Animal Models for Neurological Disorders

By Anil Kumar, Kanwaljit Chopra and Anurag Kuhad

Animal disease models are a vital tool to study diseases and associated conditions. Studies on animal models can, in some cases, be used as a basis for modeling and understanding human diseases. Biomedical scientists face a challenge to choose the correct animal model to study disease pathology, and neurological diseases are no exception to this rule.

Animal Models for Neurological Disorders covers different animal models which have been used for studying neurological disorders. 13 topical chapters have been contributed by a group of experts on the subject with an aim to cover emerging experimental models of a range of neurological diseases encountered in the clinic including Alzheimer’s disease, psychosis, Parkinson’s, Huntington’s disease, vascular dementia, schizophrenia, multiple sclerosis and brain tumors, among others. The chapters also inform readers about relevant clinical correlations in each disease model where appropriate.

Animal Models for Neurological Disorders is intended for all scholarly researchers and students of biomedical sciences, pharmacology, medicine (oncology, neurology, psychiatry), pharmacy, biochemistry, and biotechnology. The organized contents of the book also serve as a quick reference point for scientists working in applied areas of neuroscience including the study of neurodegenerative diseases and cognitive dysfunction in living organisms.

• Language: English
• Publisher: Bentham Science Publishers
• Release date: Dec 24, 2021
• ISBN: 9789815039689

Anil Kumar

Dr. Anil Kumar is a Staff Scientist at the National Institute of Immunology, New Delhi. Dr. Kumar received his master’s in biotechnology from Indian Institute of Roorkee, Roorkee and completed his Ph.D. from Institute of Genomics and Integrative Biology (CSIR), New Delhi, India. His research interest focuses on understanding the interactions within gut bacteria and between the gut flora, as well as how the result of the investigation may be helpful to devise strategies to promote human health and prevent diseases. As an inventor, he credits more than 50 granted patents for developing product & processes useful in different industries. He’s also published 50 research publications in national and international journals. He had participated in the development of biosensor which has been transferred to industry. In 2012, one of his patents has been selected for CSIR Technology Award 2012 and other US patent won Merck Millipore India Innovation Award 2012.

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Accelerating Alzheimer’s Disease Research by Pharmacologic, Genetic, and Computational Based Animal Models

Monika Kadian¹, Nitin Rawat¹, Hemprabha Tainguriya¹, Anil Kumar¹, *

¹ Pharmacology Department, University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Studies (UGC-CAS), Panjab University, Chandigarh 160014, India

Abstract

Alzheimer’s disease (AD) is a type of dementia characterized pathologically by inappropriate neuronal loss in the specific brain regions, mainly in the hippocampus and cerebral cortex, where an accumulation of insoluble plaques of amyloid-beta (Aβ) and tau tangles formation occurs, resulting in progressive memory loss, impaired thinking, deterioration and changes in personality and mood. Alzheimer’s disease now possesses a significant health burden and is considered the main source of inability among aged individuals. Recently, Alzheimer's Disease International (ADI) evaluations of 2019 featured that there would be more than 50 million individuals living with dementia around the world, a figure set to increment to 152 million by 2050. Somebody creates dementia-like clockwork, and the current year expense of dementia is assessed at US $1trillion, a figure set to twofold by 2030. AD is the leading cause of dementia and accounts for 60-80% of cases. In spite of the fact that Aβ conglomeration and neurofibrillary tangles (NFTs) development are notable major causative components engaged with AD pathogenesis, the researchers failed to cure or prevent progression of disease effectively by focusing on these pathogenic variables. Thus, tackling AD is a complex job, as we have erudite lately by continuous phase III clinical trial programs failures. Due to the lack of a clear etiology and increased morbidity associated with Alzheimer's disease, there is an immediate need to investigate the underlying causes of the disease and design and develop novel therapeutic agents to slow or reverse disease progression. Animal models mimicking different types of AD-like pathological conditions, which is an essential component in discovering potential therapeutic targets and studying mechanism of action behind that therapeutic agent, as we know, are primary tools in the field of biomedical research including AD. This chapter discusses emerging pathophysiological mechanisms and drug targets, as well as a summary of in-vivo/ex-vivo, in-vitro, QSAR, and in-silico models commonly used in Alzheimer's disease research. Moreover, we will also describe how to select suitable

and valid models and the specifications and relevance of a couple of behavioral assessment methods.

Keywords: Alzheimer’s disease, Behavioral animal models, In-silico models, Therapeutic strategies, Transgenic animal models.

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* Corresponding author Anil Kumar: Pharmacology Division, University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Study, Panjab University, Chandigarh 160014, India; Fax: [phone], 4106; Tel: [phone]; E-mail: [e-mail]

INTRODUCTION

Alzheimer’s disease (AD) is a progressive neurodegenerative disease of the brain involving neuropathological hallmarks such as deposition of plaques of amyloid-beta (Aβ) (outside nerve terminals), the existence of neurofibrillary tangles (NFTs- inside the neurons) produced by aberrantly hyper phosphorylated tau, progressive synaptic loss and neuron degeneration which further leads to decline in memory and cognitive functions as shown in Fig. (1) [1, 2]. For quite a long time, AD research has concentrated on the two obsessive neuropathological signs of the disease, i.e., amyloid plaques and NFTs. In spite of the fact that amyloid-beta conglomeration and NFTs development are notable major causative components engaged with AD pathogenesis, the researchers failed to cure or prevent the progression of disease effectively by focusing on these pathogenic variables. Tackling AD is a complex job, as we have erudite lately by continuous phase III clinical trial programs failures. The majority of these projects depended on the focusing of Aβ, prompted by amazing research discoveries that Aβ can be cleared from the human mind. Albeit some Aβ-bringing down compounds have applied quantifiable impacts on psychological results, these impacts have commonly been too little to even consider being genuinely critical and clinically significant [3]. Generally, AD is of two types; one is familial Alzheimer’s disease (FAD) and other sporadic Alzheimer’s disease (SAD), which is also known as early-onset of AD (EOAD) and late-onset AD (LOAD), respectively. Heredity of specific genes is a danger factor for AD, with both familial and sporadic cases happening. Genetic variations in amyloid precursor protein (APP), beta-secretase, and in presinilin-1 (PS1) and presenilin-2 (PS2) genes are thought to be liable for disease production in the FAD. Whereas, in SAD, which is the more normal category, there is a connection with the apolipoprotein 4 (APOE4) allele. The danger is more noteworthy in homozygotic circumstances and metabolic cycle disturbance [4-7]. In addition, ecological elements, vascular components, and psychical factors likewise add to the evolution of SAD. As of now, no medications are accessible to end the occurrence of neurodegeneration in AD; the idea of AD treatment is suggestive. For example, acetylcholinesterase enzyme inhibitors, Donepezil (brand name Aricept), Galantamine (Reminyl), Rivastigmine, and Tacrine (Cognex), that advance cholinergic neuronal signaling are utilized in gentle to direct instances of AD [8]. An alternate sort of medication, memantine (Namenda), antagonize N-methyl-D-aspartate (NMDA) receptor, may likewise be utilized, alone or in the mix with a cholinesterase enzyme inhibitor in moderate to serious cases to forestall excitotoxicity, and antipsychotics and antidepressants are utilized in the treatment of neuropsychiatric side effects [9]. At present, there is no established way to cure AD although research into prevention strategies is ongoing. Due to its complexity, it is far-fetched that any one medication or other intercessions can effectively prompt its legitimate treatment. Recent approaches center around assisting individuals with keeping up mental capacity, overseeing social side effects, and moderating or deferring the manifestations of illness [10, 11]. Scientists desire to create treatments focusing on explicit hereditary, sub-atomic, and cell systems with the goal that the genuine hidden reason for the sickness can be halted or forestalled.

Fig. (1))

Molecular mechanism in inhibit A-beta production, clearance, and prevent aggregation. APP: Amyloid precursor protein; AICD: APP intracellular domain; Aβ: Amyloid-beta; BACE: beta-site APP cleaving enzyme 1.

The biggest problem in AD drug development is doubtful mechanisms inherent AD pathogenesis and pathophysiology. Several reported research and existing literature aid the concept that AD is a complex illness. While there is ample manifestation that amyloid plaque is responsible for the pathogenesis of AD, other possible mechanisms have been involved in AD-like tangle formation (tau-tangle) and outspread, neuroinflammation, and altered protein degradation pathways. Therefore, the present-day epitome of AD drug design and development has been modified from a one-on-one target area to a multi-target approach. Here, in this chapter, we will also sum up current techniques and a new way of drug development in the area of AD research, including animal-based (pre-clinical) and human-based (clinical trials), studies that mark on the various facet of the disease [12]. As we know, animal models intended to be used for examining human sicknesses came out in the 1800s and presented a leading hike during the last few decades. Rodents models are primary tools in the field of biomedical research, including AD [13]. The animal models mimic different types of AD-like pathological conditions, which is an essential component in discovering potential therapeutic targets and studying the mechanism of action behind that therapeutic agent. They are also helpful in the development and assessment of mechanical hypotheses about neurological and neurodegenerative disorders, including AD, and in identifying and screening novel therapeutic agents. Several rodent models are present to interpret the basic underlying pathological mechanism of AD and screen novel therapeutically active agents for the treatment of AD. Although the rodent models do not reproduce true clinical conditions of the AD, however, neuropathological similarity to human AD patients make them a valuable mean of studying AD pathology [6]. The real value of an animal model and its applicability are ascertained by various levels of validity [14, 15], as depicted in Table 1.

Table 1 Animal models: levels of validity.

The more degrees of legitimacy a model fulfills, the more prominent its worth, utility, and pertinence to the human condition. However, generally, animal models do not meet all of these criteria. Generally, the most common manifestation of AD is cognitive decline. The final output signal for any intercessions ought to be assessed by the trial of learning and memory. Although countless rodent models and behavior assessment strategies have been extensively utilized in studies of underlying mechanisms and screening of novel remedial moieties, a big variableness still exists within the methodological analysis, particularly in how rodent models are being used and why the specific one. For selecting a suitable and effective model for AD research studies, it is crucial to realize the basic fundamental properties and relevance of the animal models and behavioral change screening methods [16]. This chapter also provides a brief summary of in-vivo/ex-vivo, in-vitro, QSAR or in-silico models that are commonly used in AD research.

Current AD Therapeutic Strategies and Targets

In this section, we are focusing on current AD restorative techniques which involve system based methodologies including Aβ drainage, tau protein stores, ApoE capacity, neuroprotection, and neuroinflammation, just as non-mechanism based methodologies including indicative psychological incitement, AD anticipation, way of life adjustments, and hazard factor the executives including non-pharmacological intercessions [12] as shown in Fig. (2). Here, we also described AD drugs and targeted therapies studied in clinical trials (Table 2). Moreover, we also provide a brief description of behavioral models (Table 3), chemically induced animal models and their reported studies (Tables 4 & 5), transgenic animal models (Table 6), miscellaneous animal models (Table 7) of AD. Later, we described in-vitro models (Table 8) and experimental species used for AD and their significance and limitations (Table 9) and also depicted translational concerns with animal models in AD (Fig. 3).

Fig. (2))

Current AD therapeutic strategies and targets. Aβ: amyloid-beta, AD: Alzheimer’s disease, ApoE: apolipoprotein-E.

Table 2 AD drugs and targeted therapies studied in clinical trials [12].

Table 3 Commonly used behavioral model in AD [17].

Table 4 Chemically induced animal models of AD.