Animal Models of Neurodegenerative Diseases

Author(s):  
David Baglietto-Vargas ◽  
Rahasson R. Ager ◽  
Rodrigo Medeiros ◽  
Frank M. LaFerla

The incidence and prevalence of neurodegenerative disorders (e.g., Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD), etc.) are growing rapidly due to increasing life expectancy. Researchers over the past two decades have focused their efforts on the development of animal models to dissect the molecular mechanisms underlying neurodegenerative disorders. Existing models, however, do not fully replicate the symptomatic and pathological features of human diseases. This chapter focuses on animal models of AD, as this disorder is the most prevalent of the brain degenerative conditions afflicting society. In particular, it briefly discusses the current leading animal models, the translational relevance of the preclinical studies using such models, and the limitations and shortcomings of using animals to model human disease. It concludes with a discussion of potential means to improve future models to better recapitulate human conditions.

Biomolecules ◽  
2020 ◽  
Vol 10 (8) ◽  
pp. 1158 ◽  
Author(s):  
Dongmei Chen ◽  
Tao Zhang ◽  
Tae Ho Lee

Neurodegenerative diseases are the second most common cause of death and characterized by progressive impairments in movement or mental functioning in the central or peripheral nervous system. The prevention of neurodegenerative disorders has become an emerging public health challenge for our society. Melatonin, a pineal hormone, has various physiological functions in the brain, including regulating circadian rhythms, clearing free radicals, inhibiting biomolecular oxidation, and suppressing neuroinflammation. Cumulative evidence indicates that melatonin has a wide range of neuroprotective roles by regulating pathophysiological mechanisms and signaling pathways. Moreover, melatonin levels are decreased in patients with neurodegenerative diseases. In this review, we summarize current knowledge on the regulation, molecular mechanisms and biological functions of melatonin in neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, vascular dementia and multiple sclerosis. We also discuss the clinical application of melatonin in neurodegenerative disorders. This information will lead to a better understanding of the regulation of melatonin in the brain and provide therapeutic options for the treatment of various neurodegenerative diseases.


Author(s):  
Debanjan Kundu ◽  
Vikash Kumar Dubey

Abstract:: Various neurodegenerative disorders have molecular origin but some common molecular mechanisms. In the current scenario, there are very few treatment regimens present for advanced neurodegenerative diseases. In this context, there is an urgent need for alternate options in the form of natural compounds with an ameliorating effect on patients. There have been individual scattered experiments trying to identify potential values of various intracellular metabolites. Purines and Pyrimidines, which are vital molecules governing various aspects of cellular biochemical reactions, have been long sought as crucial candidates for the same, but there are still many questions that go unanswered. Some critical functions of these molecules associated with neuromodulation activities have been identified. They are also known to play a role in foetal neurodevelopment, but there is a lacuna in understanding their mechanisms. In this review, we have tried to assemble and identify the importance of purines and pyrimidines, connecting them with the prevalence of neurodegenerative diseases. The leading cause of this class of diseases is protein misfolding and the formation of amyloids. A direct correlation between loss of balance in cellular homeostasis and amyloidosis is yet an unexplored area. This review aims at bringing the current literature available under one umbrella serving as a foundation for further extensive research in this field of drug development in neurodegenerative diseases.


2021 ◽  
Vol 16 ◽  
pp. 263310552110187
Author(s):  
Christopher D Link

Numerous studies have identified microbial sequences or epitopes in pathological and non-pathological human brain samples. It has not been resolved if these observations are artifactual, or truly represent population of the brain by microbes. Given the tempting speculation that resident microbes could play a role in the many neuropsychiatric and neurodegenerative diseases that currently lack clear etiologies, there is a strong motivation to determine the “ground truth” of microbial existence in living brains. Here I argue that the evidence for the presence of microbes in diseased brains is quite strong, but a compelling demonstration of resident microbes in the healthy human brain remains to be done. Dedicated animal models studies may be required to determine if there is indeed a “brain microbiome.”


Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 142
Author(s):  
Mariella Cuomo ◽  
Luca Borrelli ◽  
Rosa Della Monica ◽  
Lorena Coretti ◽  
Giulia De Riso ◽  
...  

The bidirectional microbiota–gut–brain axis has raised increasing interest over the past years in the context of health and disease, but there is a lack of information on molecular mechanisms underlying this connection. We hypothesized that change in microbiota composition may affect brain epigenetics leading to long-lasting effects on specific brain gene regulation. To test this hypothesis, we used Zebrafish (Danio Rerio) as a model system. As previously shown, treatment with high doses of probiotics can modulate behavior in Zebrafish, causing significant changes in the expression of some brain-relevant genes, such as BDNF and Tph1A. Using an ultra-deep targeted analysis, we investigated the methylation state of the BDNF and Tph1A promoter region in the brain and gut of probiotic-treated and untreated Zebrafishes. Thanks to the high resolution power of our analysis, we evaluated cell-to-cell methylation differences. At this resolution level, we found slight DNA methylation changes in probiotic-treated samples, likely related to a subgroup of brain and gut cells, and that specific DNA methylation signatures significantly correlated with specific behavioral scores.


Author(s):  
Diane Moujalled ◽  
Andreas Strasser ◽  
Jeffrey R. Liddell

AbstractTightly orchestrated programmed cell death (PCD) signalling events occur during normal neuronal development in a spatially and temporally restricted manner to establish the neural architecture and shaping the CNS. Abnormalities in PCD signalling cascades, such as apoptosis, necroptosis, pyroptosis, ferroptosis, and cell death associated with autophagy as well as in unprogrammed necrosis can be observed in the pathogenesis of various neurological diseases. These cell deaths can be activated in response to various forms of cellular stress (exerted by intracellular or extracellular stimuli) and inflammatory processes. Aberrant activation of PCD pathways is a common feature in neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, resulting in unwanted loss of neuronal cells and function. Conversely, inactivation of PCD is thought to contribute to the development of brain cancers and to impact their response to therapy. For many neurodegenerative diseases and brain cancers current treatment strategies have only modest effect, engendering the need for investigations into the origins of these diseases. With many diseases of the brain displaying aberrations in PCD pathways, it appears that agents that can either inhibit or induce PCD may be critical components of future therapeutic strategies. The development of such therapies will have to be guided by preclinical studies in animal models that faithfully mimic the human disease. In this review, we briefly describe PCD and unprogrammed cell death processes and the roles they play in contributing to neurodegenerative diseases or tumorigenesis in the brain. We also discuss the interplay between distinct cell death signalling cascades and disease pathogenesis and describe pharmacological agents targeting key players in the cell death signalling pathways that have progressed through to clinical trials.


2016 ◽  
Vol 116 (6) ◽  
pp. 2777-2788 ◽  
Author(s):  
Richard F. Lewis

Damage to the peripheral vestibular system can result in debilitating postural, perceptual, and visual symptoms. A potential new treatment for this clinical problem is to replace some aspects of peripheral vestibular function with an implant that senses head motion and provides this information to the brain by stimulating branches of the vestibular nerve. In this review I consider animal studies performed at our institution over the past 15 years, which have helped elucidate how the brain processes information provided by a vestibular (semicircular canal) implant and how this information could be used to improve the problems experienced by patients with peripheral vestibular damage.


2020 ◽  
Vol 40 (1) ◽  
Author(s):  
Kento Otani ◽  
Takashi Shichita

AbstractTherapeutic strategies for regulating neuroinflammation are expected in the development of novel therapeutic agents to prevent the progression of central nervous system (CNS) pathologies. An understanding of the detailed molecular and cellular mechanisms of neuroinflammation in each CNS disease is necessary for the development of therapeutics. Since the brain is a sterile organ, neuroinflammation in Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS) is triggered by cerebral cellular damage or the abnormal accumulation of inflammatogenic molecules in CNS tissue through the activation of innate and acquired immunity. Inflammation and CNS pathologies worsen each other through various cellular and molecular mechanisms, such as oxidative stress or the accumulation of inflammatogenic molecules induced in the damaged CNS tissue. In this review, we summarize the recent evidence regarding sterile immune responses in neurodegenerative diseases.


2020 ◽  
Vol 10 (11) ◽  
pp. 858
Author(s):  
Antonio Dominguez-Meijide ◽  
Eftychia Vasili ◽  
Tiago Fleming Outeiro

Tauopathies are neurodegenerative disorders characterized by the deposition of aggregates composed of abnormal tau protein in the brain. Additionally, misfolded forms of tau can propagate from cell to cell and throughout the brain. This process is thought to lead to the templated misfolding of the native forms of tau, and thereby, to the formation of newer toxic aggregates, thereby propagating the disease. Therefore, modulation of the processes that lead to tau aggregation and spreading is of utmost importance in the fight against tauopathies. In recent years, several molecules have been developed for the modulation of tau aggregation and spreading. In this review, we discuss the processes of tau aggregation and spreading and highlight selected chemicals developed for the modulation of these processes, their usefulness, and putative mechanisms of action. Ultimately, a stronger understanding of the molecular mechanisms involved, and the properties of the substances developed to modulate them, will lead to the development of safer and better strategies for the treatment of tauopathies.


Author(s):  
William Harnett ◽  
Margaret M. Harnett

There has been an alarming increase in the incidence of autoimmune and allergic diseases in Western countries in the past few decades. However, in countries endemic for parasitic helminth infections, such diseases remain relatively rare. Hence, it has been hypothesised that helminths may protect against the development of autoimmunity and allergy. This article reviews the evidence supporting this idea with respect to helminths of the phylum Nematoda (nematodes), considering data from human studies and animal models of inflammatory disease. The nature and mode of action of nematode-derived molecules with immunomodulatory properties are considered, and their therapeutic efficacy in models of autoimmunity and allergy described. The recent and future use of nematodes and their products in treating human disease are also discussed.


e-Neuroforum ◽  
2017 ◽  
Vol 23 (4) ◽  
Author(s):  
Olga Garaschuk

AbstractMicroglia are the main immune cells of the brain contributing, however, not only to brain’s immune defense but also to many basic housekeeping functions such as development and maintenance of functional neural networks, provision of trophic support for surrounding neurons, monitoring and modulating the levels of synaptic activity, cleaning of accumulating extracellular debris and repairing microdamages of the brain parenchyma. As a consequence, age-related alterations in microglial function likely have a manifold impact on brain’s physiology. In this review, I discuss the recent data about physiological properties of microglia in the adult mammalian brain; changes observed in the brain innate immune system during healthy aging and the probable biological mechanisms responsible for them as well as changes occurring in humans and mice during age-related neurodegenerative disorders along with underlying cellular/molecular mechanisms. Together these data provide a new conceptual framework for thinking about the role of microglia in the context of age-mediated brain dysfunction.


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