Alzheimer's disease (AD) is a progressive, degenerative, and often fatal neurological disorder. This disorder is clinically attributed to a progressive loss of memory and cognitive functions, eventually culminating in difficulty in carrying out the simplest of tasks. Currently, AD is ranked as the sixth leading cause of death in the United States but is projected to be ranked third, just after cardiovascular diseases and cancer. In 2020, the total payments for healthcare, long-term and hospice care for people aged 65 years and above, amounted to around $305 billion, raising a grave public health concern. Despite epidemiological research statistics directed towards a global Alzheimer’s epidemic, the current physician’s armamentarium comprises only treatments that provide brief symptomatic relief to the patients.
The prime intent of the book titled, ‘Enzymatic Targets for Drug Discovery against Alzheimer’s Disease’, is to present a comprehensive approach to AD sheerly based on molecular, clinical, and translational research, while addressing the novel targets and recent research in the progression, development, and prevention of AD. However, all the broad multi-disciplinary research in AD would be beyond the purview of the book. Instead, the book would shed light on the various novel mechanistic pathways in the development, diagnosis, and prevention of AD, which would certainly be thoroughly studied and established in the years to come. These chapters address thought-provoking and challenging ideas that could be of great interest to those, both in and out of the AD sector. It is gratifying to receive 15 exceptional contributions that skillfully craft the current book.
Globally, researchers have been relentlessly working to develop treatments and therapeutics to curb the risk and danger inflicted by AD. This has facilitated the unfolding of the byzantine signaling pathways and several contributing factors that form the basis of sporadic AD. The revelation of the latter has engaged multidisciplinary research converging from genetics, pharmacogenomics, proteomics, cell signaling and metabolomics, human nutrition, and physical education, to list a few. The most noteworthy grounds of research include the mechanisms of amyloid plaque depositions, the natural mechanism of deposited amyloid- β plaques (Aβ), and employing anti-Aβ antibodies. However, a deeper understanding of byzantine pathways precedes the development of newer drug molecules and treatment regimens. This would result in the formulation and development of novel drugs for the treatment of AD, and alleviating the symptoms associated with the latter.
This book comprises 15 chapters written by a group of eminent experts in various facets of AD research. These chapters elucidate the recent advances, observations, challenges, and future prospects of various pathways involved in the precipitation of AD. This would further direct the development of drugs that modulate and/or intercept these signaling pathways in a variety of ways.
AD has become the prototype of menacing neurodegenerative diseases. The rising public health concern has elicited the need for remedies at affordable prices, to ensure universal health coverage. In the first chapter, Dorababu underscores recent advances in the design and development of various tacrine-based anti-Alzheimer’s. Recent research also reveals that heterocyclic scaffold-based drugs have potent pharmacology. Tacrine was one such quinoline-containing heterocyclic compound, which was an acetylcholinesterase inhibitor. However, it was withdrawn from the commercial markets because of its toxicity profile. To address this, tacrine is currently being chemically modified to produce safer, more effective, and more potent anti-Alzheimer’s drugs and to develop their structure-activity relationship maps.
To develop these drugs and ensure their efficient delivery, it is imperative to understand the causal mechanism underlying the pathogenesis. From a clinical point of view, another challenge would be to distinguish and diagnose the type and velocity of AD, to devise the treatment regimen. Chapter 2 authored by Adiga et al. aims to explore the epigenetics of AD, which have transpired as key modulators in the pathogenesis and progression of AD. The authors opine that these modalities would prove to be novel and reliable in diagnosing and demarcating different types of AD, directing towards personalized medications.
With the advent of technology in the healthcare sector, there have been several signaling pathways that have been attributed to the progression and development of AD. One such molecule is TMP21, which is imperative in the trafficking of cellular proteins. Dysregulation of this protein has been linked to the production of neurotic plaques, which is the clinical characteristic of AD. The article would aim to explore the various facets that have been correlated to TMP21 dysregulation and the formation of neurofibrillary tangles, synaptic disbalance, and subsequent nerve cell death.
Although Aβ plaques and neurofibrillary tangles (NFT) are potential neuropathological markers, the role of inflammation in the pathogenesis of AD cannot be ignored. Neurodegeneration is caused by abnormal detachment of microtubules (MT) from axon MTs, cellular mislocalization, and tau hyperphosphorylation. Tau's ability to aggregate and form NFTs is thought to be regulated by post-translational modifications, which are thought to be an important regulatory mechanism. Drugs that target tau phosphorylation and aggregation have so far failed to show any therapeutic benefit. The recent finding including deleterious mutations in enzymes involved in the surface modification of MT adds to the relevance of such enzymatic machinery in neurobiology. Chapter 4 authored by Shrivastava et al., presents the therapeutic potential of pharmacologically targeting tubulin-modifying enzymes in the treatment of neurodegenerative diseases, especially AD.
Although several drugs have been studied and researched for the treatment of AD, only a few therapies have been approved by the FDA, especially due to neurotoxicity issues. Memantine is one such drug that resolves the neurotoxicity issue. It acts on glutamate and its receptors to provide a treatment to combat AD. Chapter 5 authored by Kore et al. attempts to review the available literature on memantine and other glutamate antagonists used to alleviate symptoms associated with AD.
Irrespective of the causal factor, neuronal cell depletion is often the predominant factor for AD. However, for the treatment of AD, drug delivery remains a major concern, due to poor permeability, which limits the therapeutic utility of drugs. Chapter 6 of this book authored by Geetha et al, intends to review the novel approaches reported for therapeutic management, as well as to counteract the conventional therapeutic limitation of AD.
With conventional therapies tossed out, nanotechnology has become the new promising hope for the treatment of AD. Since, the constraints created by the blood-brain barrier surrounding the CNS impede drug delivery to the central nervous system for AD therapy, decreasing therapeutic bioavailability. To overcome these barriers to the effective delivery of medications to the CNS, a wide range of nanoparticle devices are available. The goal of chapter 7 authored by Yadav et al. is to describe and highlight recent advances in nanotechnology-based medicines and their implications for the treatment of AD.
However, these nanotechnological interventions must be attributed to a target for the successful therapeutic outcome in the patient. In addition, many targets have been identified for possible therapeutics, and from these targets, numerous drug candidates have been evaluated in clinical trials. Unfortunately, most of these trials failed due to the enigmatic nature of this disease. Currently, there are 7103 AD targets listed on the Open Targets Platform, where 1240 of them are enzyme-related. The chapter by Ozgen et al. aims to explore the various enzymatic targets of AD, which have been claimed to possess disease-modifying effects, according to their clinical significance.
After the administration of the drug, the side effects are often inevitable, due to the intrinsic nature of the drug and/or drug therapy. Furthermore, the growing body of evidence has implied that the regular use of currently available anti-Alzheimer's drugs, which provide symptomatic relief in AD, still causes harmful effects such as mood disorders, sleeplessness, and depression. The importance of sirtuins in cellular biological control and neurological deficits has increased understanding of their novel role, with particular relevance to Alzheimer's disease. The data curated by Bhushan et al. in Chapter 9 have thoroughly reviewed the imperative role of sirtuins in the pathogenesis of AD, while simultaneously providing a prospect for drug discovery and delivery.
The structure-activity relationship for various benzothiazolourea derivatives has demonstrated outstanding potential in the alteration of illnesses against the CNS. Chapter 10, by Tiwari et al., aims to curate and compare the statistics acquired from several data sources that demonstrate the potential effect of benzothiazolourea derivatives on the production of a significant lead compound. To date, inhibiting acetylcholine esterase is one of the key Alzheimer's processes discovered. Thus, innovative benzothiazole design and development could have a wide range of applications in the treatment of Alzheimer's disease.
Tau neuronal and glial abnormalities drive the clinical symptoms of Alzheimer's disease (AD) and are often related to human tauopathies. Due to its lack of a stable structure and high flexibility, tau, a microtubule-associated protein, is intrinsically disordered. In the brains of people diagnosed with AD and other tauopathies, intracellular inclusions of fibrillar tau with a sheet structure accumulate. As a result, tau dissociation from microtubules and tau transformation from a disordered to an improperly aggregated state are crucial processes before tau-related disorders manifest. Chapter 11, by Dubey et al., aims to explore the efficacy of some of the most well-developed and/or commercialized molecules, in both pre-clinical and clinical studies for research pertaining to tau-targeted therapies.
The effectiveness of traditional Alzheimer's medications is heavily dependent on physiological factors such as the blood-brain barrier, the blood-cerebrospinal fluid barrier, and drug efflux by P-glycoprotein, all of which limit AD therapies' ability to make it to the central nervous system (CNS). The blood-brain barrier protects the central nervous system, while simultaneously limiting the access of therapeutic compounds to it. Therefore, to overcome the barrier and existing restrictions that CNS drugs face in crossing the BBB, novel drug development approaches have become a necessity. Several nano carrier-based techniques successfully address this goal by improving efficacy and facilitating the continuous release of encapsulated AD medication via targeted drug delivery. The study in chapter 12 by Kumari et al. aims to review these nanocarriers, which would mark a milestone in the nanotechnology-based drug delivery options to alleviate symptoms and provide remission from AD.
The function of carbonic anhydrase (CA) and its isoenzymes in Alzheimer's disease (AD) pathology have garnered the interest of researchers all over the world since their discovery in several AD models and the brains of AD patients. The release of the pro-apoptotic factor Cytochrome C (Cyt C) from challenged mitochondria was significantly reduced after treatment with a carbonic anhydrase inhibitor (CAI). As a result, a link was discovered between aging, oxidative stress, mitochondrial malfunction, and AD etiology. Chapter 13 by Bhatnagar et al. aims to review the effects of these CAIs on mitochondrial dysfunction and consequently on AD, which could prove to be a viable strategy for future developments.
Despite decades of study on novel drugs and therapy regimens, AD still has limited treatment options. Although currently available drugs for AD do not slow or stop the progression of the disease, they are used to treat symptoms and provide temporary relief to patients. In recent years, there has been a rise in interest in understanding the mechanism of AD due to the introduction of drugs and other therapy modalities to address an unmet medical need. Somatostatin-evoked Aβ catabolism in the brain is intercepted via the -endosulfan-KATP channel route, according to a growing body of evidence. Chapter 14 by Varghese et al. aims to explore Somatostatin-evoked Aβ catabolism in their endeavour for the pursuit of drug design in Alzheimer’s disease. The latter can be accomplished by repurposing or repositioning medications that have previously been approved by regulatory bodies and are used to treat different ailments. This study can potentially be a landmark in the treatment of diseases and could revolutionize the way neurodegenerative diseases, especially AD, are perceived and treated. Additionally, the repurposing of the pre-approved drugs would mean no loss of time for the conduction of extensive clinical trials for safety and toxicity profiles. Thus, success in this could potentially be the next treatment regimen for remission from AD. The last chapter 15 by Manjunath et al. delves deep into non-invasive, patient-affordable diagnosis methods that are also potential targets to discover new drugs beyond conventional and available drugs against Alzheimer's disease.
In short, this book shows a window to the future, with the potential remedies and treatment regimen concisely penned down in 15 multidisciplinary yet interconnected chapters. Finally, I extend my gratitude to all authors for their valuable contributions, their perseverance through the peer review process, and their patience with the publication process. The editors and the publishing team appreciate the researchers who contributed to the peer-review, verifying and amending various chapters and the editorial. I would also express my appreciation and gratitude to the authors and publisher of ‘Enzymatic Targets for Drug Discovery against Alzheimer’s Disease’ for their unwavering guidance, unabated efforts, and unrelenting assistance in the development of this book. It is a pleasure to thank Ms. Humaira Hashmi, the Editorial Manager of Publications, and Ms. Asma Ahmed, Senior Manager of Bentham Publication for their valuable assistance during this whole journey.
Department of Pharmaceutical Chemistry
Poona College of Pharmacy, Bharti Vidyapeeth
Pune, 411038, India
Department of Entomology and Nematology
UC Davis Comprehensive Cancer Center
University of California Davis
CA 95616, USA
Department of Pharmacology
College of Pharmaceutical Sciences
Dayananda Sagar University
Bengaluru, 560111, Karnataka