Network Approaches to the Understanding of Alzheimer’s Disease: From Model Organisms to Humans

2016 ◽  
pp. 447-458 ◽  
Author(s):  
Justin Yerbury ◽  
Dan Bean ◽  
Giorgio Favrin
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Model Organisms ◽  
Network Approaches

scholarly journals Unraveling the Gordian knot: genetics and the troubled road to effective therapeutics for Alzheimer’s disease

Genetics ◽  
2021 ◽  
Author(s):  
Linda L Restifo
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Enzyme Inhibitors ◽  
Genetic Model ◽  
Late Onset ◽  
Model Organisms ◽  
Major Protein ◽  
Late 20Th Century ◽  
Protein Components

Abstract In the late 20th century, identification of the major protein components of amyloid plaques and neurofibrillary tangles provided a window into the molecular pathology of Alzheimer’s disease, ushering in an era of optimism that targeted therapeutics would soon follow. The amyloid-cascade hypothesis took hold very early, supported by discoveries that dominant mutations in APP, PSEN1, and PSEN2 cause the very rare, early-onset, familial forms of the disease. However, in the past decade a stunning series of failed Phase-3 clinical trials, testing anti-amyloid antibodies or processing-enzyme inhibitors, prompts the question, What went wrong? The FDA’s recent controversial approval of aducanumab, despite widespread concerns about efficacy and safety, only amplifies the question. The assumption that common, late-onset Alzheimer's is a milder form of the familial disease was not adequately questioned. The differential timing of discoveries, including blood-brain-barrier-penetrant tracers for imaging of plaques and tangles, made it easy to focus on amyloid. Furthermore, the neuropathology community initially implemented Alzheimer's diagnostic criteria based on plaques only. The discovery that MAPT mutations cause frontotemporal dementia with tauopathy made it even easier to overlook the tangles in Alzheimer's. Many important findings were simply ignored. The accepted mouse models did not predict the human clinical trials data. Given this lack of pharmacological validity, input from geneticists in collaboration with neuroscientists is needed to establish criteria for valid models of Alzheimer's disease. More generally, scientists using genetic model organisms as whole-animal bioassays can contribute to building the pathogenesis network map of Alzheimer’s disease.

scholarly journals Using Drosophila to Identify Naturally-Occurring Modifiers of Alzheimer's Disease

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 641-642
Author(s):  
Adrienne Wang ◽  
Ming Yang ◽  
Cecilia Fitzgerald-Cook ◽  
Ben Harrison ◽  
Akimi Green ◽  
...  
Keyword(s):  
Risk Factors ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Late Onset ◽  
Enrichment Analysis ◽  
Model Organisms ◽  
Naturally Occurring ◽  
Small Effect Size ◽  
Forward Genetic Screens ◽  
Potential Risk Factors

Abstract Despite significant progress in identifying risk factors for late-onset Alzheimer’s Disease (LOAD), much of the variance in disease pathogenesis remains unexplained, likely due to the contribution of many genes of small effect size. Model organisms such as Drosophila Melanogaster exhibit conservation in both disease-causing genes and cellular processes implicated in Alzheimer’s Disease (AD), offering a genetically tractable model that can be statistically leveraged to identify causal variants. Here, we combine a Drosophila model of AD with the Drosophila Genetic Reference Panel (DGRP), a model of natural variation consisting of over 200 fully sequenced, isogenic lines derived from a wild-caught population. Expression of two proteins closely associated with AD pathogenesis, A□42 and Tau, in the Drosophila eye results in a “rough eye” phenotype, an easily quantifiable phenotype caused by degeneration of the ommatidial array. By quantifying the degree of A□42- and Tau-mediated degeneration across 164 lines of the DGRP and using a gene-based approach to map associations, we have identified and validated a subset of naturally occurring modifiers of degeneration in Drosophila. Enrichment analysis reveals that the set of genes identified in our screen show significant enrichment for genes identified as significant or suggestive (4x10-6>p>2x10-11) in human GWAS studies. The results presented here provide proof-of-principal for an approach that combines the strengths of forward genetic screens in model organisms with the power of human GWAS studies to identify and validate potential risk factors that have been difficult to detect in human studies alone.

scholarly journals Drosophila melanogaster: A Veritable Genetic Tool and in vivo Model for Human Alzheimer’s Disease

2019 ◽  
pp. 1-9
Author(s):  
Oluwatosin Imoleayo, Oyeniran
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Drosophila Melanogaster ◽  
Molecular Mechanisms ◽  
Fruit Fly ◽  
Human Diseases ◽  
Model Organisms ◽  
In Vivo Model ◽  
Brain Functions ◽  
Drosophila Models

The rise in the cases of neurodegenerative diseases, such as the familial forms of Alzheimer’s disease is worrisome and a burden to many societies in our ever-increasing world. Due to the complexity in the nature of the brain and spinal cord characterized by an extremely organized network of neuronal cells, there is a need to answer scientific inquiries in uncomplicated, though similar, systems. Drosophila melanogaster (fruit-fly) is a well-studied and easily managed genetic model organism used for discerning the molecular mechanisms of many human diseases. There are strong conservations of several basic biological, physiological and neurological features between D. melanogaster and mammals, as about 75% of all human disease-causing genes are considered to possess a functional homolog in the fruit-fly. The development of Drosophila models of several neurodegenerative disorders via developed transgenic technologies has presented spectacular similarities to human diseases. An advantage that the fruit-fly has over other model organisms, such as the mouse, is its comparatively brief lifespan, which allows complex inquiries about brain functions to be addressed more quickly. Furthermore, there have been steady increases in understanding the pathophysiological basis of many neurological disorders via genetic screenings with the aid of Drosophila models. This review presents a widespread summary of the fruit-fly models relevant to Alzheimer’s disease, and highlight important genetic modifiers that have been recognized using this model.

scholarly journals Selective human tau protein expression in different clock circuits of the Drosophila brain disrupts different aspects of sleep and circadian rhythms

2020 ◽  
Author(s):  
David Jaciuch ◽  
Jack Munns ◽  
Sangeeta Chawla ◽  
Seth J. Davis ◽  
Mikko Juusola
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Locomotor Activity ◽  
Protein Expression ◽  
Tau Protein ◽  
Tau Proteins ◽  
Model Organisms ◽  
Neuron Network ◽  
Main Site ◽  
The Impact

AbstractCircadian behavioural deficits, such as increased daytime naps and reduced night-time sleep, are common in Alzheimer’s disease and other tauopathies. But it has remained unclear whether these circadian abnormalities arise from tau pathology in either the master pacemaker or downstream neurons. Here we study this question by selectively expressing different human tau proteins in specific Drosophila brain circuits and monitoring locomotor activity under light-dark (LD) and in “free-running” dark-dark (DD) conditions. We show that expressing human tau proteins in the fly brain recapitulates faithfully several behavioural changes found in tauopathies. We identify discrete neuronal subpopulations within the clock network as the primary target of distinct circadian behavioural disturbances in different environmental conditions. Specifically, we show that the PDF-positive pacemaker neurons are the main site for night-activity gain and -sleep loss, whereas the non-PDF clock-neurons are the main site of reduced intrinsic behavioural rhythmicity. Bioluminescence measurements revealed that the molecular clock is intact despite the behavioural arrhythmia. Our results establish that dysfunction in both the central clock- and afferent clock-neurons jointly contribute to the circadian locomotor activity rhythm disruption in Drosophila expressing human tau.Significance StatementThis study directly links in vivo human tau protein expression in region-specific Drosophila clock-neurons with the resulting sleep and circadian rhythm deficits to extract new knowledge of how Alzheimer’s disease and other tauopathies perturb the balance of activity and sleep. We anticipate that this novel approach will provide a useful general template for other studies of neurodegeneration in model organisms, seeking to dissect the impact of neurodegenerative disease on circadian behaviour, and further deepening our understanding of how the clock-neuron network works.

scholarly journals Genetic perturbations of disease risk genes in mice capture transcriptomic signatures of late-onset Alzheimer’s disease

2019 ◽  
Vol 14 (1) ◽  
Author(s):  
Ravi S. Pandey ◽  
Leah Graham ◽  
Asli Uyar ◽  
Christoph Preuss ◽  
Gareth R. Howell ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Animal Models ◽  
Mouse Models ◽  
Genetic Risk ◽  
Late Onset ◽  
Model Organisms ◽  
Similar Data ◽  
Risk Genes ◽  
Genetic Perturbations

Abstract Background New genetic and genomic resources have identified multiple genetic risk factors for late-onset Alzheimer’s disease (LOAD) and characterized this common dementia at the molecular level. Experimental studies in model organisms can validate these associations and elucidate the links between specific genetic factors and transcriptomic signatures. Animal models based on LOAD-associated genes can potentially connect common genetic variation with LOAD transcriptomes, thereby providing novel insights into basic biological mechanisms underlying the disease. Methods We performed RNA-Seq on whole brain samples from a panel of six-month-old female mice, each carrying one of the following mutations: homozygous deletions of Apoe and Clu; hemizygous deletions of Bin1 and Cd2ap; and a transgenic APOEε4. Similar data from a transgenic APP/PS1 model was included for comparison to early-onset variant effects. Weighted gene co-expression network analysis (WGCNA) was used to identify modules of correlated genes and each module was tested for differential expression by strain. We then compared mouse modules with human postmortem brain modules from the Accelerating Medicine’s Partnership for AD (AMP-AD) to determine the LOAD-related processes affected by each genetic risk factor. Results Mouse modules were significantly enriched in multiple AD-related processes, including immune response, inflammation, lipid processing, endocytosis, and synaptic cell function. WGCNA modules were significantly associated with Apoe−/−, APOEε4, Clu−/−, and APP/PS1 mouse models. Apoe−/−, GFAP-driven APOEε4, and APP/PS1 driven modules overlapped with AMP-AD inflammation and microglial modules; Clu−/− driven modules overlapped with synaptic modules; and APP/PS1 modules separately overlapped with lipid-processing and metabolism modules. Conclusions This study of genetic mouse models provides a basis to dissect the role of AD risk genes in relevant AD pathologies. We determined that different genetic perturbations affect different molecular mechanisms comprising AD, and mapped specific effects to each risk gene. Our approach provides a platform for further exploration into the causes and progression of AD by assessing animal models at different ages and/or with different combinations of LOAD risk variants.

scholarly journals Alzheimer’s disease: presence and role of microRNAs

2016 ◽  
Vol 7 (4) ◽  
pp. 241-252 ◽  
Author(s):  
Manasa Basavaraju ◽  
Alexandre de Lencastre
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Late Onset ◽  
Early Stage ◽  
Regulatory Elements ◽  
Amyloid Peptide ◽  
Model Organisms ◽  
Gene Regulatory Elements ◽  
Β Amyloid Peptide

AbstractAlzheimer’s disease (AD) is a progressive neurodegenerative disorder that accounts for the most cases of dementia. AD affects more than 25 million people globally and is predicted to affect nearly one in 85 people worldwide by 2050. AD is characterized by the accumulation of dense plaques of β-amyloid peptide (Aβ) and neurofibrillary tangles of hyperphosphorylated tau that cause impairment in memory, cognition, and daily activities. Although early-onset AD has been linked to several mutations, reliable genetic markers for late-onset AD are lacking. Further, the diagnosis of AD biomarkers has its limitations and cannot detect early-stage AD. The identification of accurate, early, and non-invasive biomarkers for AD is, therefore, an unmet challenge. Recently, microRNAs (miRNAs) have emerged as a novel class of gene regulatory elements with conserved roles in development and disease. Recent discoveries have uncovered roles of miRNAs in several model organisms during aging and have identified potential miRNAs biomarkers of AD. Here we will discuss this emerging field of miRNAs associated with AD and prospects for the future.

scholarly journals Does Diet Have a Role in the Treatment of Alzheimer's Disease?

2020 ◽  
Vol 12 ◽  
Author(s):  
Mitchell Thelen ◽  
Holly M. Brown-Borg
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Risk Factor ◽  
Neurodegenerative Diseases ◽  
Therapeutic Options ◽  
Model Organisms ◽  
Dietary Interventions ◽  
Important Distinction ◽  
Methionine Restriction ◽  
The Brain

The aging process causes many changes to the brain and is a major risk factor for the development of neurodegenerative diseases such as Alzheimer's Disease (AD). Despite an already vast amount of research on AD, a greater understanding of the disease's pathology and therapeutic options are desperately needed. One important distinction that is also in need of further study is the ability to distinguish changes to the brain observed in early stages of AD vs. changes that occur with normal aging. Current FDA-approved therapeutic options for AD patients have proven to be ineffective and indicate the need for alternative therapies. Aging interventions including alterations in diet (such as caloric restriction, fasting, or methionine restriction) have been shown to be effective in mediating increased health and lifespan in mice and other model organisms. Because aging is the greatest risk factor for the development of neurodegenerative diseases, certain dietary interventions should be explored as they have the potential to act as a future treatment option for AD patients.

scholarly journals Genetic perturbations of disease risk genes in mice capture transcriptomic signatures of late-onset Alzheimer’s disease

2019 ◽  
Author(s):  
Ravi S. Pandey ◽  
Leah Graham ◽  
Asli Uyar ◽  
Christoph Preuss ◽  
Gareth R. Howell ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Animal Models ◽  
Mouse Models ◽  
Genetic Risk ◽  
Late Onset ◽  
Model Organisms ◽  
Similar Data ◽  
Risk Genes ◽  
Genetic Perturbations

ABSTRACTBackgroundNew genetic and genomic resources have identified multiple genetic risk factors for late-onset Alzheimer’s disease (LOAD) and characterized this common dementia at the molecular level. Experimental studies in model organisms can validate these associations and elucidate the links between specific genetic factors and transcriptomic signatures. Animal models based on LOAD-associated genes can potentially connect common genetic variation with LOAD transcriptomes, thereby providing novel insights into basic biological mechanisms underlying the disease.MethodsWe performed RNA-Seq on whole brain samples from a panel of six-month-old female mice, each carrying one of the following mutations: homozygous deletions of Apoe and Clu; hemizygous deletions of Bin1 and Cd2ap; and a transgenic APOEε4. Similar data from a transgenic APP/PS1 model was included for comparison to early-onset variant effects. Weighted gene co-expression network analysis (WGCNA) was used to identify modules of correlated genes and each module was tested for differential expression by strain. We then compared mouse modules with human postmortem brain modules from the Accelerating Medicine’s Partnership for AD (AMP-AD) to determine the LOAD-related processes affected by each genetic risk factor.ResultsMouse modules were significantly enriched in multiple AD-related processes, including immune response, inflammation, lipid processing, endocytosis, and synaptic cell function. WGCNA modules were significantly associated with Apoe−/−, APOEε4, Clu−/−, and APP/PS1 mouse models. Apoe−/−, GFAP-driven APOEε4, and APP/PS1 driven modules overlapped with AMP-AD inflammation and microglial modules; Clu−/− driven modules overlapped with synaptic modules; and APP/PS1 modules separately overlapped with lipid-processing and metabolism modules.ConclusionsThis study of genetic mouse models provides a basis to dissect the role of AD risk genes in relevant AD pathologies. We determined that different genetic perturbations affect different molecular mechanisms comprising AD, and mapped specific effects to each risk gene. Our approach provides a platform for further exploration into the causes and progression of AD by assessing animal models at different ages and/or with different combinations of LOAD risk variants.

Cognitive control constrains memory attributions

2019 ◽  
Vol 42 ◽  
Author(s):  
Colleen M. Kelley ◽  
Larry L. Jacoby
Keyword(s):  
Alzheimer’S Disease ◽  
Older Adults ◽  
Alzheimer's Disease ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Cognitive Control

Abstract Cognitive control constrains retrieval processing and so restricts what comes to mind as input to the attribution system. We review evidence that older adults, patients with Alzheimer's disease, and people with traumatic brain injury exert less cognitive control during retrieval, and so are susceptible to memory misattributions in the form of dramatic levels of false remembering.

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