Journal ArticleDOI
Advanced glycation endproduct precursor alters intracellular amyloid- β/AβPP carboxy-terminal fragment aggregation and cytotoxicity
TLDR
It is shown that A beta/CTF aggregation and cytotoxicity may be profoundly altered by aldehydes associated with diabetes and that in the case of MG, this process is suppressed by alpha-tocopherol.Abstract:
Carbonyl stress from products of lipid peroxidation, such as 4-hydroxynonenal (HNE), and products of sugars in diabetes mellitus, such as methylglyoxal (MG) and glyoxal (G), may contribute to neurodegeneration in Alzheimer's disease (AD). We tested the hypothesis that these carbonyls alter the proposed central pathogenic mechanism of AD, intracellular amyloid-beta (A beta)-mediated cytotoxicity, using a human neuroblastoma cell line that conditionally expresses carboxy-terminal fragments (CTFs) of the amyloid precursor protein. HNE was a potent cytotoxin, whereas G was mildly cytotoxic; cytotoxicity from each was independent of A beta/CTF expression and not altered by alpha-tocopherol. In contrast, MG cytotoxicity was enhanced by the induced expression of A beta/CTFs and suppressed by alpha-tocopherol. alpha-tocopherol cytoprotection was accompanied by decreased A beta/CTF aggregation. G also promoted beta/CTF aggregation but by mechanisms unaffected by alpha-tocopherol treatment. Our findings showed that A beta/CTF aggregation and cytotoxicity may be profoundly altered by aldehydes associated with diabetes and that in the case of MG, this process is suppressed by alpha-tocopherol. Moreover, our results suggest that while intracellular aggregation of A beta/CTFs may be necessary for the development of toxicity attributable to their expression in this model, the presence of high-molecular weight aggregated A beta/CTFs does not invariably lead to cytotoxicity.read more
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Journal ArticleDOI
Advanced glycation end products and RAGE: a common thread in aging, diabetes, neurodegeneration, and inflammation
Ravichandran Ramasamy,Susan J. Vannucci,Shirley ShiDu Yan,Kevan C. Herold,Shi Fang Yan,Ann Marie Schmidt +5 more
TL;DR: It is hypothesized that AGEs cause perturbation in a diverse group of diseases, such as diabetes, inflammation, neurodegeneration, and aging, and it is proposed that targeting this pathway may represent a logical step in the prevention/treatment of the sequelae of these disorders.
Journal ArticleDOI
Is Alzheimer's disease a Type 3 Diabetes? A critical appraisal.
TL;DR: Significant shared mechanisms between AD and diabetes are discussed and therapeutic avenues for diabetes and AD are provided and the effects of insulin in the pathology of AD through cellular and molecular mechanisms are provided.
Journal ArticleDOI
The Role of Advanced Glycation End Products in Aging and Metabolic Diseases: Bridging Association and Causality.
Jyotiska Chaudhuri,Yasmin Bains,Sanjib Guha,Arnold Kahn,David Hall,Neelanjan Bose,Neelanjan Bose,Alejandro Gugliucci,Pankaj Kapahi,Pankaj Kapahi +9 more
TL;DR: It is shown how invertebrate models, notably Drosophila melanogaster and Caenorhabditis elegans, can be used to explore AGE-related pathways in depth and to identify and assess drugs that will mitigate against the detrimental effects of AGEs-adduct development.
Journal ArticleDOI
Intervention strategies to inhibit protein carbonylation by lipoxidation-derived reactive carbonyls.
TL;DR: This review focuses on fundamental studies on lipid‐derived RCS generation, their biological effects, and their reactivity with proteins, with particular emphasis to 4‐hydroxy‐trans‐2‐nonenal (HNE)‐, acrolein‐, malondialdehyde‐, and glyoxal (GO)‐modified proteins.
Journal ArticleDOI
Glycation-altered proteolysis as a pathobiologic mechanism that links dietary glycemic index, aging, and age-related disease (in nondiabetics).
Tomoaki Uchiki,Karen A. Weikel,Wangwang Jiao,Fu Shang,Andrea Caceres,Dorota B Pawlak,James T. Handa,Michael Brownlee,Ram H. Nagaraj,Allen Taylor +9 more
TL;DR: Data from live cell and cell‐free systems show that the ubiquitin–proteasome system (UPS) and lysosome/autophagy pathway [lysosomal proteolytic system (LPS)] are involved in the degradation of AGEs, which explains why A GEs accumulate as glycative stress increases.
References
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