterring the occurrence of AD. Additionally, various phenolic, flavonoid, and terpenoid phytocompounds have been extensively described as potential palliative agents for AD progression. Preclinical studies have shown their involvement in modulating the cellular redox balance and minimizing ROS formation, displaying them as antioxidant agents with neuroprotective abilities. This review emphasizes the mechanistic role of natural products in the treatment of AD and discusses the various pathological hypotheses proposed for AD. [ABSTRACT FROM AUTHOR]

Biliverdin reductase-A (BVR-A) is a pleiotropic enzyme and plays pivotal role in the antioxidant defense against free radicals as well as in cell homeostasis. Together with heme oxygenase, BVR-A forms a powerful system involved in the cell stress response during neurodegenerative disorders including Alzheimer's disease (AD), whereas due to the serine/threonine/tyrosine kinase activity the enzyme regulates glucose metabolism and cell proliferation. In this paper, we report results that demonstrate BVR-A undergoes post-translational oxidative and nitrosative modifications in the hippocampus, but not cerebellum, of subjects with AD and amnestic mild cognitive impairment (MCI). A significant increase of nitrated BVR-A was demonstrated only in AD and MCI hippocampi, whereas no significant modifications were found in cerebellar tissue. In addition, a significant reduction in protein carbonyl-derivatives of BVR-A was found in both AD and MCI hippocampi (15% and 18%, respectively). Biliverdin reductase-bound 4-hydroxynonenals were not modified in hippocampi and cerebella from AD and MCI subjects. These results supported the hypothesis of a prevalence of nitrosative stress-induced modifications on BVR-A structure, and this evidence was confirmed by a significant upregulation of inducible nitric oxide synthase in hippocampal tissue of subjects with AD and MCI that was not present in cerebellum. In conclusion, nitrosative stress-induced modifications on hippocampal BVR-A are an early event in the pathogenesis of AD since they appear also in MCI subjects and could contribute to the antioxidant and metabolic derangement characteristic of these neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is histopathologically characterized by the presence of senile plaques, neurofibrillary tangles, and synapse loss. The main component of senile plaques is amyloid β-peptide (Aβ), which has been shown to induce oxidative stress in in vitro and in vivo studies. AD is associated with elevated levels of oxidative damage in brain and peripheral lymphocytes. Further Aβ has been found to be accumulated in mitochondria, which might contribute to the reported alterations in the mitochondrial morphology, and impaired mitochondrial energy metabolism in AD brain. Biomarkers are desperately needed for earlier diagnosis of AD and to monitor efficacy of new therapies. Hence, in the present study we show that markers of oxidative damage are elevated in mitochondria isolated from AD lymphocytes suggesting that these oxidative stress indices potentially could serve as a viable biomarker for AD. [ABSTRACT FROM AUTHOR]

Amyloid â-peptide (Aâ) is a 42-43 amino acid peptide known to accumulate in Alzheimer's disease (AD) brain. We previously reported that the neurotoxicity caused by Aâ is a result of its associated free radicals, which can play an important role in generating oxidative stress. Aâ(25-35)-associated oxidative stress-induced neuronal death in vitro is well established by many laboratories, including ours. However, the oxidative stress-induced by the full-length [Aâ(1-42)] peptide is not well investigated.  The protective effect of antioxidant vitamin E in full-length peptide-induced oxidative stress also has not been reported.  Here, we report that the increased protein oxidation, reactive oxygen species (ROS) formation, and neurotoxicity induced by Aâ(1-42) in primary rat embryonic hippocampal neuronal culture are prevented by the free radical scavenger and antioxidant vitamin E.  To test the hypothesis that vitamin E's protective effect may be due to inhibition of fibril formation, electron microscopy studies were undertaken. Vitamin E does not inhibit Aâ(1-42) fibril formation, suggesting that the neuroprotection afforded by this molecule stems from other processes, most probably through the scavenging of Ab-associated free radicals.  These results may have implications on the treatment of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

After over 50 years of use, lithium-salts remain the first-line therapy for the management of bipolar disorder. Throughout this period, the potential for lithium salts has been extensively studied and numerous data favor its use in the treatment of neurodegenerative disorders such as Alzheimer's disease (AD). We reviewed existing evidence gathered from clinical case reports and studies on the effect of lithium on neuropsychological symptoms of AD and as a disease-modifying treatment acting on cognitive symptoms. The review summarizes the molecular pathways, involving GSK-3β inhibition and neuroprotection, through which lithium is proposed to exert its effect. Limitations to its current use in AD are discussed and future perspectives as a potential treatment option for AD are considered in regard to ongoing clinical trials using different forms of lithium. [ABSTRACT FROM AUTHOR]

Malignant brain aging corresponds to accelerated age-related declines in brain functions eventually derailing the self-sustaining forces that govern independent vitality. Malignant brain aging establishes the path toward dementing neurodegeneration, including Alzheimer's disease (AD). The full spectrum of AD includes progressive dysfunction of neurons, oligodendrocytes, astrocytes, microglia, and the microvascular systems, and is mechanistically driven by insulin and insulin-like growth factor (IGF) deficiencies and resistances with accompanying deficits in energy balance, increased cellular stress, inflammation, and impaired perfusion, mimicking the core features of diabetes mellitus. The underlying pathophysiological derangements result in mitochondrial dysfunction, abnormal protein aggregation, increased oxidative and endoplasmic reticulum stress, aberrant autophagy, and abnormal post-translational modification of proteins, all of which are signature features of both AD and dysregulated insulin/IGF-1-mechanistic target of rapamycin (mTOR) signaling. This article connects the dots from benign to malignant aging to neurodegeneration by reviewing the salient pathologies associated with initially adaptive and later dysfunctional mTOR signaling in the brain. Effective therapeutic and preventive measures must be two-pronged and designed to 1) address complex and shifting impairments in mTOR signaling through the re-purpose of effective anti-diabetes therapeutics that target the brain, and 2) minimize the impact of extrinsic mediators of benign to malignant aging transitions, e.g., inflammatory states, obesity, systemic insulin resistance diseases, and repeated bouts of general anesthesia, by minimizing exposures or implementing neuroprotective measures. [ABSTRACT FROM AUTHOR]

Background: In the digital era monitoring the patient's health status is more effective and consistent with smart healthcare systems. Smart health care facilitates secure and reliable maintenance of patient data. Sensors, machine learning algorithms, Internet of things, and wireless technology has led to the development of Artificial Intelligence-driven Internet of Things models. Objective: This research study proposes an Artificial Intelligence driven Internet of Things model to monitor Alzheimer's disease patient condition. The proposed Smart health care system to monitor and alert caregivers of Alzheimer's disease patients includes different modules to monitor the health parameters of the patients. This study implements the detection of fall episodes using an artificial intelligence model in Python. Methods: The fall detection model is implemented with data acquired from the IMU open dataset. The ensemble machine learning algorithm AdaBoost performs classification of the fall episode and daily life activity using the feature set of each data sample. The common machine learning classification algorithms are compared for their performance on the IMU fall dataset. Results: AdaBoost ensemble classifier exhibits high performance compared to the other machine learning algorithms. The AdaBoost classifier shows 100% accuracy for the IMU dataset. This high accuracy is achieved as multiple weak learners in the ensemble model classify the data samples in the test data accurately. Conclusions: This study proposes a smart healthcare system for monitoring Alzheimer's disease patients. The proposed model can alert the caregiver in case of fall detection via mobile applications installed in smart devices. [ABSTRACT FROM AUTHOR]

Sporadic Alzheimer's disease (AD) is a complex, multifactorial disease. We should therefore expect to find many factors involved in its causation. The known neuropathology seen at autopsy in patients dying with AD is not consistently seen in all patients with AD and is sometimes seen in patients without dementia. This suggests that patients follow different paths to AD, with different people having slightly different combinations of predisposing physical, chemical and biologic risk factors, and varying neuropathology. This review summarizes what is known of the biologic and chemical predisposing factors and features in AD. We postulate that, underlying the neuropathology of AD is a progressive failure of neurons, with advancing age or other morbidity, to rid themselves of entropy, i.e., the disordered state resulting from brain metabolism. Understanding the diverse causes of AD may allow the development of new therapies targeted at blocking the paths that lead to dementia in each subset of patients. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is a neurodegenerative and progressive disorder with no cure and constant failures in clinical trials. The main AD hallmarks are amyloid-β (Aβ) plaques, neurofibrillary tangles, and neurodegeneration. However, many other events have been implicated in AD pathogenesis. Epilepsy is a common comorbidity of AD and there is important evidence indicating a bidirectional link between these two disorders. Some studies suggest that disturbed insulin signaling might play an important role in this connection. Objective: To understand the effects of neuronal insulin resistance in the AD-epilepsy link. Methods: We submitted the streptozotocin (STZ) induced rat AD Model (icv-STZ AD) to an acute acoustic stimulus (AS), a known trigger of seizures. We also assessed animals' performance in the memory test, the Morris water maze and the neuronal activity (c-Fos protein) induced by a single audiogenic seizure in regions that express high levels of insulin receptors. Results: We identified significant memory impairment and seizures in 71.43% of all icv-STZ/AS rats, in contrast to 22.22% of the vehicle group. After seizures, icv-STZ/AS rats presented higher number of c-Fos immunopositive cells in hippocampal, cortical, and hypothalamic regions. Conclusion: STZ may facilitate seizure generation and propagation by impairment of neuronal function, especially in regions that express high levels of insulin receptors. The data presented here indicate that the icv-STZ AD model might have implications not only for AD, but also for epilepsy. Finally, impaired insulin signaling might be one of the mechanisms by which AD presents a bidirectional connection to epilepsy. [ABSTRACT FROM AUTHOR]

Citrate synthase is a key mitochondrial enzyme that utilizes acetyl-CoA and oxaloacetate to form citrate in the mitochondrial membrane, which participates in energy production in the TCA cycle and linked to the electron transport chain. Citrate transports through a citrate malate pump and synthesizes acetyl-CoA and acetylcholine (ACh) in neuronal cytoplasm. In a mature brain, acetyl-CoA is mainly utilized for ACh synthesis and is responsible for memory and cognition. Studies have shown low citrate synthase in different regions of brain in Alzheimer's disease (AD) patients, which reduces mitochondrial citrate, cellular bioenergetics, neurocytoplasmic citrate, acetyl-CoA, and ACh synthesis. Reduced citrate mediated low energy favors amyloid-β (Aβ) aggregation. Citrate inhibits Aβ25–35 and Aβ1–40 aggregation in vitro. Hence, citrate can be a better therapeutic option for AD by improving cellular energy and ACh synthesis, and inhibiting Aβ aggregation, which prevents tau hyperphosphorylation and glycogen synthase kinase-3 beta. Therefore, we need clinical studies if citrate reverses Aβ deposition by balancing mitochondrial energy pathway and neurocytoplasmic ACh production. Furthermore, in AD's silent phase pathophysiology, when neuronal cells are highly active, they shift ATP utilization from oxidative phosphorylation to glycolysis and prevent excessive generation of hydrogen peroxide and reactive oxygen species (oxidative stress) as neuroprotective action, which upregulates glucose transporter-3 (GLUT3) and pyruvate dehydrogenase kinase-3 (PDK3). PDK3 inhibits pyruvate dehydrogenase, which decreases mitochondrial-acetyl-CoA, citrate, and cellular bioenergetics, and decreases neurocytoplasmic citrate, acetyl-CoA, and ACh formation, thus initiating AD pathophysiology. Therefore, GLUT3 and PDK3 can be biomarkers for silent phase of AD. [ABSTRACT FROM AUTHOR]

Background: Centella asiatica (L.) (C. asiatica) is commonly known in South East and South East Asia communities for its nutritional and medicinal benefits. Besides being traditionally used to enhance memory and accelerate wound healing, its phytochemicals have been extensively documented for their neuroprotective, neuroregenerative, and antioxidant properties. Objective: The present study aims to investigate the effects of a standardized raw extract of C. asiatica (RECA) on hydrogen peroxide (H2O2)-induced oxidative stress and apoptotic death in neural-like cells derived from mouse embryonic stem (ES) cell line. Methods: A transgenic mouse ES cell (46C) was differentiated into neural-like cells using 4-/4+ protocol with addition of all-trans retinoic acid. These cells were then exposed to H2O2 for 24 h. The effects of RECA on H2O2-induced neural-like cells were assessed through cell viability, apoptosis, and reactive oxygen species (ROS) assays, as well as neurite length measurement. The gene expression levels of neuronal-specific and antioxidant markers were assessed by RT-qPCR analysis. Results: Pre-treatment with H2O2 for 24 hours, in a dose-dependent manner, damaged neural-like cells as marked by a decrease in cell viability, substantial increase in intracellular ROS accumulation, and increase in apoptotic rate compared to untreated cells. These cells were used to treat with RECA. Treatment with RECA for 48 h remarkably restored cell survival and promoted neurite outgrowth in the H2O2- damaged neurons by increasing cell viability and decreasing ROS activity. RT-qPCR analysis revealed that RECA upregulated the level of antioxidant genes such as thioredoxin-1 (Trx-1) and heme oxygenase-1 (HO-1) of treated cells, as well as the expression level of neuronal-specific markers such as Tuj1 and MAP2 genes, suggesting their contribution in neuritogenic effect. Conclusion: Our findings indicate that RECA promotes neuroregenerative effects and exhibits antioxidant properties, suggesting a valuable synergistic activity of its phytochemical constituents, thus, making the extract a promising candidate in preventing or treating oxidative stress-associated Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Dementia is understood to arise from a mixed etiology, enveloping chronic inflammatory and vascular impacts on the brain, driven by a constellation of modifiable risk factors which are largely mediated by lifestyle-related behaviors. These risk factors manifest over a prolonged preclinical period and account for up to 40% of the population attributable risk for dementia, representing viable targets for early interventions aimed at abating disease onset and progression. Here we outline the protocol for a 12-week randomized control trial (RCT) of a multimodal Lifestyle Intervention Study for Dementia Risk Reduction (LEISURE), with longitudinal follow-up at 6-months and 24-months post-intervention. This trial integrates exercise, diet, sleep, and mindfulness to simultaneously target multiple different etiopathogenetic mechanisms and their interplay in a healthy older adult population (aged 50–85 years), and assesses dementia risk reduction as the primary endpoint. The LEISURE study is located in the Sunshine Coast region of Australia, which has one of the nation's highest proportions of adults aged over 50 years (36.4%), and corresponding dementia prevalence. This trial is novel in its inclusion of mindfulness and sleep as multidomain lifestyle targets, and in its comprehensive suite of secondary outcomes (based on psychological, physical health, sleep activity, and cognitive data) as well as exploratory neuroimaging (magnetic resonance imaging and electroencephalography) and molecular biology measures. These measures will provide greater insights into the brain-behavioral underpinnings of dementia prevention, as well as the predictors and impacts of the proposed lifestyle intervention. The LEISURE study was prospectively registered (ACTRN12620000054910) on 19 January 2020. [ABSTRACT FROM AUTHOR]

Background: There is limited information about gene-environment interaction on the occurrence and the progression of Alzheimer's disease. Objective: To explore the effect of environmental low-dose cadmium (Cd) exposure on the progress of Alzheimer's disease and the underlining mechanism. Methods: We administered 1 mg/L, 10 mg/L cadmium chloride (treated groups), and water (control group) to C57BL/6J and APP/PS1 mice through drinking water, from one week before mating, until the offspring were sacrificed at 6 months of age. The behaviors, Cd level, blood-brain barrier (BBB) leakage, Aβ1-42 deposition, and inflammation expression were evaluated in these mice. Results: Mice of both genotypes had similar blood Cd levels after exposure to the same dose of Cd. The toxic effects of Cd on the two genotypes differed little in terms of neuronal histomorphology and BBB permeability. Cd caused a series of pathological morphological changes in the mouse brains and more fluorescent dye leakage at higher doses. Furthermore, the APP/PS1 mice had more severe damage than the C57BL/6J mice, based on the following five criteria. They were increasing anxiety-like behavior and chaos movement, spatial reference memory damage, Aβ plaque deposition in mouse brains, increasing microglia expression in the brain, and IL-6 higher expression in the cortex and in the serum. Conclusion: Low-dose Cd exposure for 6 months increases Aβ plaque deposition and BBB permeability, exacerbates inflammatory responses, and activates microglia, in APP/PS1 mice. APP/PS1 gene-environmental Cd interaction aggravates the progression of Alzheimer's disease in mice. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive degenerative disease of the nervous system (CNS) with an insidious onset. Clinically, it is characterized by a full range of dementia manifestations including memory impairment, aphasia, loss of speech, loss of use, loss of recognition, impairment of visuospatial skills, and impairment of executive function, as well as changes in personality and behavior. The exact cause of AD has not yet been identified. Nevertheless, modern research indicates that genetic factors contribute to 70% of human's risk of AD. Apolipoprotein (APOE) accounts for up to 90% of the genetic predisposition. APOE is a crucial gene that cannot be overstated. In addition, innate immunity plays a significant role in the etiology and treatment of AD. Understanding the different subtypes of APOE and their interconnections is of paramount importance. APOE and innate immunity, along with their relationship to AD, are primary research motivators for in-depth research and clinical trials. The exploration of novel technologies has led to an increasing trend in the study of AD at the cellular and molecular levels and continues to make more breakthroughs and progress. As of today, there is no effective treatment available for AD around the world. This paper aims to summarize and analyze the role of APOE and innate immunity, as well as development trends in recent years. It is anticipated that APOE and innate immunity will provide a breakthrough for humans to hinder AD progression in the near future. [ABSTRACT FROM AUTHOR]

The pathogenesis of Alzheimer's disease (AD) is complicated and involves multiple contributing factors. Mounting evidence supports the concept that AD is an age-related metabolic neurodegenerative disease mediated in part by brain insulin resistance, and sharing similar metabolic dysfunctions and brain pathological characteristics that occur in type 2 diabetes mellitus (T2DM) and other insulin resistance disorders. Brain insulin signal pathway is a major regulator of branched-chain amino acid (BCAA) metabolism. In the past several years, impaired BCAA metabolism has been described in several insulin resistant states such as obesity, T2DM and cardiovascular disease. Disrupted BCAA metabolism leading to elevation in circulating BCAAs and related metabolites is an early metabolic phenotype of insulin resistance and correlated with future onset of T2DM. Brain is a major site for BCAA metabolism. BCAAs play pivotal roles in normal brain function, especially in signal transduction, nitrogen homeostasis, and neurotransmitter cycling. Evidence from animal models and patients support the involvement of BCAA dysmetabolism in neurodegenerative diseases including Huntington's disease, Parkinson's disease, and maple syrup urine disease. More recently, growing studies have revealed altered BCAA metabolism in AD, but the relationship between them is poorly understood. This review is focused on the recent findings regarding BCAA metabolism and its role in AD. Moreover, we will explore how impaired BCAA metabolism influences brain function and participates in the pathogenesis of AD. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is mainly characterized by cognitive deficits. Although many studies have been devoted to developing disease-modifying therapies, there has been no effective therapy until now. However, dietary interventions may be a potential strategy to treat AD. The ketogenic diet (KD) is a high-fat and low-carbohydrate diet with adequate protein. KD increases the levels of ketone bodies, providing an alternative energy source when there is not sufficient energy supply because of impaired glucose metabolism. Accumulating preclinical and clinical studies have shown that a KD is beneficial to AD. The potential underlying mechanisms include improved mitochondrial function, optimization of gut microbiota composition, and reduced neuroinflammation and oxidative stress. The review provides an update on clinical and preclinical research on the effects of KD or medium-chain triglyceride supplementation on symptoms and pathophysiology in AD. We also detail the potential mechanisms of KD, involving amyloid and tau proteins, neuroinflammation, gut microbiota, oxidative stress, and brain metabolism. We aimed to determine the function of the KD in AD and outline important aspects of the mechanism, providing a reference for the implementation of the KD as a potential therapeutic strategy for AD. [ABSTRACT FROM AUTHOR]