ABSTRACT
Alzheimer's disease (AD) is a recognized international public health crisis. There is an urgent need for public and private funding agencies around the world to coordinate funding strategies and leverage existing resources to enhance and expand support of AD research. To capture and compare their existing investments in AD research and research-related resources, major funding organizations are starting to utilize the Common Alzheimer's Disease Research Ontology (CADRO) to categorize their funding information. This information is captured in the International Alzheimer's Disease Research Portfolio (IADRP) for further analysis. As of January, 2014, over fifteen organizations from the US, Canada, Europe and Australia have contributed their information. The goal of the IADRP project is to enable funding organizations to assess the changing landscape of AD research and coordinate strategies, leverage resources, and avoid duplication of effort.
Subject(s)
Alzheimer Disease , Biomedical Research/economics , Research Support as Topic , Alzheimer Disease/classification , Alzheimer Disease/economics , Financing, Organized , Humans , International Cooperation , Investments , Organizations , Vocabulary, ControlledSubject(s)
Academies and Institutes/organization & administration , Contract Services/organization & administration , Drug Discovery/methods , Technology, Pharmaceutical/organization & administration , Academies and Institutes/economics , Academies and Institutes/standards , Capacity Building/organization & administration , Capacity Building/standards , Contract Services/economics , Contract Services/methods , Contract Services/standards , Drug Discovery/economics , Drug Discovery/organization & administration , Interdisciplinary Communication , Technology, Pharmaceutical/economics , Technology, Pharmaceutical/methodsABSTRACT
Alzheimer's disease is recognized as a public health crisis worldwide. As public and private funding agencies around the world enhance and expand their support of Alzheimer's disease research, there is an urgent need to coordinate funding strategies and leverage resources to maximize the impact on public health and avoid duplication of effort and inefficiency. Such coordination requires a comprehensive assessment of the current landscape of Alzheimer's disease research in the United States and internationally. To this end, the National Institute on Aging at the National Institutes of Health and the Alzheimer's Association developed the Common Alzheimer's Disease Research Ontology (CADRO) as a dynamic portfolio analysis tool that can be used by funding agencies worldwide for strategic planning and coordination.
Subject(s)
Alzheimer Disease/diagnosis , Alzheimer Disease/therapy , Biomedical Research , Cooperative Behavior , National Institute on Aging (U.S.) , Organizations, Nonprofit , Humans , United StatesABSTRACT
Animal models have contributed significantly to our understanding of the underlying biological mechanisms of Alzheimer's disease (AD). As a result, over 300 interventions have been investigated and reported to mitigate pathological phenotypes or improve behavior in AD animal models or both. To date, however, very few of these findings have resulted in target validation in humans or successful translation to disease-modifying therapies. Challenges in translating preclinical studies to clinical trials include the inability of animal models to recapitulate the human disease, variations in breeding and colony maintenance, lack of standards in design, conduct and analysis of animal trials, and publication bias due to under-reporting of negative results in the scientific literature. The quality of animal model research on novel therapeutics can be improved by bringing the rigor of human clinical trials to animal studies. Research communities in several disease areas have developed recommendations for the conduct and reporting of preclinical studies in order to increase their validity, reproducibility, and predictive value. To address these issues in the AD community, the Alzheimer's Drug Discovery Foundation partnered with Charles River Discovery Services (Morrisville, NC, USA) and Cerebricon Ltd. (Kuopio, Finland) to convene an expert advisory panel of academic, industry, and government scientists to make recommendations on best practices for animal studies testing investigational AD therapies. The panel produced recommendations regarding the measurement, analysis, and reporting of relevant AD targets, th choice of animal model, quality control measures for breeding and colony maintenance, and preclinical animal study design. Major considerations to incorporate into preclinical study design include a priori hypotheses, pharmacokinetics-pharmacodynamics studies prior to proof-of-concept testing, biomarker measurements, sample size determination, and power analysis. The panel also recommended distinguishing between pilot 'exploratory' animal studies and more extensive 'therapeutic' studies to guide interpretation. Finally, the panel proposed infrastructure and resource development, such as the establishment of a public data repository in which both positive animal studies and negative ones could be reported. By promoting best practices, these recommendations can improve the methodological quality and predictive value of AD animal studies and make the translation to human clinical trials more efficient and reliable.
Subject(s)
Drug Design , Financing, Government/economics , Interinstitutional Relations , Neurodegenerative Diseases/drug therapy , Neurodegenerative Diseases/economics , Private Sector/economics , Drug Industry/economics , Drug Industry/organization & administration , Financial Support , Financing, Government/organization & administration , Foundations/economics , Foundations/organization & administration , Fund Raising/economics , Fund Raising/organization & administration , Humans , Private Sector/organization & administration , Universities/economics , Universities/organization & administrationSubject(s)
Academies and Institutes/trends , Alzheimer Disease/drug therapy , Drug Design , Academies and Institutes/history , Alzheimer Disease/metabolism , Alzheimer Disease/physiopathology , Brain/metabolism , Brain/pathology , Brain/physiopathology , Drug Therapy/economics , Drug Therapy/trends , History, 20th Century , History, 21st Century , Humans , Interdisciplinary Communication , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic useABSTRACT
Alzheimer's disease (AD) is defined by deposits of the 42-residue amyloid-beta peptide (Abeta42) in the brain. Abeta42 is a minor metabolite of the amyloid precursor protein (APP), but its relative levels are increased by mutations on APP and presenilins 1 and 2 linked to familial AD. beta-secretase (BACE-1), an aspartyl protease, cleaves approx 10% of the APP in neuronal cells on the N-terminal side of Abeta to produce the C-terminal fragment (CTFbeta), which is cleaved by gamma-secretase to produce mostly Abeta of 40 residues (90%) and approx10% Abeta42. A third enzyme, alpha-secretase, cleaves APP after Abeta16 to secrete sAPPalpha and CTFalpha, the major metabolites of APP. Moreover, previous studies have demonstrated that phorbol esters stimulate processing of APP by alpha-secretase. Because alpha-secretase and BACE-1 cleave APP within the secretory pathway, it is likely that the two enzymes compete for the APP substrate. This type of competition can explain the failure to saturate the minor BACE-1 pathway by overexpressing APP in the cell. In this study, we demonstrate that inhibition of constitutive alpha-secretase processing in a human neuroblastoma cell line does not increase the yield of Abeta, suggesting that the APP substrate targeted for alpha-secretase processing is not diverted to the BACE-1 pathway. However, when phorbol ester-induced alpha-secretase was similarly inhibited, we detected an increase in BACE-1 processing and AB yield. We explain these results compartmentalization of BACE-1 and alpha-secretase with processing depending on sorting of APP to the two compartments. The simplest explanation for the detection of competition between the two pathways upon phorbol ester stimulation is the partial failure of this compartmentalization by phorbol ester-induced release of secretory vesicles.
Subject(s)
Alzheimer Disease/enzymology , Amyloid beta-Peptides/biosynthesis , Amyloid beta-Protein Precursor/metabolism , Cell Compartmentation/physiology , Peptide Fragments/biosynthesis , ADAM Proteins , ADAM17 Protein , Alzheimer Disease/genetics , Amyloid Precursor Protein Secretases , Amyloid beta-Protein Precursor/drug effects , Aspartic Acid Endopeptidases/drug effects , Aspartic Acid Endopeptidases/metabolism , Cell Compartmentation/drug effects , Cell Line, Tumor , Dipeptides/pharmacology , Endopeptidases/drug effects , Endopeptidases/metabolism , Enzyme Inhibitors/pharmacology , Humans , Hydroxamic Acids/pharmacology , Metalloendopeptidases/antagonists & inhibitors , Metalloendopeptidases/metabolism , Phorbol Esters/pharmacology , Protein Transport/drug effects , Protein Transport/physiology , Secretory Vesicles/drug effects , Secretory Vesicles/metabolismABSTRACT
The identification of factors that influence the onset or progression of the sporadic form of Alzheimer's disease (AD) is a key step toward understanding its mechanism(s) and developing successful rational therapies. The apoE genotype has been identified as a powerful risk factor for AD that may account for as much as 50% of the sporadic form of the disease. As the major risk factor for late-onset AD, apolipoprotein E4 (apoE4) should be considered a good target for AD drug discovery. However, despite knowing for over a decade that apoE4 is detrimental to the disease process, we still remain uncertain about the molecular mechanisms subserving the risk-factor activity of apoE4. This, coupled with the fact that we know relatively little about the function(s) of apoE in brain, has presented a barrier to developing apoE-based therapeutics for AD. Progress has been made in understanding the neurobiology of apoE; a number of potentially overlapping functions have been ascribed, which include lipid transport, neuronal repair, dendritic growth, maintenance of synaptic plasticity, and anti-inflammatory activities. Until the gaps are filled in our understanding of the pathogenic function(s) of apoE4, therapeutic strategies targeting this protein will lag behind the development of other AD therapies. Putative pathological functions, or risk-factor activities, of apoE4 include its role in beta-amyloid deposition, neurofibrillary tangle formation, synaptic loss, lipid dysfunction, neuroinflammation, and oxidative stress.
Subject(s)
Alzheimer Disease/genetics , Apolipoproteins E/genetics , Alzheimer Disease/therapy , Amyloid beta-Peptides/genetics , Apolipoprotein E4 , Genotype , Humans , Protein Isoforms/genetics , Risk FactorsABSTRACT
Apolipoprotein E (ApoE) influences the risk of late onset Alzheimer's disease (AD) in an isoform-dependent manner, such that the presence of the apoE epsilon4 allele increases the risk of AD while the presence of the apoE epsilon2 allele appears to be protective. Although a number of ApoE functions are isoform dependent and may underlie the "risk factor" activity of AD, its ability to bind amyloid beta peptides and influence their clearance and/or deposition has gained strong experimental support. Evidence suggests that in addition to genotype, increased ApoE transcription can contribute to AD risk. There is growing evidence in support of the hypothesis that disrupted cholesterol metabolism is an early risk factor for AD. Studies in animal models have shown that chronic changes in cholesterol metabolism associate with changes in brain Abeta accumulation, a process instrumental for establishing AD pathology. ApoE mediates cholesterol homeostasis in the body and is a major lipid carrier in brain. As such, its expression in the periphery and in brain changes in response to changes in cholesterol metabolism. Here, we used a transgenic mouse model of Alzheimer's amyloidosis to examine whether the diet-induced or pharmacologically induced changes in plasma cholesterol that result in altered brain amyloidosis also affect ApoE content in liver and in brain. We found that chronic changes in total cholesterol in plasma lead to changes in ApoE mRNA levels in brain. We also found that cholesterol loading of primary glial cells increases cellular and secreted ApoE levels and that long-term treatment of astrocytes and microglia with statins leads to a decrease in the cellular and/or secreted ApoE. These observations suggest that disrupted cholesterol metabolism may increase the risk of developing AD in part due to the effect of cholesterol on brain ApoE expression.
Subject(s)
Alzheimer Disease/blood , Apolipoproteins E/metabolism , Cholesterol/blood , Genetic Predisposition to Disease/genetics , Hypercholesterolemia/complications , Alzheimer Disease/genetics , Alzheimer Disease/physiopathology , Amyloid beta-Peptides/biosynthesis , Animals , Apolipoproteins E/genetics , Astrocytes/drug effects , Astrocytes/metabolism , Brain/drug effects , Brain/metabolism , Brain/physiopathology , Cells, Cultured , Cholesterol/pharmacology , Female , Food, Formulated , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Hypercholesterolemia/metabolism , Hypercholesterolemia/physiopathology , Liver/drug effects , Liver/metabolism , Liver/physiopathology , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Microglia/drug effects , Microglia/metabolism , Risk FactorsABSTRACT
Increased levels of a 40-42 amino-acid peptide called the amyloid beta protein (A beta) and evidence of oxidative damage are early neuropathological markers of Alzheimer's disease (AD). Previous investigations have demonstrated that melatonin is decreased during the aging process and that patients with AD have more profound reductions of this hormone. It has also been recently shown that melatonin protects neuronal cells from A beta-mediated oxidative damage and inhibits the formation of amyloid fibrils in vitro. However, a direct relationship between melatonin and the biochemical pathology of AD had not been demonstrated. We used a transgenic mouse model of Alzheimer's amyloidosis and monitored over time the effects of administering melatonin on brain levels of A beta, abnormal protein nitration, and survival of the mice. We report here that administration of melatonin partially inhibited the expected time-dependent elevation of beta-amyloid, reduced abnormal nitration of proteins, and increased survival in the treated transgenic mice. These findings may bear relevance to the pathogenesis and therapy of AD.
Subject(s)
Alzheimer Disease/drug therapy , Amyloidosis/drug therapy , Melatonin/therapeutic use , Alzheimer Disease/complications , Alzheimer Disease/pathology , Amyloid beta-Peptides/drug effects , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/metabolism , Amyloidosis/complications , Amyloidosis/pathology , Animals , Disease Models, Animal , Humans , Mice , Mice, Transgenic , Nitrates/analysis , Nitrates/metabolism , Oxidation-Reduction/drug effects , Proteins/metabolism , Survival RateABSTRACT
Disease-modifying therapies are being developed for Alzheimer's disease (AD). These are expected to slow the clinical progression of the disease or delay its onset. Cerebral accumulation of amyloid beta (A beta) peptides is an early and perhaps necessary event for establishing AD pathology. Consequently therapies aimed at attenuating brain amyloidosis are expected to be disease modifying. Based on the epidemiological evidence pointing to a link between cholesterol metabolism and AD and the numerous laboratory studies implicating cholesterol in the process of A beta production and accumulation, it is now believed that cholesterol-lowering therapies will be of value as disease modifying agents. Several epidemiological studies revealed that statin use for the treatment of coronary arterial disease is associated with a decreased prevalence or a decreased risk of developing AD. These observations require both preclinical and clinical validation. The former involves testing statins in one or more animal models of AD in order to establish which disease features are affected by statin treatment, the relative efficacy with which different statins modify these features and the mechanism(s) by which statins affect AD phenotypes. The latter requires prospective, randomized, placebo controlled trials to evaluate the effect of statin treatment on cognitive and AD biomarker outcomes. We have initiated a study aimed at determining the effects of atorvastatin (Lipitor), a statin with the largest US market share, on brain A beta deposition in the PSAPP transgenic mouse model of Alzheimer's amyloidosis. Our results indicate that Lipitor treatment markedly attenuates A beta deposition in this animal model.
Subject(s)
Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Anticholesteremic Agents/pharmacology , Brain/drug effects , Brain/metabolism , Heptanoic Acids/pharmacology , Pyrroles/pharmacology , Amyloid beta-Peptides/drug effects , Animals , Anticholesteremic Agents/therapeutic use , Atorvastatin , Cholesterol/metabolism , Drug Evaluation, Preclinical , Heptanoic Acids/therapeutic use , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Immunohistochemistry , Mice , Mice, Transgenic , Models, Animal , Pyrroles/therapeutic useABSTRACT
Recent epidemiological, clinical, and experimental data suggest that cholesterol may play a role in Alzheimer's disease (AD). We have recently shown that cholesterolemia has a profound effect in the development and modulation of amyloid pathology in a transgenic model of AD. This review summarizes recent advancements in our understanding of the potential role of cholesterol and the amyloid beta protein in initiating the generation of free radicals and points out their role in a chain of events that causes damage of essential macromolecules in the central nervous system and culminates in neuronal dysfunction and loss. Experimental data links cholesterol and oxidative stress with some neurodegenerative aspects of AD.