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Progressive Neurodegenerative Disease (progressive + neurodegenerative_disease)

Distribution by Scientific Domains

Medical Sciences	85%

Selected Abstracts

Translational medicine perspective in development of disease modifying therapies for Alzheimer's disease: biomarkers to buy down the risk

DRUG DEVELOPMENT RESEARCH, Issue 2 2009
Hong I. Wan
Abstract Alzheimer's disease (AD) is a progressive neurodegenerative disease and the most common cause of age-related dementia. Currently available pharmacologic therapies, including acetylcholinesterase (AChE) inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists, only treat symptoms and do not address the underlying neurodegeneration. In addition to potentially improve the accuracy of diagnosis, biomarkers serve important roles for the development of putative disease-modifying drugs for AD. In this article, we review the existing and emerging areas of biomarker research and development for AD. Biochemical biomarkers in cerebrospinal fluid have been used to provide a link to disease pathology and may provide important proof of concept data for several classes of emerging therapeutics. Imaging biomarkers including volumetric magnetic resonance imaging and positron emission tomography assessing either glucose utilization or radioligands binding to amyloid plaque are discussed. Appropriate uses of these biomarkers in the context of the development of disease-modifying therapies are discussed. Drug Dev Res 70, 2009. © 2009 Wiley-Liss, Inc. [source]

Cytosolic protein-protein interactions that regulate the amyloid precursor protein

DRUG DEVELOPMENT RESEARCH, Issue 2 2002
Shasta L. Sabo
Abstract Alzheimer disease (AD), a progressive neurodegenerative disease, is the most common cause of dementia in the elderly and is among the leading causes of death in adults. AD is characterized by two major pathological hallmarks, amyloid plaques and neurofibrillary tangles. For a number of reasons, amyloid plaque accumulation is widely thought to be the probable cause of AD. The amyloid plaque core is largely composed of an approximately 4-kDa peptide referred to as A,. A, is derived from its precursor, the Alzheimer amyloid protein precursor (APP), by endoproteolytic processing. APP is a type I integral membrane protein, with a long extracellular domain, one transmembrane domain, and a short (,50 amino acid) cytoplasmic tail. Despite intense efforts to decipher the function of APP, its normal physiological role has remained elusive. The carboxy-terminus of APP contains the sequence YENPTY, which is absolutely conserved across APP homologues and across species. The YENPTY sequence is important for regulation of APP processing and trafficking. Given the importance of the cytoplasmic domain in APP physiology, a number of laboratories have hypothesized that proteins that bind to the YENPTY sequence in the cytoplasmic domain of APP might regulate APP processing, trafficking, and/or function. In this article, we will discuss data revealing which proteins bind to the cytoplasmic domain of APP, how these binding-proteins regulate APP metabolism and function, and why such protein-protein interactions provide an exciting new target for therapeutic intervention in AD. Drug Dev. Res. 56:228,241, 2002. © 2002 Wiley-Liss, Inc. [source]

Altered sensorimotor development in a transgenic mouse model of amyotrophic lateral sclerosis

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 10 2004
Julien Amendola
Abstract Most neurodegenerative diseases become manifest at an adult age but abnormalities or pathological symptoms appear earlier. It is important to identify the initial mechanisms underlying such progressive neurodegenerative disease in both humans and animals. Transgenic mice expressing the familial amyotrophic lateral sclerosis (ALS)-linked mutation (G85R) in the enzyme superoxide dismutase 1 (SOD1) develop motor neuron disease at 8,10 months of age. We address the question of whether the mutation has an early impact on spinal motor networks in postnatal mutant mice. Behavioural tests showed a significant delay in righting and hind-paw grasping responses in mutant SOD1G85R mice during the first postnatal week, suggesting a transient motor deficit compared to wild-type mice. In addition, extracellular recordings from spinal ventral roots in an in vitro brainstem,spinal cord preparation demonstrated different pharmacologically induced motor activities between the two strains. Rhythmic motor activity was difficult to evoke with N -methyl- dl -aspartate and serotonin at the lumbar levels in SOD1G85R mice. In contrast to lumbar segments, rhythmic activity was similar in the sacral roots from the two strains. These results strongly support the fact that the G85R mutation may have altered lumbar spinal motor systems much earlier than previously recognized. [source]

Embryonic stem cells and prospects for their use in regenerative medicine approaches to motor neurone disease

NEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 5 2007
Y. A. Christou
Human embryonic stem cells are pluripotent cells with the potential to differentiate into any cell type in the presence of appropriate stimulatory factors and environmental cues. Their broad developmental potential has led to valuable insights into the principles of developmental and cell biology and to the proposed use of human embryonic stem cells or their differentiated progeny in regenerative medicine. This review focuses on the prospects for the use of embryonic stem cells in cell-based therapy for motor neurone disease or amyotrophic lateral sclerosis, a progressive neurodegenerative disease that specifically affects upper and lower motor neurones and leads ultimately to death from respiratory failure. Stem cell-derived motor neurones could conceivably be used to replace the degenerated cells, to provide authentic substrates for drug development and screening and for furthering our understanding of disease mechanisms. However, to reliably and accurately culture motor neurones, the complex pathways by which differentiation occurs in vivo must be understood and reiterated in vitro by embryonic stem cells. Here we discuss the need for new therapeutic strategies in the treatment of motor neurone disease, the developmental processes that result in motor neurone formation in vivo, a number of experimental approaches to motor neurone production in vitro and recent progress in the application of stem cells to the treatment and understanding of motor neurone disease. [source]

Apoptosis in amyotrophic lateral sclerosis: a review of the evidence

NEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 4 2001
S. Sathasivam
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease primarily affecting the upper and lower motor neurones of the central nervous system. Recently, a lot of interest has been generated by the possibility that a mechanism of programmed cell death, termed apoptosis, is responsible for the motor neurone degeneration in this condition. Apoptosis is regulated through a variety of different pathways which interact and eventually lead to controlled cell death. Apart from genetic regulation, factors involved in the control of apoptosis include death receptors, caspases, Bcl-2 family of oncoproteins, inhibitor of apoptosis proteins (IAPs), inhibitors of IAPs, the p53 tumour suppressor protein and apoptosis-related molecules. The first part of this article will give an overview of the current knowledge of apoptosis. In the second part of this review, we will examine in detail the evidence for and against the contribution of apoptosis in motor neurone cell death in ALS, looking at cellular-, animal- and human post-mortem tissue-based models. In a chronic neurodegenerative disease such as ALS, conclusive evidence of apoptosis is likely to be difficult to detect, given the rapidity of the apoptotic cell death process in relation to the relatively slow time course of the disease. Although a complete picture of motor neurone death in ALS has not been fully elucidated, there is good and compelling evidence that a programmed cell death pathway operates in this disorder. The strongest body of evidence supporting this comes from the findings that, in ALS, changes in the levels of members of the Bcl-2 family of oncoproteins results in a predisposition towards apoptosis, there is increased expression or activation of caspases-1 and -3, and the dying motor neurones in human cases exhibit morphological features reminiscent of apoptosis. Further supporting evidence comes from the detection of apoptosis-related molecules and anti-Fas receptor antibodies in human cases of ALS. However, the role of the p53 protein in cell death in ALS is at present unclear. An understanding of the mechanism of programmed cell death in ALS may provide important clues for areas of potential therapeutic intervention for neuroprotection in this devastating condition. [source]

Serum-soluble receptor for advanced glycation end product levels in patients with amyotrophic lateral sclerosis

ACTA NEUROLOGICA SCANDINAVICA, Issue 2 2009
eckaArticle first published online: 2 DEC 200
Objectives,,, Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease. There is evidence that oxidative stress is implicated in the pathophysiology of the neurodegenerative disorders, including ALS. Data from the literature suggests that the receptor for advanced glycation end products (RAGE) participates in pathological conditions, including oxidative stress and neurodegeneration. Materials and methods,,, The study involved 20 patients with ALS and 20 patients from the control group. The serum-soluble RAGE (sRAGE) levels were measured using the enzyme-linked immunosorbent method. Results,,, The study showed that sRAGE levels are significantly decreased in serum of the patients with ALS comparing to the control group (P < 0.05). The correlation between the serum sRAGE levels and clinical parameters of the disease was not significant (P > 0.05). Conclusions,,, The results indicate that sRAGE participates in pathophysiology of the ALS. It is possible that low sRAGE levels may influence neurodegeneration. [source]

Gene-based treatment of motor neuron diseases,

MUSCLE AND NERVE, Issue 3 2006
Thais Federici PhD
Abstract Motor neuron diseases (MND), such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), are progressive neurodegenerative diseases that share the common characteristic of upper and/or lower motor neuron degeneration. Therapeutic strategies for MND are designed to confer neuroprotection, using trophic factors, anti-apoptotic proteins, as well as antioxidants and anti-excitotoxicity agents. Although a large number of therapeutic clinical trials have been attempted, none has been shown satisfactory for MND at this time. A variety of strategies have emerged for motor neuron gene transfer. Application of these approaches has yielded therapeutic results in cell culture and animal models, including the SOD1 models of ALS. In this study we describe the gene-based treatment of MND in general, examining the potential viral vector candidates, gene delivery strategies, and main therapeutic approaches currently attempted. Finally, we discuss future directions and potential strategies for more effective motor neuron gene delivery and clinical translation. Muscle Nerve, 2005 [source]