A Human-Based Integrated Framework forAlzheimer’s Disease Research

Pistollato, Francesca; Cavanaugh, Sarah E.; Chandrasekera, P. Charukeshi

doi:10.3233/jad-150281

Cited by 17 publications

(8 citation statements)

References 128 publications

(144 reference statements)

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“…However, Tg animals, despite presenting several of the typical AD traits, such as amyloid β (Aβ) formation, neuritic plaques, neurofibrillary tangles (NFT), gliosis, synaptic alterations and signs of neurodegeneration, do not develop the clinicopathological complexities of human AD [12–15]. Moreover, treatments that seem to work in such models have not translated to humans [11, 16–18]. This indicates the existence of a clear disconnection between the (animal) model and the human condition [17] that is not taken into sufficient account by investigators.…”

Section: The Ad Research Paradigm Is Failing: Main Facts Supporting Tmentioning

confidence: 99%

“…These techniques include: (1) several human-based models focused on the use of patient-derived cells, such as induced pluripotent stem cells (iPSCs) and neuronal and glial cultures, (2) multiple ‘omic’ technologies (e.g., genomics, proteomics, lipidomics, transcriptomics, metabolomics, etc.) resulting from overall analyses of biological samples by high-throughput analytical approaches and databases, (3) computational analytical approaches and (4) novel neuroimaging readouts [17, 18, 45]. …”

Section: Addressing Human Relevance In Ad Research With the Use Of Almentioning

confidence: 99%

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Alzheimer disease research in the 21st century: past and current failures, new perspectives and funding priorities

et al. 2016

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Much of Alzheimer disease (AD) research has been traditionally based on the use of animals, which have been extensively applied in an effort to both improve our understanding of the pathophysiological mechanisms of the disease and to test novel therapeutic approaches. However, decades of such research have not effectively translated into substantial therapeutic success for human patients. Here we critically discuss these issues in order to determine how existing human-based methods can be applied to study AD pathology and develop novel therapeutics. These methods, which include patient-derived cells, computational analysis and models, together with large-scale epidemiological studies represent novel and exciting tools to enhance and forward AD research. In particular, these methods are helping advance AD research by contributing multifactorial and multidimensional perspectives, especially considering the crucial role played by lifestyle risk factors in the determination of AD risk. In addition to research techniques, we also consider related pitfalls and flaws in the current research funding system. Conversely, we identify encouraging new trends in research and government policy. In light of these new research directions, we provide recommendations regarding prioritization of research funding. The goal of this document is to stimulate scientific and public discussion on the need to explore new avenues in AD research, considering outcome and ethics as core principles to reliably judge traditional research efforts and eventually undertake new research strategies.

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Section: The Ad Research Paradigm Is Failing: Main Facts Supporting Tmentioning

confidence: 99%

Section: Addressing Human Relevance In Ad Research With the Use Of Almentioning

confidence: 99%

Alzheimer disease research in the 21st century: past and current failures, new perspectives and funding priorities

et al. 2016

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“…In recent years, the shift toward a new human-biology-focused paradigm has been broadly encouraged in toxicology and regulatory testing [ 229 ], but also in other research fields, including immunology, human infectious diseases, and nutritional research [ 7 , 80 , 230 , 231 , 232 , 233 , 234 , 235 , 236 , 237 , 238 , 239 , 240 , 241 ].…”

Section: Discussionmentioning

confidence: 99%

Links between Nutrition, Infectious Diseases, and Microbiota: Emerging Technologies and Opportunities for Human-Focused Research

et al. 2020

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The interaction between nutrition and human infectious diseases has always been recognized. With the emergence of molecular tools and post-genomics, high-resolution sequencing technologies, the gut microbiota has been emerging as a key moderator in the complex interplay between nutrients, human body, and infections. Much of the host–microbial and nutrition research is currently based on animals or simplistic in vitro models. Although traditional in vivo and in vitro models have helped to develop mechanistic hypotheses and assess the causality of the host–microbiota interactions, they often fail to faithfully recapitulate the complexity of the human nutrient–microbiome axis in gastrointestinal homeostasis and infections. Over the last decade, remarkable progress in tissue engineering, stem cell biology, microfluidics, sequencing technologies, and computing power has taken place, which has produced a new generation of human-focused, relevant, and predictive tools. These tools, which include patient-derived organoids, organs-on-a-chip, computational analyses, and models, together with multi-omics readouts, represent novel and exciting equipment to advance the research into microbiota, infectious diseases, and nutrition from a human-biology-based perspective. After considering some limitations of the conventional in vivo and in vitro approaches, in this review, we present the main novel available and emerging tools that are suitable for designing human-oriented research.

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“…Along this line, novel human-based cellular and computational models, together with epidemiological and clinical studies may facilitate the acquisition of human-relevant data to improve mechanistic understanding of AD pathology, as recently advocated ( Pistollato et al, 2015 , Pistollato et al, 2016 ). Similarly, a comprehensive molecular interaction map that integrates pathways implicated in PD has been created ( Fujita et al, 2014 ).…”

Section: Moving Towards Mechanistically Based Taxonomies Of Human Dismentioning

confidence: 99%

Adverse outcome pathways: Application to enhance mechanistic understanding of neurotoxicity

Bal‐Price

Meek

2017

Pharmacology & Therapeutics

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Recent developments have prompted the transition of empirically based testing of late stage toxicity in animals for a range of different endpoints including neurotoxicity to more efficient and predictive mechanistically based approaches with greater emphasis on measurable key events early in the progression of disease. The adverse outcome pathway (AOP) has been proposed as a simplified organizational construct to contribute to this transition by linking molecular initiating events and earlier (more predictive) key events at lower levels of biological organization to disease outcomes. As such, AOPs are anticipated to facilitate the compilation of information to increase mechanistic understanding of pathophysiological pathways that are responsible for human disease.In this review, the sequence of key events resulting in adverse outcome (AO) defined as parkinsonian motor impairment and learning and memory deficit in children, triggered by exposure to environmental chemicals has been briefly described using the AOP framework. These AOPs follow convention adopted in an Organization for Economic Cooperation and Development (OECD) AOP development program, publically available, to permit tailored application of AOPs for a range of different purposes.Due to the complexity of disease pathways, including neurodegenerative disorders, a specific symptom of the disease (e.g. parkinsonian motor deficit) is considered as the AO in a developed AOP. Though the description is necessarily limited by the extent of current knowledge, additional characterization of involved pathways through description of related AOPs interlinked into networks for the same disease has potential to contribute to more holistic and mechanistic understanding of the pathophysiological pathways involved, possibly leading to the mechanism-based reclassification of diseases, thus facilitating more personalized treatment.

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A Human-Based Integrated Framework forAlzheimer’s Disease Research

Cited by 17 publications

References 128 publications

Alzheimer disease research in the 21st century: past and current failures, new perspectives and funding priorities

Alzheimer disease research in the 21st century: past and current failures, new perspectives and funding priorities

Links between Nutrition, Infectious Diseases, and Microbiota: Emerging Technologies and Opportunities for Human-Focused Research

Adverse outcome pathways: Application to enhance mechanistic understanding of neurotoxicity

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