scholarly journals Artificial intelligence framework identifies candidate targets for drug repurposing in Alzheimer’s disease

2022 ◽  
Vol 14 (1) ◽  
Author(s):  
Jiansong Fang ◽  
Pengyue Zhang ◽  
Quan Wang ◽  
Chien-Wei Chiang ◽  
Yadi Zhou ◽  
...  
Keyword(s):  
Artificial Intelligence ◽  
Alzheimer’S Disease ◽  
Type 2 Diabetes ◽  
Alzheimer's Disease ◽  
Human Protein ◽  
Omics Data ◽  
Human Microglia ◽  
Protein Interactome

Abstract Background Genome-wide association studies (GWAS) have identified numerous susceptibility loci for Alzheimer’s disease (AD). However, utilizing GWAS and multi-omics data to identify high-confidence AD risk genes (ARGs) and druggable targets that can guide development of new therapeutics for patients suffering from AD has heretofore not been successful. Methods To address this critical problem in the field, we have developed a network-based artificial intelligence framework that is capable of integrating multi-omics data along with human protein–protein interactome networks to accurately infer accurate drug targets impacted by GWAS-identified variants to identify new therapeutics. When applied to AD, this approach integrates GWAS findings, multi-omics data from brain samples of AD patients and AD transgenic animal models, drug-target networks, and the human protein–protein interactome, along with large-scale patient database validation and in vitro mechanistic observations in human microglia cells. Results Through this approach, we identified 103 ARGs validated by various levels of pathobiological evidence in AD. Via network-based prediction and population-based validation, we then showed that three drugs (pioglitazone, febuxostat, and atenolol) are significantly associated with decreased risk of AD compared with matched control populations. Pioglitazone usage is significantly associated with decreased risk of AD (hazard ratio (HR) = 0.916, 95% confidence interval [CI] 0.861–0.974, P = 0.005) in a retrospective case-control validation. Pioglitazone is a peroxisome proliferator-activated receptor (PPAR) agonist used to treat type 2 diabetes, and propensity score matching cohort studies confirmed its association with reduced risk of AD in comparison to glipizide (HR = 0.921, 95% CI 0.862–0.984, P = 0.0159), an insulin secretagogue that is also used to treat type 2 diabetes. In vitro experiments showed that pioglitazone downregulated glycogen synthase kinase 3 beta (GSK3β) and cyclin-dependent kinase (CDK5) in human microglia cells, supporting a possible mechanism-of-action for its beneficial effect in AD. Conclusions In summary, we present an integrated, network-based artificial intelligence methodology to rapidly translate GWAS findings and multi-omics data to genotype-informed therapeutic discovery in AD.

scholarly journals Network-based Translation of GWAS Findings to Pathobiology and Drug Repurposing for Alzheimer’s Disease

2020 ◽  
Author(s):  
Jiansong Fang ◽  
Pengyue Zhang ◽  
Quan Wang ◽  
Yadi Zhou ◽  
Chien-Wei Chiang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Type 2 Diabetes ◽  
Alzheimer's Disease ◽  
Glycogen Synthase ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Omics Data ◽  
Human Microglia

AbstractGenome-wide association studies (GWAS) have identified numerous susceptibility loci for Alzheimer’s disease (AD). However, utilizing GWAS to identify high-confidence AD risk genes (ARGs) that can guide development of new therapeutics for patients suffering from AD has heretofore not been successful. To address this critical problem in the field, we have developed a genotype-informed, network-based methodology that interrogates pathogenesis to identify new therapeutics. When applied to AD, this approach integrates GWAS findings, multi-omics data from brain samples of AD patients and preclinical AD models, drug-target networks, and the human protein-protein interactome, along with large-scale patient database validation and in vitro mechanistic observations in human microglia cells. Through this approach, we identified 103 ARGs validated by various levels of pathobiological evidence in AD. Via network-based prediction and population-based validation, we then showed that pioglitazone usage is significantly associated with decreased risk of AD (hazard ratio (HR) = 0.895, 95% confidence interval [CI] 0.841-0.951, P = 3.97 × 10−4) in a retrospective case-control validation. Pioglitazone is a peroxisome proliferator-activated receptor agonist used to treat type 2 diabetes, and propensity score matching cohort studies confirmed its association with reduced risk of AD in comparison to glipizide (HR =0.921, 95% CI 0.861-0.983, P = 0.0146), an insulin secretagogue that is also used to treat type 2 diabetes. In vitro experiments showed that pioglitazone downregulated glycogen synthase kinase 3 beta (GSK3β) and cyclin-dependent kinase (CDK5) in human microglia cells, supporting a possible mechanism-of-action for its beneficial effect in AD. In summary, we present an integrated, network-based methodology to rapidly translate GWAS findings and multi-omics data to genotype-informed therapeutic discovery in AD.

Alpha-1-Antichymotrypsin: a Common Player for Type 2 Diabetes and Alzheimer's Disease

2020 ◽  
Vol 16 ◽  
Author(s):  
Nataly Guzmán-Herrera ◽  
Viridiana C. Pérez-Nájera ◽  
Luis A. Salazar-Olivo
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Type 2 Diabetes ◽  
Alzheimer's Disease ◽  
Regulatory Networks ◽  
Therapeutic Strategies ◽  
Oxidative Stresses ◽  
Bibliographic Search ◽  
And Oxidative Stress

Background: Numerous studies have shown a significant association between type 2 diabetes mellitus (T2D) and Alzheimer's disease (AD), two pathologies affecting millions of people worldwide. Chronic inflammation and oxidative stress are two conditions common to these diseases also affecting the activity of the serpin alpha-1-antichymotrypsin (ACT), but a possible common role for this serpin in T2D and AD remains unclear. Objective: To explore the possible regulatory networks linking ACT to T2D and AD. Materials and Methods: A bibliographic search was carried out in PubMed, Med-line, Open-i, ScienceDirect, Scopus and SpringerLink for data indicating or suggesting association among T2D, AD, and ACT. Searched terms like “alpha-1-antichymotrypsin”, “type 2 diabetes”, “Alzheimer's disease”, “oxidative stress”, “pro-inflammatory mediators” among others were used. Moreover, common therapeutic strategies between T2D and AD as well as the use of ACT as a therapeutic target for both diseases were included. Results: ACT has been linked with development and maintenance of T2D and AD and studies suggest their participation through activation of inflammatory pathways and oxidative stress, mechanisms also associated with both diseases. Likewise, evidences indicate that diverse therapeutic approaches are common to both diseases. Conclusion: Inflammatory and oxidative stresses constitute a crossroad for T2D and AD where ACT could play an important role. In-depth research on ACT involvement in these two dysfunctions could generate new therapeutic strategies for T2D and AD.

scholarly journals Insulin Resistance and Diabetes Mellitus in Alzheimer’s Disease

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1236
Author(s):  
Jesús Burillo ◽  
Patricia Marqués ◽  
Beatriz Jiménez ◽  
Carlos González-Blanco ◽  
Manuel Benito ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Alzheimer’S Disease ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Alzheimer's Disease ◽  
Type 2 Diabetes Mellitus ◽  
Insulin Signaling ◽  
Molecular Mechanisms ◽  
Progressive Disease

Type 2 diabetes mellitus is a progressive disease that is characterized by the appearance of insulin resistance. The term insulin resistance is very wide and could affect different proteins involved in insulin signaling, as well as other mechanisms. In this review, we have analyzed the main molecular mechanisms that could be involved in the connection between type 2 diabetes and neurodegeneration, in general, and more specifically with the appearance of Alzheimer’s disease. We have studied, in more detail, the different processes involved, such as inflammation, endoplasmic reticulum stress, autophagy, and mitochondrial dysfunction.

scholarly journals Discovery of Nonlipogenic ABCA1 Inducing Compounds with Potential in Alzheimer’s Disease and Type 2 Diabetes

2021 ◽  
Author(s):  
Manel Ben Aissa ◽  
Cutler T. Lewandowski ◽  
Kiira M. Ratia ◽  
Sue H. Lee ◽  
Brian T. Layden ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Type 2 Diabetes ◽  
Alzheimer's Disease

scholarly journals Are Tanycytes the Missing Link Between Type 2 Diabetes and Alzheimer’s Disease?

2018 ◽  
Vol 56 (2) ◽  
pp. 833-843 ◽  
Author(s):  
Sudhanshu P. Raikwar ◽  
Sachin M. Bhagavan ◽  
Swathi Beladakere Ramaswamy ◽  
Ramasamy Thangavel ◽  
Iuliia Dubova ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Type 2 Diabetes ◽  
Alzheimer's Disease ◽  
Missing Link

scholarly journals Type 2 Diabetes Mellitus and Alzheimer’s Disease: Role of Insulin Signalling and Therapeutic Implications

2018 ◽  
Vol 19 (11) ◽  
pp. 3306 ◽  
Author(s):  
Andrea Tumminia ◽  
Federica Vinciguerra ◽  
Miriam Parisi ◽  
Lucia Frittitta
Keyword(s):  
Diabetes Mellitus ◽  
Alzheimer’S Disease ◽  
Type 2 Diabetes ◽  
Alzheimer's Disease ◽  
Type 2 Diabetes Mellitus ◽  
Cell Activation ◽  
Insulin Signalling ◽  
Amyloid Β ◽  
Neuronal Stem Cell

In the last two decades, numerous in vitro studies demonstrated that insulin receptors and theirs downstream pathways are widely distributed throughout the brain. This evidence has proven that; at variance with previous believes; insulin/insulin-like-growth-factor (IGF) signalling plays a crucial role in the regulation of different central nervous system (CNS) tasks. The most important of these functions include: synaptic formation; neuronal plasticity; learning; memory; neuronal stem cell activation; neurite growth and repair. Therefore; dysfunction at different levels of insulin signalling and metabolism can contribute to the development of a number of brain disorders. Growing evidences demonstrate a close relationship between Type 2 Diabetes Mellitus (T2DM) and neurodegenerative disorders such as Alzheimer’s disease. They, in fact, share many pathophysiological characteristics comprising impaired insulin sensitivity, amyloid β accumulation, tau hyper-phosphorylation, brain vasculopathy, inflammation and oxidative stress. In this article, we will review the clinical and experimental evidences linking insulin resistance, T2DM and neurodegeneration, with the objective to specifically focus on insulin signalling-related mechanisms. We will also evaluate the pharmacological strategies targeting T2DM as potential therapeutic tools in patients with cognitive impairment.

scholarly journals Title: Biochemical linkage of type 2 diabetes mellitus and Alzheimer’s disease

2019 ◽  
Vol 0 (0) ◽  
pp. 1-14
Author(s):  
samar mahmoud ◽  
Dina Abo-El-Matty ◽  
Noha Mesbah ◽  
Eman Mehanna ◽  
Mohamed Hafez
Keyword(s):  
Diabetes Mellitus ◽  
Alzheimer’S Disease ◽  
Type 2 Diabetes ◽  
Alzheimer's Disease ◽  
Type 2 Diabetes Mellitus
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