Fourth Hungarian Conference on Alzheimer's Disease and Related Disorders Szeged, Hungary, October 7-9, 1998 (original) (raw)
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A Neuropharmacological Review of Alzheimer’s Disease
International Journal of Current Research and Review
Alzheimer is one of the most frequent diseases that affect nerve cells in various sections of the brain. Pathologically, it occurs due to intracellular neurofibrillary tangles and extracellular amyloid protein depositions that result in the obstruction of neural transmission, culminating in this neurodegenerative illness. Additionally, food and nutrition are essential for developing and preventing Alzheimer's. The biomarker utilized for detecting the disease should be able to differentiate between different causes of dementia and detect it early. Use of Induced Pluripotent Stem Cells shows to be a successful treatment for the condition mentioned. There are three main hypotheses presented as a cause of AD: the cholinergic, tau and amyloid hypothesis. Additional risk factors include advancing age, genetics, head trauma, vascular illnesses, infections, and the environment in general. The two types of approved medications to treat AD (NMDA antagonists and cholinesterase inhibitors) are successful in treating the symptoms of AD, but are not cures or preventatives of the disease. Current AD research targets multiple processes, such as the aberrant tau protein metabolism, β-amyloid, inflammatory response, and cholinergic and free radical damage, to find viable therapeutics capable of preventing or changing the progression of Alzheimer's disease. This review's purpose is to illustrate the pathway that leads to this condition and oncology treatment for it.
Recent advances in the neurobiology and neuropharmacology of Alzheimer's disease
Recent advances in the neurobiology and neuropharmacology of Alzheimer's disease, 2017
A B S T R A C T Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by progressive deterioration of cognitive functions. The pathological hallmarks are extracellular deposits of amyloid plaques and intracellular neurofibrillary tangles of tau protein. The cognitive deficits seen are thought to be due to synaptic dysfunction and neurochemical deficiencies. Various neurochemical abnormalities have been observed during progressive ageing, and are linked to cognitive abnormalities as seen with the sporadic form of AD. Acetylcholinesterase inhibitors are one of the major therapeutic strategies used for the treatment of AD. During the last decade, various new therapeutic strategies have shown beneficial effects in preclinical studies and under clinical development for the treatment of AD. The present review is aimed at discussing the neurobiology of AD and association of neurochemical abnormalities associated with cognitive deterioration and new therapeutic strategies for the treatment of AD.
BRIEF OVERVIEW ON ALZHEIMER`S DISEASE WITH RECENT TREATMENT
The pathophysiology of Alzheimer Disease is very complexes, involving neurotransmitter system and processes. In this review number of diversity of aberrant mechanism increase the hope of finding and diverse therapeutic intervention for the treatment of AD. Hallmarks of AD neuritic plaque, loss of cholinergic cells, tau protein. It is the most common cause of dementia, leading to deterioration in vital cognitive process and behavioural changes. There are five drug approved for AD i.e. Acetylcholinesterase inhibitors (4), for the symptoms of mild to moderate AD and glutamate receptor antagonist (1),for the treatment of moderate to severe AD. Recent developments in the field confirm some important predictions of the hypothesis and shed new lights on potential mechanisms regarding how steady state may be achieved in severe or sporadic AD cases ,our opinion is that, strengthen the hypothesis & our studied with these drugs are focusing on longer effect or follow up.
Current drug targets for Alzheimer's disease treatment
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.
Therapeutic strategies for Alzheimer's disease based on new molecular mechanisms
Acta neurobiologiae experimentalis, 2003
Alzheimer's disease (AD)--the main cause of dementia--is characterized by the presence of neuritic plaques containing the amyloid-beta peptide (A beta) 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 course of AD there is a substantial loss in cholinergic neurons. Another registered drug used in more severe AD is NMDA antagonist--memantine. Available strategies for AD include vitamin supplementation for reducing homocysteine levels, statins and non-steroidal anti-inflammatory drugs. The big hope of the last few years--vitamin E and estrogen supplementation have not been proved efficient, but more studies are needed. There are several strategies aimed at acting directly on A beta or amyloid precursor protein (APP) processing: vaccination with A beta peptide, A beta passive immunization...
International Journal of Pharmacy and Pharmaceutical Sciences, 2016
Alzheimer's disease (AD) is a destructive neurodegenerative disorder characterized by progressive memory defeat and impairment in behavior, language, and visuospatial skills. Neuropsychiatric symptoms such as apathy, depression, aggression, agitation, sleep disruption, and psychosis are now recognized as core symptoms of AD that are expressed to varying degrees throughout the course of disease. The neuro pathological features of AD comprise extracellular senile plaques constituted of β-amyloid (Aβ) pledges, intracellular neurofibrillary tangles (NFTs), and cerebral atrophy; others include apolipoprotein E, oxidative stress, mitochondrial dysfunction and cholinergic hypothesis. Anti-amyloid therapy is available for the treatment of Alzheimer's disease, others are anticholinergic therapy, and therapy for mitochondrial dysfunction, γ-secretase inhibitors (GSI) and modulators (GSM),-secretase (BACE1) inhibitors, Glial modulating drugs includes RAGE receptor antagonists, TNF-α antagonists, neuroprotective drugs such as antioxidants, phosphodiesterase inhibitors, PPARγ agonists, and anti-tau or tau modulators like microtubule stabilizers, kinase inhibitors. This review includes discussion on neurobiological mechanisms and newly developed compounds which have lesser side effects and are proving more efficient for treatment of Alzheimer's disease.
Neurobiological aspects of Alzheimer's disease
Expert Opinion on Therapeutic Targets, 2011
Introduction: The molecular pathogenesis of Alzheimer's disease (AD) includes a variety of risk factors, extracellular deposition of b-amyloid, accumulation of intracellular neurofibrillary tangles, oxidative neuronal damage and inflammatory cascades. Although amyloid-b-containing senile plaques and phospho-tau-containing neurofibrillary tangles are hallmark lesions of AD, neither is specific to nor even a marker of the disease. From a biochemical point of view the most consistent finding is a decreased level of choline acetyltransferase. In recent years, cumulative evidence has been gained on the involvement of neuronal lipoprotein activity, and on the role of cholesterol and other lipids in pathogenesis. Although basic research has made remarkable progress in the past two decades, currently available drugs are only able to improve cognitive symptoms temporarily and no treatment can reverse, stop or even slow this inexorable neurodegenerative process. Areas covered: The various neurobiological events associated with development of AD and the multiple treatment approaches for combating this disorder. Expert opinion: AD is a complex multifactorial disorder and thus a single target or pathogenic pathway is unlikely to be identified. Developing therapeutic interventions demands a greater understanding of the processes and the differential involvement of the various mediators. Effective therapeutics are urgently needed, and it is hoped that anti-amyloid strategies will offer a significant step towards a causal therapy.
Alzheimer’s disease pathogenesis and therapeutic interventions
Journal of Clinical Neuroscience, 2004
Alzheimer's disease (AD) is a neurodegenerative disorder of the central nervous system associated with progressive cognitive and memory loss. Molecular hallmarks of the disease are characterized by extracellular deposition of the amyloid b peptide (Ab) in senile plaques, the appearance of intracellular neurofibrillary tangles (NFT), cholinergic deficit, extensive neuronal loss and synaptic changes in the cerebral cortex and hippocampus and other areas of brain essential for cognitive and memory functions. Ab deposition causes neuronal death via a number of possible mechanisms including oxidative stress, excitotoxicity, energy depletion, inflammation and apoptosis. Despite their multifactorial etiopathogenesis, genetics plays a primary role in progression of disease. To date genetic studies have revealed four genes that may be linked to autosomal dominant or familial early onset AD (FAD). These four genes include: amyloid precursor protein (APP), presenilin 1 (PS1), presenilin 2 (PS2) and apolipoprotein E (ApoE). Plaques are formed mostly from the deposition of Ab, a peptide derived from APP. The main factors responsible for Ab formation are mutation of APP or PS1 and PS2 genes or ApoE gene. All mutations associated with APP and PS proteins can lead to an increase in the production of Ab peptides, specifically the more amyloidogenic form, Ab42. In addition to genetic influences on amyloid plaque and intracellular tangle formation, environmental factors (e.g., cytokines, neurotoxins, etc.) may also play important role in the development and progression of AD. A direct understanding of the molecular mechanism of protein aggregation and its effects on neuronal cell death could open new therapeutic approaches. Some of the therapeutic approaches that have progressed to the clinical arena are the use of acetylcholinesterase inhibitors, nerve growth factors, nonsteroidal inflammatory drugs, estrogen and the compounds such as antioxidants, neuronal calcium channel blockers or antiapoptotic agents. Inhibition of secretase activity and blocking the formation of bamyloid oligomers and fibrils which may inhibit fibrilization and fibrilization-dependent neurotoxicity are the most promising therapeutic strategy against the accumulation of b-amyloid fibrils associated with AD. Furthermore, development of immunotherapy could be an evolving promising therapeutic approach for the treatment of AD.