scholarly journals Identification and drug-induced reversion of molecular signatures of Alzheimer’s disease onset and progression in AppNL-G-F, AppNL-F, and 3xTg-AD mouse models

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Eduardo Pauls ◽  
Sergi Bayod ◽  
Lídia Mateo ◽  
Víctor Alcalde ◽  
Teresa Juan-Blanco ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Models ◽  
Disease Onset ◽  
Accelerated Aging ◽  
Complete Characterization ◽  
Protein Quantification ◽  
Drug Induced ◽  
Signature Genes

Abstract Background In spite of many years of research, our understanding of the molecular bases of Alzheimer’s disease (AD) is still incomplete, and the medical treatments available mainly target the disease symptoms and are hardly effective. Indeed, the modulation of a single target (e.g., β-secretase) has proven to be insufficient to significantly alter the physiopathology of the disease, and we should therefore move from gene-centric to systemic therapeutic strategies, where AD-related changes are modulated globally. Methods Here we present the complete characterization of three murine models of AD at different stages of the disease (i.e., onset, progression and advanced). We combined the cognitive assessment of these mice with histological analyses and full transcriptional and protein quantification profiling of the hippocampus. Additionally, we derived specific Aβ-related molecular AD signatures and looked for drugs able to globally revert them. Results We found that AD models show accelerated aging and that factors specifically associated with Aβ pathology are involved. We discovered a few proteins whose abundance increases with AD progression, while the corresponding transcript levels remain stable, and showed that at least two of them (i.e., lfit3 and Syt11) co-localize with Aβ plaques in the brain. Finally, we found two NSAIDs (dexketoprofen and etodolac) and two anti-hypertensives (penbutolol and bendroflumethiazide) that overturn the cognitive impairment in AD mice while reducing Aβ plaques in the hippocampus and partially restoring the physiological levels of AD signature genes to wild-type levels. Conclusions The characterization of three AD mouse models at different disease stages provides an unprecedented view of AD pathology and how this differs from physiological aging. Moreover, our computational strategy to chemically revert AD signatures has shown that NSAID and anti-hypertensive drugs may still have an opportunity as anti-AD agents, challenging previous reports.

scholarly journals Identification and drug-induced reversion of molecular signatures of Alzheimer’s disease onset and progression in AppNL-G-F, AppNL-F and 3xTg-AD mouse models

2021 ◽  
Author(s):  
Eduardo Pauls ◽  
Sergi Bayod ◽  
Lídia Mateo ◽  
Víctor Alcalde ◽  
Teresa Juan-Blanco ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mouse Models ◽  
Neurodegenerative Disorder ◽  
Disease Onset ◽  
Protein Quantification ◽  
Clear Correlation ◽  
Gene And Protein Expression

AbstractAlzheimer’s disease (AD) is the most common form of dementia. Over fifty years of intense research have revealed many key elements of the biology of this neurodegenerative disorder. However, our understanding of the molecular bases of the disease is still incomplete, and the medical treatments available for AD are mainly symptomatic and hardly effective. Indeed, the robustness of biological systems has revealed that the modulation of a single target is unlikely to yield the desired outcome and we should therefore move from gene-centric to systemic therapeutic strategies. Here we present the complete characterization of three murine models of AD at different stages of the disease (i.e. onset, progression and advanced). To identify genotype-to-phenotype relationships, we combine the cognitive assessment of these mice with histological analyses and full transcriptional and protein quantification profiling of the hippocampus. Comparison of the gene and protein expression trends observed in AD progression and physiological aging revealed certain commonalities, such as the upregulation of microglial and inflammation markers. However, although AD models show accelerated aging, other factors specifically associated with Aβ pathology are involved. Despite the clear correlation between mRNA and protein levels of the dysregulated genes, we discovered a few proteins whose abundance increases with AD progression, while the corresponding transcript levels remain stable. Indeed, we show that at least two of these proteins, namely lfit3 and Syt11, co-localize with Aβ plaques in the brain. Finally, we derived specific Aβ-related molecular AD signatures and looked for drugs able to globally revert them. We found two NSAIDs (dexketoprofen and etodolac) and two anti-hypertensives (penbutolol and bendroflumethiazide) that overturn the cognitive impairment in AD mice while reducing Aβ plaques in the hippocampus and partially restoring the physiological levels of AD signature genes to wild-type levels.TeaserThe comprehensive characterization of three AD mouse models reveals disease signatures that we used to identify approved drugs able to modify the etiology of the pathology and overturn cognitive impairment.

scholarly journals P2-133: INITIAL CHARACTERIZATION OF NOVEL MOUSE MODELS OF LATE ONSET ALZHEIMER'S DISEASE BASED ON HUMAN GENETIC ASSOCIATIONS

2019 ◽  
Vol 15 ◽  
pp. P623-P623
Author(s):  
Michael Sasner ◽  
Adrian L. Oblak ◽  
Christoph Preuss ◽  
Dylan Garceau ◽  
Harriett Williams ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Models ◽  
Late Onset ◽  
Genetic Associations ◽  
Initial Characterization

P3-296: Characterization of Vascular Alterations in Human Alzheimer's Disease Patients in Comparison to the AppSL and 5XFAD Mouse Models

2016 ◽  
Vol 12 ◽  
pp. P954-P954
Author(s):  
Vera Niederkofler ◽  
Magdalena Temmel ◽  
Karin Lanegger ◽  
Joerg Neddens ◽  
Ewald Auer ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Models ◽  
5Xfad Mouse

scholarly journals Metabolic, Phenotypic, and Neuropathological Characterization of the Tg4-42 Mouse Model for Alzheimer’s Disease

2021 ◽  
Vol 80 (3) ◽  
pp. 1151-1168
Author(s):  
Barbara Hinteregger ◽  
Tina Loeffler ◽  
Stefanie Flunkert ◽  
Joerg Neddens ◽  
Thomas A. Bayer ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Mouse Models ◽  
Neuronal Degeneration ◽  
Integrated Approach ◽  
In Vivo Model ◽  
Preclinical Research

Background: Preclinical Alzheimer’s disease (AD) research strongly depends on transgenic mouse models that display major symptoms of the disease. Although several AD mouse models have been developed representing relevant pathologies, only a fraction of available mouse models, like the Tg4-42 mouse model, display hippocampal atrophy caused by the death of neurons as the key feature of AD. The Tg4-42 mouse model is therefore very valuable for use in preclinical research. Furthermore, metabolic biomarkers which have the potential to detect biochemical changes, are crucial to gain deeper insights into the pathways, the underlying pathological mechanisms and disease progression. Objective: We thus performed an in-depth characterization of Tg4-42 mice by using an integrated approach to analyze alterations of complex biological networks in this AD in vivo model. Methods: Therefore, untargeted NMR-based metabolomic phenotyping was combined with behavioral tests and immunohistological and biochemical analyses. Results: Our in vivo experiments demonstrate a loss of body weight increase in homozygous Tg4-42 mice over time as well as severe impaired learning behavior and memory deficits in the Morris water maze behavioral test. Furthermore, we found significantly altered metabolites in two different brain regions and metabolic changes of the glutamate/4-aminobutyrate-glutamine axis. Based on these results, downstream effects were analyzed showing increased Aβ42 levels, increased neuroinflammation as indicated by increased astro- and microgliosis as well as neuronal degeneration and neuronal loss in homozygous Tg4-42 mice. Conclusion: Our study provides a comprehensive characterization of the Tg4-42 mouse model which could lead to a deeper understanding of pathological features of AD. Additionally this study reveals changes in metabolic biomarker which set the base for future preclinical studies or drug development.

The Therapeutic Potential of Purinergic Receptors in Alzheimer’s Disease and Promising Therapeutic Modulators

2020 ◽  
Vol 20 ◽  
Author(s):  
Lili Pan ◽  
Yu Ma ◽  
Yunchun Li ◽  
Haoxing Wu ◽  
Rui Huang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Purinergic Receptors ◽  
Therapeutic Potential ◽  
Purinergic Signaling ◽  
Memory Loss ◽  
Related Research ◽  
Central Nervous System Disorders ◽  
G Protein Coupled

Abstract:: Recent studies have proven that the purinergic signaling pathway plays a key role in neurotransmission and neuromodulation, and is involved in various neurodegenerative diseases and psychiatric disorders. With the characterization of the subtypes of receptors in purinergic signaling, i.e. the P1 (adenosine), P2X (ion channel) and P2Y (G protein-coupled), more attentions were paid to the pathophysiology and therapeutic potential of purinergic signaling in central nervous system disorders. Alzheimer’s disease (AD) is a progressive and deadly neurodegenerative disease that is characterized by memory loss, cognitive impairment and dementia. However, as drug development aimed to prevent or control AD follows a series of failures in recent years, more researchers focused on the neuroprotection-related mechanisms such as purinergic signaling in AD patients to find a potential cure. This article reviews the recent discoveries of purinergic signaling in AD, summaries the potential agents as modulators for the receptors of purinergic signaling in AD related research and treatments. Thus, our paper provided an insight for purinergic signaling in the development of anti-AD therapies.

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