Frontiers in Clinical Drug Research - Alzheimer Disorders Volume 8

Atta-ur-Rahman

• Publisher: Bentham Science Publishers
• Year: 2019
• Print ISBN: 9789811401909
• eBook ISBN: 9789811401893
• Topic: Physical Sciences
• Subtopic: Clinical Chemistry

Frontiers in Clinical Drug Research - Alzheimer Disorders is a book series concerned with Alzheimer's disease (AD), a disease that causes dementia, or loss of brain function. This disease affects parts of the brain that affect memory, thought, and language. Chapters in each volume focus on drug research with special emphasis on clinical trials, research on drugs in advanced stages of development and cure for Alzheimer's disease and related disorders. Frontiers in Clinical Drug Research - Alzheimer Disorders will be of particular interest to readers interested in drug therapy of this specific neurodegenerative condition and related brain disorders as the series provides relevant reviews written by experts in the field of Alzheimer's disease research. The eighth volume of this series features chapters covering critical discussions on new therapies for AD. The reviews in this volume include: - Novel Molecular Targets of Tauopathy; Therapeutic and Diagnostic Applications - The Therapy of Alzheimer's Disease: Towards a New Generation of Drugs - Could Antibiotics Be Therapeutic Agents in Alzheimer's Disease? - Use of Antipsychotics in Patients with Alzheimer's Disease - Approaches Based on Cholinergic Hypothesis and Cholinesterase Inhibitors in the Treatment of Alzheimer's Disease - Potential Biological Mechanisms with Prophylactic Action in Rapid Cognitive Impairment in Late-Onset Alzheimer's Disease

The Therapy of Alzheimer’s Disease: Towards a New Generation of Drugs

Luca Piemontese^{1, *}, Fulvio Loiodice¹, Sílvia Chaves², Maria Amélia Santos²

¹ Dipartimento di Farmacia–Scienze del Farmaco, Università degli Studi di Bari “Aldo Moro”, Via E. Orabona 4, 70125 Bari, Italy

² Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1, 1049-001 Lisboa, Portugal

Abstract

The treatment of neurodegenerative diseases is one of the most urgent challenges for pharmaceutical industry and public institutions. Alzheimer’s disease (AD), in particular, is a severe age-dependent dementia, currently affecting 44.4 million people worldwide, and this number is estimated to rise to 131.5 million in 2050.

Only a few drugs are currently available for AD therapy, but these molecules are just able to temporarily improve the symptoms of the patients. Recently, important advancements have been achieved about the knowledge of this complex disease, even if, unfortunately, every attempt to obtain new efficient drugs for its therapy has failed.

Following the theory of the multifactorial origin of the disease, in the last decade, researchers mainly focused on the development of multi-target agents, acting on the classical features recognized as important against the onset of AD, such as NMDA receptor antagonism, inhibition of cholinesterases (ChEs) and beta-Secretase (BACE), as well as inhibition of beta amyloid peptide (Aβ) aggregation and antioxidant activity.

More recently, the modulation of dyshomeostasis of metal ions (i.e. copper, zinc and iron) in the AD patient brains, has been proposed as a disease-modifying therapeutic (DMT) strategy, due to their involvement in Aβ aggregation and in the formation of Reactive Oxygen Species (ROS). Noteworthy is the role of Peroxisome Proliferator-Activated Receptors (PPARs) in the onset of neurodegenerative diseases as well. PPARα expression levels have been reported to significantly decline in central nervous system (CNS) during the aging process. PPARγ, instead, is reported to have a neuroprotective effect, with a different mechanism that influences the Aβ precursor protein (APP) cleavage and the inflammatory response. The overexpression of certain types of ApoE also seems to increase the risk of developing AD. Therefore, the modulation of both PPAR subtypes seems to be a new interesting target to be explored.

Other innovative targets as well are currently studied to find the final breakthrough for the therapy of AD: a number of years have passed since the approval of the last active drug in the treatment of this pathology and people now need a new hope.

Keywords: Alzheimer’s Disease, Aβ Amyloid Plaques, Acetylcholinesterase Inhibitors, Disease-Modifying Agents, Donepezil, Innovative Targets, Insulin, Multi-Functional Drugs, Multitarget Therapy, Neurodegenerative Disease, Pioglitazone, PPARs, Type 2 Diabetes Mellitus, Type 3 Diabetes, Tacrine.

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^* Corresponding author Luca Piemontese: Dipartimento di Farmacia–Scienze del Farmaco, Università degli Studi di Bari “Aldo Moro”, Via E. Orabona 4, 70125 Bari, Italy; Tel: [phone]; E-mail: [email protected]

INTRODUCTION

Alzheimer’s disease (AD) is a widely recognized socioeconomic problem. Indeed, the average annual cost per patient is estimated in $15,000–20,000, firstly due to the assistance expenses for not auto-sufficient people [1], taking into account that the annual incidence is around 34/1000 persons over 60 years old, and the prevalence is up to 42.1% at age > 95 years [1^-4]. The impact of the pathology will be higher considering the wide increase of life expectancy in most of the world countries: it is estimated that, in the absence of effective therapies, the number of people with this dementia will reach 131.5 million by 2050 [5].

The pathology has been described for the first time by Aloïs Alzheimer in 1907 as an “unusual illness of the cerebral cortex”. His short communication, published in German language, was recently translated [6] to English and it reported the experience of the physician with a 51 years old woman, who suffered from uncommon cognitive impairment, characterized by disorientation in space and time, hallucinations, and progressive memory loss [6]. The post-mortem exam of the patient’s neuronal tissues showed a uniformly atrophic brain without macroscopic focal degeneration. However, further studies revealed many fibrils located next to each other, corresponding to the first observation of beta amyloid (Aβ) plaques [6]. This occurred around one century ago, but now this pathology is the most widespread neurodegenerative disease. It has a name (Alzheimer’s disease) but its etiology continues to be unknown [7, 8].

AD is characterized by a progressive deterioration of cognitive functions that can be linked to a significant reduction of the volume of the brain, the degeneration of synapses and the death of neurons, especially in hippocampus (this being the reason of progressive memory loss) [8^-10]. The Aβ plaques are located in the extracellular space while another kind of aggregates, very frequently found inside neuronal cells, are constituted by the so-called neurofibrillary tangles. These aggregates, which are also observed in Parkinson’s disease (PD), are composed of hyper-phosphorylated Tau proteins [8]. The presence of both structures is very often correlated in AD patients [8].

In the last years, many routes have been suggested for understanding AD pathogenesis and addressing relevant drug strategies to fight this pathology. The most commonly pursued approaches are the cholinergic and the amyloid hypotheses [11].

According to numerous research works, the damage of cholinergic neurons or simply the cholinergic activity deficit, frequently linked with AD onset, leads to an overall loss of acetylcholine activity [12]. Moreover, acetylcholinesterase (AChE) seems to play also a certain role in several secondary non-cholinergic functions and particularly in the deposition of Aβ in the extracellular environment of AD diagnosed brains [12]. A recent research has shown that, in addition to AChE, also butyrylcholinesterase (BChE) plays an important role in cholinergic neurotransmission, especially in normal central nervous system (CNS) [12, 13]. Based on this consideration, many studies suggest that a non-selective ChE inhibitor should lead to better clinical results [12, 14].

The Aβ peptides are produced by cleavage operated by β- and γ-secretase enzymes in the inter-synaptic environment on the membrane-anchored APP (β-Amyloid Precursor Protein). The activity of these proteases leads to oligomeric fragments that, following a natural aggregation process, become themselves active neurotoxins, therefore causing neuronal dysfunction, loss of synaptic connections and cell death [15]. Aβ peptide aggregates lead to the formation of amyloid plaques ...

Table of contents

• Welcome
• Table of Contents
• Title
• BENTHAM SCIENCE PUBLISHERS LTD.
• PREFACE
• List of Contributors
• Novel Molecular Targets of Tauopathy; Therapeutic and Diagnostic Applications
• The Therapy of Alzheimer’s Disease: Towards a New Generation of Drugs
• Could Antibiotics Be Therapeutic Agents in Alzheimer’s Disease?
• Use of Antipsychotics in Patients with Alzheimer’s Disease
• Approaches Based on Cholinergic Hypothesis and Cholinesterase Inhibitors in the Treatment of Alzheimer's Disease
• Potential Biological Mechanisms with Prophylactic Action in Rapid Cognitive Impairment in Late-Onset Alzheimer's Disease