Drug repurposing for Alzheimer’s disease based on transcriptional profiling of human iPSC-derived cortical neurons

AbstractWe have previously shown that blood astrocytic-origin extracellular vesicles (AEVs) from Alzheimer’s disease (AD) patients contain high complement levels. To test the hypothesis that circulating EVs from AD patients can induce complement-mediated neurodegeneration, we assessed the neurotoxicity of immunocaptured AEVs (with anti-GLAST antibody), neuronal-origin NEVs (with anti-L1CAM antibody), and multicellular-origin (with anti-CD81 antibody) EVs from the plasma of AD, frontotemporal lobar degeneration (FTLD) and control participants. AEVs (and, less effectively, NEVs) of AD participants induced Membrane Attack Complex (MAC) expression on recipient neurons, membrane disruption, reduced neurite density, and decreased cell viability in rat cortical neurons and human IPSC-derived neurons. Neurodegenerative effects were not produced by multicellular-origin EVs from AD participants or AEVs/NEVs from FTLD or control participants, and were suppressed by the MAC inhibitor CD59 and other complement inhibitors. Our results support the stated hypothesis and suggest that neuronal MAC deposition is necessary for AEV/NEV-mediated neurodegeneration in AD.

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Old Drugs with New Tricks; Paradigm in Drug Development Pipeline for Alzheimer’s Disease

Central Nervous System Agents in Medicinal Chemistry ◽

10.2174/1871524920666201021164805 ◽

2020 ◽

Vol 20 ◽

Author(s):

Tanay Dalvi ◽

Bhaskar Dewangan ◽

Rudradip Das ◽

Jyoti Rani ◽

Suchita Dattatray Shinde ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Drug Development ◽

Molecular Targets ◽

Drug Repurposing ◽

Phase Iii ◽

Complex Nature ◽

New Drug ◽

Development Pipeline ◽

Old Drugs

: The most common reason behind dementia is Alzheimer’s disease (AD) and it is predicted to be the third lifethreatening disease apart from stroke and cancer for the geriatric population. Till now only four drugs are available in the market for symptomatic relief. The complex nature of disease pathophysiology and lack of concrete evidences of molecular targets are the major hurdles for developing new drug to treat AD. The the rate of attrition of many advanced drugs at clinical stages, makes the de novo discovery process very expensive. Alternatively, Drug Repurposing (DR) is an attractive tool to develop drugs for AD in a less tedious and economic way. Therefore, continuous efforts are being made to develop a new drug for AD by repursing old drugs through screening and data mining. For example, the survey in the drug pipeline for Phase III clinical trials (till February 2019) which has 27 candidates, and around half of the number are drugs which have already been approved for other indications. Although in the past the drug repurposing process for AD has been reviewed in the context of disease areas, molecular targets, there is no systematic review of repurposed drugs for AD from the recent drug development pipeline (2019-2020). In this manuscript, we are reviewing the clinical candidates for AD with emphasis on their development history including molecular targets and the relevance of the target for AD.

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Systematic Design and Evaluation of Drug Repurposing-Oriented Alzheimer’s Disease Ontology (Preprint)

10.2196/preprints.17944 ◽

2020 ◽

Author(s):

Fang Li ◽

Muhammad "Tuan" Amith ◽

Grace Xiong ◽

Jingcheng Du ◽

Yang Xiang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Drug Targets ◽

Drug Repurposing ◽

Essential Elements ◽

Genomic Research ◽

Core Knowledge ◽

Disease Ontology ◽

Hybrid Strategy ◽

Complementary Strategy

BACKGROUND Alzheimer’s Disease (AD) is a devastating neurodegenerative disease, of which the pathophysiology is insufficiently understood, and the curative drugs are long-awaited to be developed. Computational drug repurposing introduces a promising complementary strategy of drug discovery, which benefits from an accelerated development process and decreased failure rate. However, generating new hypotheses in AD drug repurposing requires multi-dimensional and multi-disciplinary data integration and connection, posing a great challenge in the era of big data. By integrating data with computable semantics, ontologies could infer unknown relationships through automated reasoning and fulfill an essential role in supporting computational drug repurposing. OBJECTIVE The study aimed to systematically design a robust Drug Repurposing-Oriented Alzheimer’s Disease Ontology (DROADO), which could model fundamental elements and their relationships involved in AD drug repurposing and integrate their up-to-date research advance comprehensively. METHODS We devised a core knowledge model of computational AD drug repurposing, based on both pre-genomic and post-genomic research paradigms. The model centered on the possible AD pathophysiology and abstracted the essential elements and their relationships. We adopted a hybrid strategy to populate the ontology (classes and properties), including importing from well-curated databases, extracting from high-quality papers and reusing the existing ontologies. We also leveraged n-ary relations and nanopublication graphs to enrich the object relations, making the knowledge stored in the ontology more powerful in supporting computational processing. The initially built ontology was evaluated by a semiotic-driven and web-based tool Ontokeeper. RESULTS The current version of DROADO was composed of 1,021 classes, 23 object properties and 3,207 axioms, depicting a fundamental network related to computational neuroscience concepts and relationships. Assessment using semiotic evaluation metrics by OntoKeeper indicated sufficient preliminary quality (semantics, usefulness and community-consensus) of the ontology. CONCLUSIONS As an in-depth knowledge base, DROADO would be promising in enabling computational algorithms to realize supervised mining from multi-source data, and ultimately, facilitating the discovery of novel AD drug targets and the realization of AD drug repurposing.

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Quantifying scaling exponents for neurite morphology of in vitro-cultured human iPSC-derived neurons using discrete Loewner evolution: A statistical−physical approach to the neuropathology in Alzheimer's disease

Chaos An Interdisciplinary Journal of Nonlinear Science ◽

10.1063/5.0048559 ◽

2021 ◽

Vol 31 (7) ◽

pp. 073140

Author(s):

Yusuke Shibasaki ◽

Narumi Maeda ◽

Chihiro Oshimi ◽

Yuka Shirakawa ◽

Minoru Saito

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Scaling Exponents ◽

Physical Approach ◽

Loewner Evolution ◽

Human Ipsc

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Culture Variabilities of Human iPSC-Derived Cerebral Organoids Are a Major Issue for the Modelling of Phenotypes Observed in Alzheimer’s Disease

Stem Cell Reviews and Reports ◽

10.1007/s12015-021-10147-5 ◽

2021 ◽

Author(s):

Damián Hernández ◽

Louise A. Rooney ◽

Maciej Daniszewski ◽

Lerna Gulluyan ◽

Helena H. Liang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Human Ipsc

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[P3-170]: HUMAN IPSC-DERIVED ALZHEIMER's DISEASE ASTROCYTES RECAPITULATE DISEASE-RELATED PHENOTYPES

Alzheimer s & Dementia ◽

10.1016/j.jalz.2017.06.1382 ◽

2017 ◽

Vol 13 (7S_Part_21) ◽

pp. P999-P1000

Author(s):

Minna Oksanen ◽

Andrew J. Petersen ◽

Katja Puttonen ◽

Riikka H. Hämäläinen ◽

Šárka Lehtonen ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Human Ipsc

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Neuropathology of the Brainstem to Mechanistically Understand and to Treat Alzheimer’s Disease

Journal of Clinical Medicine ◽

10.3390/jcm10081555 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1555

Author(s):

Ágoston Patthy ◽

János Murai ◽

János Hanics ◽

Anna Pintér ◽

Péter Zahola ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cortical Neurons ◽

Molecular Mechanisms ◽

Neurodegenerative Disorder ◽

Brain Structures ◽

Specific Information ◽

Cellular Mechanisms ◽

Monoaminergic System ◽

Monoaminergic Neurons

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder as yet without effective therapy. Symptoms of this disorder typically reflect cortical malfunction with local neurohistopathology, which biased investigators to search for focal triggers and molecular mechanisms. Cortex, however, receives massive afferents from caudal brain structures, which do not only convey specific information but powerfully tune ensemble activity. Moreover, there is evidence that the start of AD is subcortical. The brainstem harbors monoamine systems, which establish a dense innervation in both allo- and neocortex. Monoaminergic synapses can co-release neuropeptides either by precisely terminating on cortical neurons or, when being “en passant”, can instigate local volume transmission. Especially due to its early damage, malfunction of the ascending monoaminergic system emerges as an early sign and possible trigger of AD. This review summarizes the involvement and cascaded impairment of brainstem monoaminergic neurons in AD and discusses cellular mechanisms that lead to their dysfunction. We highlight the significance and therapeutic challenges of transmitter co-release in ascending activating system, describe the role and changes of local connections and distant afferents of brainstem nuclei in AD, and summon the rapidly increasing diagnostic window during the last few years.

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