Practical Considerations of Genetic Rodent Models for Neurodegenerative Diseases

After the discovery of ERβ, a novel role for DHT in estrogen signaling was revealed. Instead of just being a better androgen, DHT was found to be a precursor of the ERβ agonist 5α-androstane-3β, 17β-diol (3βAdiol), the second estrogen in the body which did not require aromatase for its synthesis. ERβ was found to oppose androgen signaling and thus a potential target for treatment of prostate cancer. ERβ was also found to have effects that were independent of androgen signaling, particularly in the CNS. Although in rodent models of neurodegenerative diseases, ERβ agonists are very effective, this has not proven to be the case in humans. In this review we will focus on the main differences in ERβ signaling between rodents and humans and will make the point that the difference is in the splice variants which are expressed in humans and not rodents. The main conclusion is that before we think of using ERβ agonists clinically, much more work on ERβ signaling in the primate brain is needed.

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Behavior Testing in Rodents: Highlighting Potential Confounds Affecting Variability and Reproducibility

Brain Sciences ◽

10.3390/brainsci11040522 ◽

2021 ◽

Vol 11 (4) ◽

pp. 522

Author(s):

Rachel Michelle Saré ◽

Abigail Lemons ◽

Carolyn Beebe Smith

Keyword(s):

Neurodegenerative Diseases ◽

Outcome Measures ◽

Reproducibility Of Results ◽

Preclinical Studies ◽

Rodent Models ◽

Brain Disorders ◽

Housing Conditions ◽

Behavioral Measures ◽

Preclinical Testing ◽

Underlying Pathology

Rodent models of brain disorders including neurodevelopmental, neuropsychiatric, and neurodegenerative diseases are essential for increasing our understanding of underlying pathology and for preclinical testing of potential treatments. Some of the most important outcome measures in such studies are behavioral. Unfortunately, reports from different labs are often conflicting, and preclinical studies in rodent models are not often corroborated in human trials. There are many well-established tests for assessing various behavioral readouts, but subtle aspects can influence measurements. Features such as housing conditions, conditions of testing, and the sex and strain of the animals can all have effects on tests of behavior. In the conduct of behavior testing, it is important to keep these features in mind to ensure the reliability and reproducibility of results. In this review, we highlight factors that we and others have encountered that can influence behavioral measures. Our goal is to increase awareness of factors that can affect behavior in rodents and to emphasize the need for detailed reporting of methods.

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Animal Models of Metabolic Disorders in the Study of Neurodegenerative Diseases: An Overview

Frontiers in Neuroscience ◽

10.3389/fnins.2020.604150 ◽

2021 ◽

Vol 14 ◽

Author(s):

Andreza Fabro de Bem ◽

Rachel Krolow ◽

Hémelin Resende Farias ◽

Victória Linden de Rezende ◽

Daniel Pens Gelain ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Neurodegenerative Diseases ◽

Neurodegenerative Disorders ◽

Neuronal Death ◽

Metabolic Disorders ◽

Rodent Models ◽

Degenerative Diseases ◽

Barrier Dysfunction ◽

Interesting Approach

The incidence of metabolic disorders, as well as of neurodegenerative diseases—mainly the sporadic forms of Alzheimer’s and Parkinson’s disease—are increasing worldwide. Notably, obesity, diabetes, and hypercholesterolemia have been indicated as early risk factors for sporadic forms of Alzheimer’s and Parkinson’s disease. These conditions share a range of molecular and cellular features, including protein aggregation, oxidative stress, neuroinflammation, and blood-brain barrier dysfunction, all of which contribute to neuronal death and cognitive impairment. Rodent models of obesity, diabetes, and hypercholesterolemia exhibit all the hallmarks of these degenerative diseases, and represent an interesting approach to the study of the phenotypic features and pathogenic mechanisms of neurodegenerative disorders. We review the main pathological aspects of Alzheimer’s and Parkinson’s disease as summarized in rodent models of obesity, diabetes, and hypercholesterolemia.

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What is the pathological significance of tau oligomers?

Biochemical Society Transactions ◽

10.1042/bst20120135 ◽

2012 ◽

Vol 40 (4) ◽

pp. 693-697 ◽

Cited By ~ 34

Author(s):

Catherine M. Cowan ◽

Shmma Quraishe ◽

Amritpal Mudher

Keyword(s):

Neurodegenerative Diseases ◽

Tau Proteins ◽

Therapeutic Interventions ◽

Hyperphosphorylated Tau ◽

Rodent Models ◽

Protein Tau ◽

Microtubule Associated Protein Tau ◽

Toxic Species ◽

Tau Oligomers

Insoluble aggregates of the microtubule-associated protein tau characterize a number of neurodegenerative diseases collectively termed tauopathies. These aggregates comprise abnormally hyperphosphorylated and misfolded tau proteins. Research in this field has traditionally focused on understanding how hyperphosphorylated and aggregated tau mediates dysfunction and toxicity in tauopathies. Recent findings from both Drosophila and rodent models of tauopathy suggest that large insoluble aggregates such as tau filaments and tangles may not be the key toxic species in these diseases. Thus some investigators have shifted their focus to study pre-filament tau species such as tau oligomers and hyperphosphorylated tau monomers. Interestingly, tau oligomers can exist in a variety of states including hyperphosphorylated and unphosphorylated forms, which can be both soluble and insoluble. It remains to be determined which of these oligomeric states of tau are causally involved in neurodegeneration and which signal the beginning of the formation of inert/protective filaments. It will be important to better understand this so that tau-based therapeutic interventions can target the most toxic tau species.

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Autophagy and ageing: implications for age-related neurodegenerative diseases

Essays in Biochemistry ◽

10.1042/bse0550119 ◽

2013 ◽

Vol 55 ◽

pp. 119-131 ◽

Cited By ~ 37

Author(s):

Bernadette Carroll ◽

Graeme Hewitt ◽

Viktor I. Korolchuk

Keyword(s):

Neurodegenerative Diseases ◽

Energy Availability ◽

Future Studies ◽

Intracellular Degradation ◽

Age Related ◽

Autophagy Induction ◽

Social Importance ◽

Cellular Dysfunction ◽

Autophagy Activity ◽

Intense Research

Autophagy is a process of lysosome-dependent intracellular degradation that participates in the liberation of resources including amino acids and energy to maintain homoeostasis. Autophagy is particularly important in stress conditions such as nutrient starvation and any perturbation in the ability of the cell to activate or regulate autophagy can lead to cellular dysfunction and disease. An area of intense research interest is the role and indeed the fate of autophagy during cellular and organismal ageing. Age-related disorders are associated with increased cellular stress and assault including DNA damage, reduced energy availability, protein aggregation and accumulation of damaged organelles. A reduction in autophagy activity has been observed in a number of ageing models and its up-regulation via pharmacological and genetic methods can alleviate age-related pathologies. In particular, autophagy induction can enhance clearance of toxic intracellular waste associated with neurodegenerative diseases and has been comprehensively demonstrated to improve lifespan in yeast, worms, flies, rodents and primates. The situation, however, has been complicated by the identification that autophagy up-regulation can also occur during ageing. Indeed, in certain situations, reduced autophagosome induction may actually provide benefits to ageing cells. Future studies will undoubtedly improve our understanding of exactly how the multiple signals that are integrated to control appropriate autophagy activity change during ageing, what affect this has on autophagy and to what extent autophagy contributes to age-associated pathologies. Identification of mechanisms that influence a healthy lifespan is of economic, medical and social importance in our ‘ageing’ world.

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Nanotheranostic agents for neurodegenerative diseases

Emerging Topics in Life Sciences ◽

10.1042/etls20190141 ◽

2020 ◽

Vol 4 (6) ◽

pp. 645-675

Author(s):

Parasuraman Padmanabhan ◽

Mathangi Palanivel ◽

Ajay Kumar ◽

Domokos Máthé ◽

George K. Radda ◽

...

Keyword(s):

Drug Delivery ◽

Neurodegenerative Diseases ◽

Cell Types ◽

Specific Cell ◽

Ageing Population ◽

Target Tissue ◽

Therapeutic Approaches ◽

Surface Receptors ◽

Theranostic Agents ◽

Preclinical Animal Models

Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD) and Parkinson's disease (PD), affect the ageing population worldwide and while severely impairing the quality of life of millions, they also cause a massive economic burden to countries with progressively ageing populations. Parallel with the search for biomarkers for early detection and prediction, the pursuit for therapeutic approaches has become growingly intensive in recent years. Various prospective therapeutic approaches have been explored with an emphasis on early prevention and protection, including, but not limited to, gene therapy, stem cell therapy, immunotherapy and radiotherapy. Many pharmacological interventions have proved to be promising novel avenues, but successful applications are often hampered by the poor delivery of the therapeutics across the blood-brain-barrier (BBB). To overcome this challenge, nanoparticle (NP)-mediated drug delivery has been considered as a promising option, as NP-based drug delivery systems can be functionalized to target specific cell surface receptors and to achieve controlled and long-term release of therapeutics to the target tissue. The usefulness of NPs for loading and delivering of drugs has been extensively studied in the context of NDDs, and their biological efficacy has been demonstrated in numerous preclinical animal models. Efforts have also been made towards the development of NPs which can be used for targeting the BBB and various cell types in the brain. The main focus of this review is to briefly discuss the advantages of functionalized NPs as promising theranostic agents for the diagnosis and therapy of NDDs. We also summarize the results of diverse studies that specifically investigated the usage of different NPs for the treatment of NDDs, with a specific emphasis on AD and PD, and the associated pathophysiological changes. Finally, we offer perspectives on the existing challenges of using NPs as theranostic agents and possible futuristic approaches to improve them.

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