Nanomedicine and Neurosciences: Advantages, Limitations and Safety Aspects

Giovanni Tosi

• Publisher: Bentham Science Publishers
• Year: 2017
• Print ISBN: 9781681084947
• eBook ISBN: 9781681084930
• Topic: Physical Sciences
• Subtopic: Nanoscience

Frontiers in Nanomedicine offers an up-to-date understanding of nanomaterials to readers having clinical or biomolecular research interests. Scientists, both aspiring and experienced, will find, in each volume, a comprehensive overview of current molecular strategies for using nanoscale materials in medicine.
Nanomedicine and Neurosciences: Advantages, Limitations and Safety Aspects presents different aspects of nanomedicine applied to neuroscience for the diagnosis of disease and the role of nanoparticles in targeted drug delivery systems for neurodegenerative disorders. Topics covered in this volume cover the physiology of neurodegeneration, targeted therapies for Alzheimer's disease and Parkinson's disease, blood brain barrier drug delivery systems, in vivo studies of drug nanoconjugates, nanomedicine safety, and more.

Nanomedicine and Neurodegenerative Diseases: An Introduction to Pathology and Drug Targets

Tasnuva Sarowar¹, Andreas M. Grabrucker^{2, *}

¹ Institute for Anatomy and Cell Biology, Ulm University, Ulm, Germany

² Department of Biological Sciences, University of Limerick, Limerick, Ireland

Abstract

Neurodegenerative diseases are debilitating conditions that result in progressive degeneration and death of neuronal cells. One of the hallmarks of neurodegenerative diseases is the formation of protein aggregates. Progressive accumulation of similar protein aggregates is recognized as a characteristic feature of many neurodegenerative diseases. Particularly in Parkinson’s Disease (PD), aggregated forms of the protein α-synuclein (α-syn); and in Alzheimer's Disease (AD) and cerebral amyloid angiopathy (CAA), aggregated Aβ amyloid fibrils form the basis of parenchymal plaques and of perivascular amyloid deposits, respectively. In Amyotrophic Lateral Sclerosis (ALS), the RNA-binding protein TDP-43 is prone to aggregation. The focal aggregates at early disease stages later on result in the spreading of deposits into other brain areas and many neurodegenerative diseases display a characteristic spreading pattern. Here, we will summarize the anatomy and pathology of the predominant neurodegenerative diseases focusing on AD and PD and review their clinical manifestation to highlight the urge of novel therapeutic strategies. Additionally, given that development of treatments requires suitable animal models, the most commonly used model systems are introduced and their pathology compared to the human situation is mentioned briefly. Finally, possible drug targets in neurodegenerative diseases are discussed.

Keywords: Alzheimer’s Disease, Amyotrophic Lateral Sclerosis, Animal models, Drug targets, Dementia, Lewy Bodies, Neurodegeneration, Parkinson’s Disease, Synuclein, TDP-43 Tau pathology, β-Amyloid.

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^* Corresponding author Andreas M. Grabrucker: Department of Biological Sciences, University of Limerick, Limerick, Ireland; Tel: [phone]; E-mail: [email protected]

INTRODUCTION

The foundation for the definition of modern neurological disease entities was laid in the middle of the 19th century when Jean-Martin Charcot tried to relate - at this time mysterious - clinical phenotypes toneuro-anatomical findings. In post mortem studies, he demonstrated such a relation for Amyotrophic Lateral Sclerosis (ALS) and Multiple Sclerosis (MS). Subsequently, the increasing interest in therapeutic approaches, including disease modification and prevention, fueled the interest in longitudinally studies that formally assess disease pathology. To that end, the use of molecular markers for a specific pathology such as synuclein for Parkinson´s Disease (PD) and tau for Alzheimer´s Disease (AD) became a useful tool to describe the pre-symptomatic and symptomatic stages of a disorder. Findings from these studies led to the current understanding of the pathology of neurodegenerative diseases, which is characterized by an initiation- and propagation phase of the disease process.

Today, the term “Neurodegenerative disease” is used for a wide range of conditions primarily affecting neurons in the brain and spinal cord. Given the inability of neurons to perform cell division and to replace themselves, progressive neuronal cell death is an irrevocable and, over time, cumulative process. The most prominent examples of neurodegenerative diseases include Parkinson’s, Alzheimer’s, Huntington’s Disease (HD) and Amyotrophic Lateral Sclerosis (ALS). Neurodegenerative diseases may be hereditary or sporadic conditions.

Ongoing neuronal loss ultimately leads to problems with movement (called ataxias), or mental functioning (called dementias). With approximately 60-70% of cases, AD represents the greatest burden within the group of dementias. Other neurodegenerative diseases are Prion Disease, Multiple Sclerosis, Spino-cerebellarataxia (SCA) or Spinal Muscular Atrophy (SMA). However, hundreds of different disorders fulfill the criteria for a neurodegenerative disease.

Currently, the life expectancies of the general populations in both developed and developing countries are increasing, which affect the prevalence of neurodegenerative disorders (Table. 1). This creates an enormous socio-economic burden with a total cost of hundreds of billion Euro per year in Europe alone [1].

Table 1 Age and gender specific prevalence rates (%) of dementia and PD in Europe [2].

	Dementia		Parkinson
Age group (years)	♂	♀	♂	♀
65-69	1.8	1.4	0.7	0.6
70-74	3.2	3.8	1	1
75-79	7	7.6	2.7	2.8
80-84	14.5	16.4	4.3	3.1
85-89	20.9	28.5	3.8	3.4
>90	32.4	48.8	2.2	2.6

Thus, research in the field of neurodegenerative disorders and the translation of the findings in this area to novel treatment strategies are an urgent and important goal. Fortunately, in recent years, our understanding of the anatomy and pathology of neurodegenerative diseases have made good progress.

CLINICAL REPRESENTATIONS

Alzheimer's Disease

AD is a progressive neurodegenerative disorder, which is described as the most common form of dementia nowadays. It was first described in 1907 by the German psychiatrist and neuropathologist Dr. Alois Alzheimer after observing a 55 years old patient named Auguste Deter. In general, AD patients suffer from disturbances in cognitive function or information processing like reasoning, planning, language & perception; which lead to a significant decrease in the quality of life. Besides other factors, age is the main contributing factor (Table. 1) where 30% of individuals aged more than 85, develop the disease. A new case of AD is diagnosed worldwide every 7 seconds [3] and it is estimated that at least 34 million people will be suffering from AD by 2025, in both industrialized and developing countries [4].

Core Features of AD

AD can be divided into two groups based on the onset of the disease- early onset AD and late onset AD. In early onset, the disease occurs before the age of 65 and in late onset, the disease occurs after 65. Most of the patients are usually late onset as early onset accounts for only around 5% of the total disease occurrence. However, studies show that early onset AD is associated with high mortality and morbidity whereas late onset is much more common with less morbidity and mortality [5]. The disease progression of early onset AD is often predictable and it is possible to express the stage numerically using scales like Global Deterioration Scale [6] or Clinical Dementia Rating Scale [7]. The symptoms usually start around the age of 70. Patients show impairment in memory, problem solving, planning, judgment, language and visual perception. Some also suffer from hallucination and delusion. Eventually, the condition worsens and the patients are unable to carry out normal day-to-day functions and become bed-ridden. They need extensive palliative care and often die of other medical conditions [8^-10].

Symptoms & Diagnosis of AD

The accuracy of diagnosis has increased many-fold since 1970. Today, it is possible to diagnose AD with more than 90% accuracy. However, except for brain autopsy, there is currently no definitive way to diagnose AD. To differentiate AD accurately from other forms of dementia, physicians rely on neuroimaging, psychiatric assessments, laboratory assessments and various other diagnostic tools.

Since 1984, AD has been diagnosed according to the National Institute of Neurological and Communicative Disorders an...

Table of contents

• Welcome
• Table of Contents
• Title Page
• BENTHAM SCIENCE PUBLISHERS LTD.
• FOREWORD
• PREFACE
• List of Contributors
• Nanomedicine and Neurodegenerative Diseases: An Introduction to Pathology and Drug Targets
• Nanoparticles Targeting Mitochondria in Neurodegenerative Diseases: Toxicity and Challenge for Nanotherapeutics
• Neuronal Mechanisms for Nanotopography Sensing
• Drug Delivery to the Brain by Liposomal Carrier Systems
• Neuronopathic LSDs: Quest for Treatments Drives Research in Nanomedicine and Nanotechnology
• Targeting Brain Disease in Mucopolysaccharidoses
• Functional Validation of Drug Nanoconjugates in vivo
• How does “Protein Corona” Affect the In vivo Efficiency of Polymeric Nanoparticles? State of Art
• Safety of Nanomedicine: Neuroendocrine Disrupting Potential of Nanoparticles and Neurodegeneration