Book Volume 7
Page: i-i (1)
List of Contributors
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Deep Brain Stimulation in the Treatment of Alzheimer's disease
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Author: Angelo Lavano, Giusy Guzzi, Attilio Della Torre, Domenico Chirchiglia, Carmelino Angelo Stroscio, Donatella Gabriele and Giorgio Volpentesta
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Alzheimer’s disease (AD) is the leading neurological cause of dementia of advanced predominance worldwide. The pathogenic mechanisms may concern accumulations of beta amyloid and tau protein, inflammatory pathways, altered oxidative metabolism and responses to oxidative stress. The currently available therapeutic options for AD have limited efficacy. Deep Brain Stimulation (DBS) may represent a chance in order to ameliorate cognitive performances modifying cortical and hippocampal circuits. Fornix and Nucleus basalis of Meynert are the most promising targets in terms of delaying and reversing the cognitive impairment; other targets like entorhinal cortex/hippocampus, pedunculopontine tegmental nucleus, anterior thalamic nucleus are under investigation with some success. The mechanism of action and stimulation parameters remain unclear.
ASS234: A New and Promising Anti-Alzheimer Agent
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Author: Alejandro Romero, Eva Ramos, Ana P. Fernandez, Julia Serrano, Ricardo Martínez-Murillo and Jose Marco-Contelles
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Physiopathological events associated with the development and progression of Alzheimer's disease (AD) are complex and require new therapeutical approaches. Consequently, N-((5-(3-(1-benzylpiperidin-4-yl) propoxy)-1- methyl-1H-indol-2-yl) methyl)-N-methylprop-2-yn-1-amine (ASS234), synthesized as a new multitargetdirected molecule, has focused a great interest in this field. In vitro, it is able to cross the blood-brain barrier and has less toxicity than donepezil. It acts simultaneously as a reversible inhibitor of both human acetyl and butyrylcholinesterase, and as an irreversible inhibitor of human monoamine oxidase A and B. It inhibits both Αß1-42 and Αß1-40 self-aggregation and possesses antioxidant and neuroprotective properties. Recently, it was demonstrated that ASS234 is able to induce the wingless-type MMTV integration site family (Wnt) signaling pathway, which is involved in neuroprotective activities related to AD and it also promotes the induction of several key antioxidant genes that counteract oxidative stress. In vivo experiments, ASS234 exhibited a reduction of amyloid plaque burden and gliosis in the cortex and hippocampus and significantly decreased scopolamine-induced learning deficits in C57BL/6J mice. Herein, we summarize the neuroprotective effects of ASS234 in counteracting several steps in the pathological processes of AD.
Recent Advances in Alzheimer's Drug Discovery Research
Page: 26-98 (73)
Author: Xin-An Liu, Brati Das, Youjun Chen, Zuxin Chen, Yosef Avchalumov, Xu Tian and Sathyanarayanan V. Puthanveettil
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Alzheimer’s disease (AD) is the most common cause of age-related dementia, a deleterious neurodegenerative disorder that impairs memory, where neuropathological changes develop gradually over years to affect cognitive functions. AD is one of the most important health-care problems with over 20 million people suffering worldwide and has become a critical issue to human health, especially in aging societies. Current treatments do not prevent, stop, or delay disease progression, despite the considerable advances in knowledge of the pathogenesis of AD and in medicinal chemistry over the past quarter of a century. The neuropathologic hallmarks of AD are extracellular senile plaques of aggregated β-amyloid and intracellular neurofibrillary tangles, mainly containing the hyperphosphorylated microtubuleassociated protein tau. Additional changes that may also occur in the brains of AD patients include age-related brain atrophy, synaptic pathology, and neuron loss, which contribute to cognitive impairment. So far, only four cholinesterase inhibitors and memantine have been marketed as the therapeutic strategies for Alzheimer’s disease. Despite advancements in prevention strategies, potential targets, effective biomarkers, clinical development methods, and the evaluation of potential treatments in clinical trials. This chapter summarizes our best understanding of the etiology, animal models currently under study, pharmacotherapeutic targets, and molecular pathways that curtail the progression of AD. This knowledge will help to strategize the development and clinical use of any new drugs for AD therapy in future.
Alzheimer’s Disease and Proteasome: The Therapeutic Development and Management
Page: 99-139 (41)
Author: Qunxing Ding and Haiyan Zhu
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The proteasome system is a cellular machinery that is responsible for the degradation of nearly 90% of the proteins in cells and is crucial in protein metabolism involved in physiological and pathological developments, especially in aging and aging-related disorders. Numerous reports indicate that impaired proteasome is involved in the pathological process of Alzheimer’s disease (AD), which is a leading form of dementia. It is well known that the pathological hallmarks of the AD are the aggregated proteins such as plaques, tangles and Lewy bodies. The formation of these aggregates is tightly associated with the dysfunction of the proteasome system, which is responsible for the degradation of oxidized, misfolded, aged and other damaged proteins. In fact, the proteasome system plays a major role in quality and quantity control in cellular protein homeostasis, and in responses to inflammatory signals, oxidative stress, and other cellular signals. This chapter will summarize the basic information and updates on the proteasome system and related cellular complexes, such as lysosome and ribosome and their alterations during aging and AD pathogenesis. In addition, some clinical trials and practical management for the AD will be discussed to explore possible strategies for pharmaceutical and clinical development associated with the proteasome system.
Alzheimer´s Disease: Fundamental Concepts, Novel Findings and Therapeutics Outcomes Coming from the Ca2+/cAMP Signalling Interaction
Page: 140-157 (18)
Author: Leandro Bueno Bergantin
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The evidences that a dysregulation of the intracellular Ca2+ homeostasis increases the incidence of the neurodegenerative diseases, such as Alzheimer´s disease (AD), have been increasing. Thus, several findings have been reinforcing the concept that a reduction of a cytosolic Ca2+ excess, achieved due to the L-type Ca2+ channel blockers (CCBs), could be an interesting pharmacological goal to alleviate the AD symptoms. In addition, aging along with a healthy brain can be endorsed by daily exercise, a self-control in caloric ingestion and participating in intellectually challenging events. Indeed, these lifestyle issues may alleviate the Ca2+ excess from neurons achieved through a Ca2+ homeostasis dysregulation. Furthermore, several studies have been indicating that increasing cAMP levels may produce neuroprotective effects, thus alleviating the AD symptoms. From these concepts in mind, we discovered that the manipulation by medicines of the Ca2+/cAMP signalling through the mutual therapy involving CCBs, and cAMP-accumulating compounds, could be a novel plausible target to treat the AD. Then, this chapter discusses the fundamental concepts and current therapies to treat AD, including therapeutics outcomes coming from the pharmacological interference on the interaction between Ca2+ and cAMP signalling.
Alzheimer's Disease: An Approach for Non- Pharmacological Therapies
Page: 158-213 (56)
Author: M. G.V. Gottlieb, V. E. Closs, V. M. Junges, A. von Gunten, Z. C.L. Lindoso, J. P. Rocha, B.J.P. Lopes Filho, C .R. Oliveira and F. Loureiro
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The increase in life expectancy and lifestyle changes, such as inadequate diets, sedentarism and social inequality have contributed to an increase in neuropsychiatric disorders, such as Alzheimer's disease (AD). AD has a multifactorial origin, with a chronic and progressive nature, leading to cognitive and functional decline, including the gradual loss of autonomy, independence and social function, severely impairing the quality of life of both patient and family. The disease onset and progression become a burden on the family and caregivers, requiring an interdisciplinary and multidisciplinary approach. AD demands continuous assistance and increasing burdens during treatment. Health professionals, such as nutritionists, physical educators, physiotherapists and occupational therapists, neuropsychologists and speech therapists, offer complimentary therapies, becoming essential for the prevention of a quick decline in quality of life, and allowing patients with AD to remain functional and cognitively active for longer. In this setting, the contributions and actions of various health professionals play a major role in managing AD, and health actions directed at the elderly should have the prime objective of keeping the person within their community, together with their families, in the most dignified and comfortable manner possible. Their transfer to long-stay institutions (asylums, hospitals, retirement homes and the like) should only be considered when all other actions have failed. In this scenario, this chapter aims to address the role of different non-pharmacological therapies administered by a multi-professional health team to delay the deterioration of cognition, autonomy, functionality and independence, maintaining an acceptable quality of life for the elderly with AD.
Past and Present Drug Development for Alzheimer's Disease
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Author: Pratap Kumar Sahu, Prashant Tiwari, Shakti Ketan Prusty and Bharat Bhusan Subudhi
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Alzheimer’s disease (AD) is a progressive and an irreversible chronic neurodegenerative disorder causing dementia. Worldwide, the prevalence of AD is estimated to be 30 million and likely to quadruple in the next 40 years. Thus, the global cost of dementia is estimated to be 1.09% of global GDP (US$ 818 billion). Several factors including age and family history are involved in its etiology and considered as the predisposing factors for AD. The neurochemical basis of AD can be explained by the ‘Cholinergic’, ‘Amyloid plaque’ and ‘Tauopathy’ hypotheses. The ‘Cholinergic’ hypothesis put forth a relationship between Acetyl choline (ACh) levels to cognitive memory and the other two hypotheses propose an excessive deposition of amyloid plaques extracellularly and accumulation of tau protein intracellularly, eventually causing neuronal death. The cholinergic system is mainly targeted for therapeutic management of AD symptoms. In view of that, acetylcholinesterase inhibitors (AChEI) such as tacrine, donepezil, rivastigmine and galantamine have been used. Memantine, an N –methyl – D - aspartate (NMDA) receptor antagonist inhibiting glutamate mediated exocitotoxicity, is also used to improve dementia symptoms. However, the degree of improvement with this approach has been minimal as no one of these drugs can reverse the course of AD, nor prevent destruction of neurons. Accordingly, amyloid based strategies including ‘secretive enzymes modulation’, ‘amyloid aggregation prevention’ and ‘amyloid clearance promotion’ have been adopted. Inhibition of tau phosphorylation/oligomerization, microtubule stabilization, reduction of stress/inflammation, modulation of neurotransmitters and cellular calcium homeostasis has also been used as strategy to manage AD with varying degree of success. A high rate of attrition combined with huge cost of new drug development has encouraged drug repurposing strategies. This approach ensures minimal developmental cost and shorter approval time to launch a drug. Moreover, the risk associated with conventional drug discovery is reduced due to existing pharmacokinetic and safety data. Thus, drug repurposing is considered to be a preferred strategy against AD. Modern advances in disease biology of AD have substantially assembled data from pre-clinical, clinical, in-vitro, epidemiological, toxicological, and computational sources. Thus, an implementation of systematic approaches using this on hand information with a clear understanding of the network pharmacology can give way the next therapeutic alternative for successful management of AD. The current chapter describes the scope and limitations of some currently marketed drugs like cholinergic drugs, cyclooxygenase (COX) and lipoxygenase (LOX) inhibitors, renin angiotensin system (RAS) inhibitors, lipid lowering drugs (statins), NMDA receptor antagonists, anti-diabetics, anti-oxidants, vitamin D etc in management of AD. Many of them have the potential against AD and some of them are validated pre-clinically and clinically. But none of them has reached the market yet. Drugs targeting neuroinflammation including COX inhibitors, LOX inhibitors and RAS inhibitors can potentially arrest the disease progression in AD. However, their repurposing potential needs to be clinically validated.
Page: 254-262 (9)
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.