New Study Links Glucose/Protein Complexes (A.G.E.s) and Alzheimer's Disease
- AD is Latest Disease of Aging Linked to the A.G.E. Pathway -
RAMSEY, N.J., Aug. 7 /PRNewswire/ -- Alteon Inc. (Amex: ALT - news) reported today that a team of researchers at Case Western Reserve University, Cleveland, Ohio, have provided further evidence that Advanced Glycation End-products (A.G.E.s) are a critical factor in the early progression of Alzheimer's disease (AD). The authors suggest that therapeutic strategies aimed at ameliorating the A.G.E. pathway hold substantial promise in the management of the disease.
A.G.E.s are naturally formed throughout the body when blood sugar (glucose) reacts with proteins, such as collagen or elastin. A.G.E.s further crosslink with each other, forming bonds that lead to a loss of flexibility and function of body tissues, organs and vessels. The formation and crosslinking of A.G.Es. are an inevitable part of the aging process, and are accelerated in diabetes, where higher sugar levels are present. The scientific literature points to A.G.E.s as a causative factor in many complications of aging and diabetes, including heart, kidney and eye diseases. Alteon's approach is to inhibit or ``break'' A.G.E.s and their chemical crosslinks, thereby potentially impacting such disease states. The company is a worldwide leader in the research and development of compounds that target the A.G.E. pathway.
``Active Glycation in Neurofibrillary pathology of Alzheimer's Disease: N-(Carboxymethyl) Lysine and Hexitol-Lysine'' is reported in the current issue of the journal Free Radical Biology & Medicine (Vol. 31, No. 2, pp. 175-180, 2001) and was authored by a research team led by George Perry, Ph.D. and Mark A. Smith, Ph.D., Institute of Pathology, Case Western Reserve University, Cleveland, OH, and included researchers from the Department of Chemistry, Case Western Reserve University; the Department of Biochemistry, Osaka University Medical School, Osaka, Japan; Division of Neurology, Duke University Medical Center, Durham, NC; and Alteon Inc., Ramsey, NJ.
The researchers examined postmortem human tissue samples from 27 pathologically confirmed AD cases. Their results suggest that A.G.E.s produce deleterious biochemical consequences, and are a factor in the accumulation of neurofibrillary tangles in AD. Their data also confirms that active glycation is still occurring in AD lesions throughout their existence.
``Furthermore, A.G.E.s predate the formation of the pathological lesions of Alzheimer's disease, suggesting they play an early and detrimental role in the disease process,'' said George Perry, Ph.D., Professor and Chair of Pathology, Case Western Reserve University.
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Text of the article's abstract from the journal (http://www.elsevier.com/locate/issn/08915849)
Abstract: Advanced glycation end products are a diverse class of posttranslational modifications, stemming from reactive aldehyde reactions, that have been implicated in the pathogenesis of a number of degenerative diseases. Because advanced glycation end products are accelerated by, and result in formation of, oxygen-derived free radicals, they represent an important component of the oxidative stress hypothesis of Alzheimer disease (AD). In this study, we used in situ techniques to assess N?-(Carboxymethyl)lysine (CML), the predominant advanced glycation end product that accumulates in vivo, along with its glycation-specific precursor hexitol-lysine, in patients with AD as well as in young and aged-matched control cases. Both CML and hexitol-lysine were increased in neurons, especially those containing intracellular neurofibrillary pathology in cases of AD. The increase in hexitol-lysine and CML in AD suggests that glycation is an early event in disease pathogenesis. In addition, because CML can result from either lipid peroxidation or advanced glycation, while hexitol-lysine is solely a product of glycation, this study, together with studies demonstrating the presence of 4-hydroxy-2-nonenal adducts and pentosidine, provides evidence of two distinct oxidative processes acting in concert in AD neuropathology. Our findings support the notion that aldehyde-mediated modifications, together with oxyradical-mediated modifications, are critical pathogenic factors in AD.
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