Alzheimer’s Disease and Its Potential Alternative Therapeutics

Drug Development Research, 2002

Alzheimer's disease (AD), the most common form of dementia among the elderly, is a progressive, degenerative disorder of the brain with a loss of memory and cognition. A defining characteristic of AD is the deposition of amyloid fibrils and neurofibrillary tangles in the brain of afflicted individuals. Biochemically, they are mainly composed of β-amyloid protein (Aβ) and phosphorylated tau proteins, respectively. There is also a loss of the presynaptic markers of the cholinergic system, such as acetylcholine, in the brain areas related to memory and learning. The biochemical pathways leading to AD are presently unknown and are a subject of intensive study with current theories favoring a hypothesis where Aβ aggregates to toxic forms that induce tau phosphorylation and aggregation. It is believed that this ultimately leads to dysfunction and death of cholinergic neurons, and compensation for this loss had been the primary focus of first generation therapeutic agents. The amyloid and tau hypotheses have lead to a focus on amyloid and tau as therapeutic targets. The current therapeutic goals are to reduce amyloid levels, prevention of amyloid aggregation/toxicity and tau phosphorylation/aggregation. AD has a heterogeneous etiology with a large percentage termed sporadic AD arising from unknown causes and a smaller fraction of early onset familial AD (FAD) caused by mutations in several genes, such as the β-amyloid precursor protein (APP) and presenilins (PS1, PS2). Other genes, such as apolipoprotein E (APOE), are considered to be risk factors for AD. Several proteins, such as APP, APOE, BACE (β-amyloid cleaving enzyme), PS1/2, secretases, and tau play important roles in the pathology of AD. Therefore, attempts are being made to develop new inhibitors for BACE, PS-1 and γ-secretase for treatment of AD. There is also a significant advancement in understanding the function of cholinesterase (ChE) in the brain and the use of ChE inhibitors in AD. The mechanism of a new generation of acetyl- and butyrylChE inhibitors is being studied and tested in human clinical trials for AD. Other strategies, such as vaccination, anti-inflammatory agents, cholesterol-lowering agents, anti-oxidants and hormone therapy, are also being studied for treating or slowing the progression of AD. Developments of early diagnostic tools based on quantitative biochemical markers will be useful to better follow the course of the disease and to evaluate different therapeutic strategies. In the present review, we attempt to critically examine recent trends in AD research from neurochemical to clinical areas. We analyze various neurobiological mechanisms that provide the basis of new targets for AD drug development. These current research efforts should lead to a deeper understanding of the pathobiochemical processes that occur in the AD brain to effectively diagnose and prevent their occurrence. Drug Dev. Res. 56:267–281, 2002. © 2002 Wiley-Liss, Inc.

Current Drug Targets, 2003

Alzheimer's disease (AD), a progressive, degenerative disorder of the brain, is believed to be the most common cause of dementia amongst the elderly. AD is characterized by the presence of amyloid deposits and neurofibrillary tangles in the brain of afflicted individuals. AD is associated with a loss of the presynaptic markers of the cholinergic system in the brain areas related to memory and learning. AD appears to have a heterogeneous etiology with a large percentage termed sporadic AD arising from unknown causes and a smaller fraction of early onset familial AD (FAD) caused by mutations in one of several genes, such as the β-amyloid precursor protein (APP) and presenilins (PS1, PS2). These proteins along with tau, secretases, such as β-amyloid cleaving enzyme (BACE), and apolipoprotein E play important roles in the pathology of AD. On therapeutic fronts, there is significant research underway in the development of new inhibitors for BACE, PS-1 and γ-secretase as targets for treatment of AD. There is also a remarkable advancement in understanding the function of cholinesterase (ChE) in the brain and the use of ChE-inhibitors in AD. A new generation of acetyl-and butyryl cholinesterase inhibitors is being studied and tested in human clinical trials for AD. The development of vaccination strategies, anti-inflammatory agents, cholesterol-lowering agents, anti-oxidants and hormone therapy are examples of new approaches for treating or slowing the progression of AD. In addition, nutritional, genetic and environmental factors highlight more effective preventive strategies for AD. Developments of early diagnostic tools and of quantitative markers are critical to better follow the course of the disease and to evaluate different therapeutic strategies. In this review, we attempt to critically examine recent trends in AD research from molecular, genetic to clinical areas. We discuss various neurobiological mechanisms that provide the basis of new targets for AD drug development. All these current research efforts should lead to a deeper understanding of the pathobiochemical processes that occur in the AD brain in order to effectively diagnose and prevent their occurrence.

Journal of Biomedicine

Alzheimer's disease (AD) is one of the most common multifactorial diseases, including a range of abnormal cellular/molecular processes occurring in different regions of the brain. This disease is considered to be a major contributor to dementia in the elderly people. The pathophysiology involves accumulation of extracellular plaques containing the β-amyloid protein which is generated by the breakdown of the β-amyloid precursor protein (APP) in the brain. Another mechanism involves formation of intracellular neurofibrillary tangles of hyperphosphorylated tau protein. The AD can be classified into two types, familial AD (FAD) and sporadic AD (SAD) based on heritability apart from this the early-onset AD (EOAD) and late-onset AD (LOAD) forms are based on the age of onset. Some proteins, such as APOE, APP, BACE (b-amyloid cleaving enzyme), secretases, PS1/2 and tau proteins are reported in AD brain and have been correlated with disease. It is still unclear whether this disease comprises genetic or environmental factors or both. Many palliative drugs are available for the disease but there is still thirst for curative drugs with greater efficacy. It is required to understand the key factors involved in disease progression and their suitability as drug targets for discovering new drugs against Alzheimer's disease. Main purpose of this review is to highlight the potential targets for Alzheimer's disease that have been studied in recent years.

Current Neuropharmacology, 2020

Alzheimer’s disease (AD) is a chronic neurodegenerative disease affecting the elderly. AD is associated with a progressive decline in memory and cognitive abilities, drastic changes in behavioural patterns and other psychiatric manifestations. It leads to a significant decline in the quality of life at personal, household as well as national level. Although AD was described about hundred years back and multiple theories have been proposed, its exact pathophysiology is unknown. There is no cure for AD and the life expectancy of AD patients remains low at 3-9 years. An accurate understanding of the molecular mechanism(s) involved in the pathogenesis of AD is imperative to devise a successful treatment strategy. This review explains and summarises the current understanding of different therapeutic strategies based on various molecular pathways known to date. Different strategies based on anti-amyloid pathology, glutamatergic pathway, anti-tau, neuroprotection through neurotrophic facto...

Journal of Cellular and Molecular Medicine, 2008

in our understanding of disease aetiology and pathogenesis, there are still no effective disease-modifying drugs available for the treatment of AD. However, numerous compounds are currently undergoing pre-clinical and clinical evaluations. These candidate pharmacotherapeutics are aimed at various aspects of the disease, such as the microtubule-associated -protein, the amyloid-␤ (A␤) peptide and metal ion dyshomeostasis -all of which are involved in the development and progression of AD. We will review the way these pharmacological strategies target the biochemical and clinical features of the disease and the investigational drugs for each category.

2003

Background and objective: Alzheimer's disease (AD) - the main cause of dementia - is characterized by the presence of neuritic plaques containing the amyloid- peptide (A) and an intraneuronal accumulation of tubule-associated protein called tau. The current and future therapeutic strategies for AD will be discussed. Currently available treatment used in AD is based on acetylcholinesterase inhibitors, since in the

Translational Neuroscience, 2014

Alzheimer’s disease (AD) is a neurodegenerative disorder that is characterized by normal memory loss and cognitive impairment in humans. Many drug targets and disease-modulating therapies are available for treatment of AD, but none of these are effective enough in reducing problems associated with recognition and memory. Potential drug targets so far reported for AD are β-secretase, Γ-secretase, amyloid beta (Aβ) and Aβ fibrils, glycogen synthase kinase-3 (GSK-3), acyl-coenzyme A: cholesterol acyl-transferase (ACAT) and acetylcholinesterase (AChE). Herbal remedies (antioxidants) and natural metal-chelators have shown a very significant role in reducing the risk of AD, as well as lowering the effect of Aβ in AD patients. Researchers are working in the direction of antisense and stem cell-based therapies for a cure for AD, which mainly depends on the clearance of misfolded protein deposits — including Aβ, tau, and alpha-synuclein. Computational approaches for inhibitor designing, inte...

Indian Journal of Psychiatry, 2009

Alzheimer's disease (AD) is a common neurodegenerative disease that affects cognitive function in the elderly. It is a common dementia related to aging and a fatal neurodegenerative disease, which is on rise in both the developed and the developing countries. The disease has a complex pathology and etiology. There are no biomarkers for early detection of the disease. There are no successful drugs either to cure or to manage the disease. It has affected 4.5 million people in the United States alone in 2000 and is expected to reach about 15 million by the year 2050 in spite of all the medical advancement. Patients develop progressive cognitive decline with psychiatric and behavioral problems that impair daily living activities and also passively affect quality of life of the patient and the family. The burden of AD has an extraordinary social and economic impact on the families and on the world itself. This makes the development of potential therapies a high priority area in biomedical research. The main challenge is to choose the right biochemical target for drug discovery because of complex neuropathology of the AD brain. The large extracellular beta-amyloid (Aβ) plaques and taucontaining intraneuronal neurofibrillary tangles characterize AD from a histopathologic perspective. [1] However, the severity of dementia in AD is more closely related to the degree of the associated neuronal and synaptic loss. It is not known how neurons die and synapses are lost in AD. [2] Most of the evidence indicates that amyloid precursor protein (APP) processing has a central role in the AD process. The Aβ in the form of plaques is a metabolite of the APP that forms when an alternative (beta-secretase and then gammasecretase enzymatic pathway) is utilized for processing. A total of six mutations have been described in the APP gene, which leads to AD by influencing APP metabolism. [3] One of the leading theories is that Aβ in plaques leads to AD because Aβ is directly toxic to the adjacent neurons. Other theories advance the notion that neuronal death is triggered How to cite this article: Sathyanarayana Rao TS, Jagannatha Rao K. New drug discovery for Alzheimer's disease: Challenges and hopes.

Journal of Internal Medicine

Alzheimer's disease (AD), the most frequent cause of dementia, is escalating as a global epidemic and so far, there is no cure nor treatment to alter its progression. The most important feature of the disease is neuronal death and loss of cognitive functions, caused probably from several pathological processes in the brain. The main neuropathological features of AD are widely described: amyloid beta (Aβ) plaques and neurofibrillary tangles of the aggregated protein tau, which contribute to the disease. Nevertheless, AD brains suffer from a variety of alterations in function, such as energy metabolism, inflammation, and synaptic activity. The latest decades have seen an explosion of genes and molecules that can be employed as targets aiming to improve brain physiology, which can result in preventive strategies for AD.

Therapeutic advances in chronic disease, 2011

Alzheimer's disease (AD) is a progressive neurodegenerative disease which begins with insidious deterioration of higher cognition and progresses to severe dementia. Clinical symptoms typically involve impairment of memory and at least one other cognitive domain.