Causes versus effects: the increasing complexities of Alzheimer's disease pathogenesis.
Ontology highlight
ABSTRACT:
SUBMITTER: Mondragon-Rodriguez S
PROVIDER: S-EPMC2922904 | biostudies-literature | 2010 May
REPOSITORIES: biostudies-literature
Publications
Causes versus effects: the increasing complexities of Alzheimer's disease pathogenesis.
Mondragón-Rodríguez Siddhartha S Basurto-Islas Gustavo G Lee Hyoung-gon HG Perry George G Zhu Xiongwei X Castellani Rudy J RJ Smith Mark A MA
Expert review of neurotherapeutics 20100501 5
Amyloid plaques and neurofibrillary tangles are the hallmarks of Alzheimer's disease and have been the focus of disease etiology and pathogenesis. However, in the larger picture of a complex disease, the precise etiology of the lesions per se, as well as the clinical disease, remain to be defined. In this regard, to date no single process has been identified as a useful target and treatment efforts have shown no meaningful progress. Therefore, alternative ideas that may lead to new and effective ...[more]
Similar Datasets
Project description:Ferrets are widely employed to study the pathogenicity, transmissibility, and tropism of influenza viruses. However, inherent variations in inoculation methods, sampling schemes, and experimental designs are often overlooked when contextualizing or aggregating data between laboratories, leading to potential confusion or misinterpretation of results. Here, we provide a comprehensive overview of parameters to consider when planning an experiment using ferrets, collecting data from the experiment, and placing results in context with previously performed studies. This review offers information that is of particular importance for researchers in the field who rely on ferret data but do not perform the experiments themselves. Furthermore, this review highlights the breadth of experimental designs and techniques currently available to study influenza viruses in this model, underscoring the wide heterogeneity of protocols currently used for ferret studies while demonstrating the wealth of information which can benefit risk assessments of emerging influenza viruses.
| S-EPMC4981671 | biostudies-other
Project description:The emergence of complement as an important player in normal brain development and pathological remodelling has come as a major surprise to most scientists working in neuroscience and almost all those working in complement. That a system, evolved to protect the host against infection, should have these unanticipated roles has forced a rethink about what complement might be doing in the brain in health and disease, where it is coming from, and whether we can, or indeed should, manipulate complement in the brain to improve function or restore homeostasis. Complement has been implicated in diverse neurological and neuropsychiatric diseases well reviewed elsewhere, from depression through epilepsy to demyelination and dementia, in most complement drives inflammation to exacerbate the disease. Here, I will focus on just one disease, the most common cause of dementia, Alzheimer's disease. I will briefly review the current understanding of what complement does in the normal brain, noting, in particular, the many gaps in understanding, then describe how complement may influence the genesis and progression of pathology in Alzheimer's disease. Finally, I will discuss the problems and pitfalls of therapeutic inhibition of complement in the Alzheimer brain.
| S-EPMC5794825 | biostudies-literature
Project description:We review the genetic risk factors for late-onset Alzheimer's disease (AD) and their role in AD pathogenesis. More recent advances in understanding of the human genome-technologic advances in methods to analyze millions of polymorphisms in thousands of subjects-have revealed new genes associated with AD risk, including ABCA7, BIN1, CASS4, CD33, CD2AP, CELF1, CLU, CR1, DSG2, EPHA1, FERMT2, HLA-DRB5-DBR1, INPP5D, MS4A, MEF2C, NME8, PICALM, PTK2B, SLC24H4-RIN3, SORL1, and ZCWPW1. Emerging technologies to analyze the entire genome in large data sets have also revealed coding variants that increase AD risk: PLD3 and TREM2. We review the relationship between these AD risk genes and the cellular and neuropathologic features of AD. Understanding the mechanisms underlying the association of these genes with risk for disease will provide the most meaningful targets for therapeutic development to date.
| S-EPMC4234692 | biostudies-literature
Project description:BackgroundSelective modulation of different A? products of an intramembrane protease ?-secretase, could be the most promising strategy for development of effective therapies for Alzheimer's disease. We describe how different drug-candidates can modulate ?-secretase activity in cells, by studying how DAPT affects changes in ?-secretase activity caused by gradual increase in A? metabolism.ResultsA? 1-40 secretion in the presence of DAPT shows biphasic activation-inhibition dose-response curves. The biphasic mechanism is a result of modulation of ?-secretase activity by multiple substrate and inhibitor molecules that can bind to the enzyme simultaneously. The activation is due to an increase in ?-secretase's kinetic affinity for its substrate, which can make the enzyme increasingly more saturated with otherwise sub-saturating substrate. The noncompetitive inhibition that prevails at the saturating substrate can decrease the maximal activity. The synergistic activation-inhibition effects can drastically reduce ?-secretase's capacity to process its physiological substrates. This reduction makes the biphasic inhibitors exceptionally prone to the toxic side-effects and potentially pathogenic. Without the modulation, ?-secretase activity on it physiological substrate in cells is only 14% of its maximal activity, and far below the saturation.SignificancePresented mechanism can explain why moderate inhibition of ?-secretase cannot lead to effective therapies, the pharmacodynamics of A?-rebound phenomenon, and recent failures of the major drug-candidates such as semagacestat. Novel improved drug-candidates can be prepared from competitive inhibitors that can bind to different sites on ?-secretase simultaneously. Our quantitative analysis of the catalytic capacity can facilitate the future studies of the therapeutic potential of ?-secretase and the pathogenic changes in A? metabolism.
| S-EPMC3538728 | biostudies-literature
Project description:Alzheimer's disease (AD), a common neurodegenerative disease in the elderly and the most prevalent cause of dementia, is characterized by progressive cognitive impairment. The prevalence of AD continues to increase worldwide, becoming a great healthcare challenge of the twenty-first century. In the more than 110 years since AD was discovered, many related pathogenic mechanisms have been proposed, and the most recognized hypotheses are the amyloid and tau hypotheses. However, almost all clinical trials targeting these mechanisms have not identified any effective methods to treat AD. Scientists are gradually moving away from the simple assumption, as proposed in the original amyloid hypothesis, to new theories of pathogenesis, including gamma oscillations, prion transmission, cerebral vasoconstriction, growth hormone secretagogue receptor 1α (GHSR1α)-mediated mechanism, and infection. To place these findings in context, we first reviewed the neuropathology of AD and further discussed new insights in the pathogenesis of AD.
| S-EPMC6965067 | biostudies-literature
Project description:A recent study suggested that insulin resistance may play a central role in the pathogenesis of Alzheimer's disease (AD). In this regard, it is of note that upregulation of plasma adiponectin (APN), a benign adipokine that sensitizes the insulin receptor signaling pathway and suppresses inflammation, has recently been associated with the severities of amyloid deposits and cognitive deficits in the elderly, suggesting that APN may enhance the risk of AD. These results are unanticipated because AD has been linked to type II diabetes and other metabolic disorders in which hypoadiponectinemia has been firmly established, and because APN ameliorated neuropathological features in a mouse model of neurodegeneration. Therefore, the objective of this study is to discuss the possible mechanisms underlying the biological actions of APN in the context of AD. Given that insulin receptor signaling is required for normal function of the nervous system, we predict that APN may be upregulated to compensate for compromised activity of the insulin receptor signaling pathway. However, increased APN might be sequestered by tau in the brain, leading to neurotoxic protein aggregation in AD. Alternatively, misfolding of APN may result in downregulation of the insulin/APN signal transduction network, leading to decreased neuroprotective and neurotrophic activities. Thus, it is possible that both 'gain of function' and 'loss of function' of APN may underlie synaptic dysfunction and neuronal cell death in AD. Such a unique biological mechanism underlying APN function in AD may require a novel therapeutic strategy that is distinct from previous treatment for metabolic disorders.
| S-EPMC5553221 | biostudies-other
Project description:Insurmountable evidence has demonstrated a strong association between Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA), along with various other cerebrovascular diseases. One form of CAA, which is the accumulation of amyloid-beta peptides (A?) along cerebral vessel walls, impairs perivascular drainage pathways and contributes to cerebrovascular dysfunction in AD. To date, CAA research has been primarily focused on arterial A?, while the accumulation of A? in veins and venules were to a lesser extent. In this review, we describe preclinical models and clinical studies supporting the presence of venular amyloid and potential downstream pathological mechanisms that affect the cerebrovasculature in AD. Venous collagenosis, impaired cerebrovascular pulsatility, and enlarged perivascular spaces are exacerbated by venular amyloid and increase A? deposition, potentially through impaired perivascular clearance. Gaining a comprehensive understanding of the mechanisms involved in venular A? deposition and associated pathologies will give insight to how CAA contributes to AD and its association with AD-related cerebrovascular disease. Lastly, we suggest that special consideration should be made to develop A?-targeted therapeutics that remove vascular amyloid and address cerebrovascular dysfunction in AD.
| S-EPMC7139584 | biostudies-literature
Project description:Protein aggregation is common to dozens of diseases including prionoses, diabetes, Parkinson's and Alzheimer's. Over the past 15 years, there has been a paradigm shift in understanding the structural basis for these proteinopathies. Precedent for this shift has come from investigation of soluble A? oligomers (A?Os), toxins now widely regarded as instigating neuron damage leading to Alzheimer's dementia. Toxic A?Os accumulate in AD brain and constitute long-lived alternatives to the disease-defining A? fibrils deposited in amyloid plaques. Key experiments using fibril-free A?O solutions demonstrated that while A? is essential for memory loss, the fibrillar A? in amyloid deposits is not the agent. The AD-like cellular pathologies induced by A?Os suggest their impact provides a unifying mechanism for AD pathogenesis, explaining why early stage disease is specific for memory and accounting for major facets of AD neuropathology. Alternative ideas for triggering mechanisms are being actively investigated. Some research favors insertion of A?Os into membrane, while other evidence supports ligand-like accumulation at particular synapses. Over a dozen candidate toxin receptors have been proposed. A?O binding triggers a redistribution of critical synaptic proteins and induces hyperactivity in metabotropic and ionotropic glutamate receptors. This leads to Ca(2+) overload and instigates major facets of AD neuropathology, including tau hyperphosphorylation, insulin resistance, oxidative stress, and synapse loss. Because different species of A?Os have been identified, a remaining question is which oligomer is the major pathogenic culprit. The possibility has been raised that more than one species plays a role. Despite some key unknowns, the clinical relevance of A?Os has been established, and new studies are beginning to point to co-morbidities such as diabetes and hypercholesterolemia as etiological factors. Because pathogenic A?Os appear early in the disease, they offer appealing targets for therapeutics and diagnostics. Promising therapeutic strategies include use of CNS insulin signaling enhancers to protect against the presence of toxins and elimination of the toxins through use of highly specific A?O antibodies. An AD-dependent accumulation of A?Os in CSF suggests their potential use as biomarkers and new A?O probes are opening the door to brain imaging. Overall, current evidence indicates that A? oligomers provide a substantive molecular basis for the cause, treatment and diagnosis of Alzheimer's disease.
| S-EPMC4390393 | biostudies-literature
Project description:BackgroundAlzheimer's disease (AD) is an extremely complicated neurodegenerative disorder, which accounts for almost 80 % of all dementia diagnoses. Due to the limited treatment efficacy, it is imperative for AD patients to take reliable prevention and diagnosis measures. This study aimed to explore potential biomarkers for AD.MethodsGSE63060 and GSE140829 datasets were downloaded from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEG) between AD and control groups in GSE63060 were analyzed using the limma software package. The mRNA expression data in GSE140829 was analyzed using weighted gene co-expression network analysis (WGCNA) function package. Protein functional connections and interactions were analyzed using STRING and key genes were screened based on the degree and Maximal Clique Centrality (MCC) algorithm. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed on the key genes.ResultsThere were 65 DEGs in GSE63060 dataset between AD patients and healthy controls. In GSE140829 dataset, the turquoise module was related to the pathogenesis of AD, among which, 42 genes were also differentially expressed in GSE63060 dataset. Then 8 genes, RPS17, RPL26, RPS3A, RPS25, EEF1B2, COX7C, HINT1 and SNRPG, were finally screened. Additionally, these 42 genes were significantly enriched in 12 KEGG pathways and 119 GO terms.ConclusionsIn conclusion, RPS17, RPL26, RPS3A, RPS25, EEF1B2, COX7C, HINT1 and SNRPG, were potential biomarkers for pathogenesis of AD, which should be further explored in AD in the future.
| S-EPMC8259215 | biostudies-literature