Is the neurotoxicity of amyloid-beta AGE-related?
Final Report Abstract
Advanced Glycation Endproducts in amyloid plaques in human AD patients. The research project has initially focused on carbonyl stress (resulting in the formation and pathological effects of Advanced Glycation Endproducts, AGEs) in Alzheimer's disease. Under normoglycemic conditions, AGEs accumulate on pathological protein deposits because of their extremely long half-life. For example, amyloid plaques in the Alzheimer's disease (AD) brain are deposited over a time period of more than 30 years, and therefore should be the most AGE modified proteins in the human body. We have demonstrated the age- and stage-dependent accumulation of AGEs in AD brains. The auditory association area of the superior temporal gyrus (Brodmann area 22) was used. AGE immunoreactivity was detected in neurons and glia of young and old non-demented controls, and compared with early- and late-stage AD. We showed that both the percentage of AGE- positive neurons and astroglia increases with age. The age-related increase is dramatically increased in AD patients and correlated with the progression of the disease defined by the Braak stages (Lüth et al., 2005). Advanced Glycation Endproducts in amyloid precursor protein (APP) overexpressing mice. However, the Tg 2576 mouse, an animal model of AD, demonstrates an inflammatory response less pronounced than in AD patients, despite high levels of soluble and fibrillar amyloid. In particular, IL-6 and iNOS are rarely detected around plaques in the Tg2576 mouse (Apelt and Schliebs, 2001). One of the reasons for the "mild inflammation" in these mice might be the lack of AGEs as a co-stimulus in plaques in these mice (Münch et al., 2003). Inflammatory pathways induced by ß-amyloid and AGEs. Furthermore, we have proposed a major role for chronic inflammation in the progression of Alzheimer's disease (AD). We have elucidated some of the pro-inflammatory signaling pathways of the jff-amyloid and AGE- receptor RAGE, and the involvement of reactive oxygen species ("redox-signalling") in this pathway in microglial cells. We have also identified a variety of ß-amyloid and AGE-regulated genes using microarrays. Whereas the AGE-induced genes were quite diverse and did belong to a definded class of genes, ß-amyloid-induced genes were mainly involved in inflammation, e.g. chemokine (C-C motif) ligand 5, chemokine (C-X-C motif) ligand 10, viral hemorrhagic septicemia virus(VHSV) induced gene 1, immunoresponsive gene 1, chemokine (C-X-C motif) ligand 2, interferon-induced protein with tetratricopeptide repeats 1, pellino 1 and chemokine (C-C motif) ligand 9 (unpublished data). Anti-Inflammatory activity of antioxidant drugs. Furthermore, we have identified a variety of anti-oxidants - including polyphenolic compounds - which interfere with the AGE and ß-amyloid-induced pro-inflammatory pathways and could thereby attenuate inflammation in AD. Future work. There appears some discrepancy between the AGE-induced proteins and the lack of a corresponding up-regulation of the gene level. Such lack of AGE-induced gene expression has been described by one other group (Valencia et al., 2004), and may indicate an effect of AGE on mRNA stability or translation. Possible applications. We have suggested that such anti-inflammatory antioxidant compounds could be clinically beneficial in the treatment of dementias including AD. Based on the in vitro screening data, we have initiated a clinical trial of the thiol antioxidant, a-lipoic acid, in dementia patients in the Henriettenstiftung Hospital in Hannover, Germany in 1999. This trial has now been running for more than 8 years and data are available for more than 40 patients over a 4 year period. 600mg a-lipoic acid was given daily to 43 patients with AD (receiving a standard treatment with choline-esterase inhibitors) in an open- label trial over an observation period of up to 48 months. In patients with mild dementia (ADAScog<15), the disease progressed extremely slowly (ADAScog: 1.2 points / year, MMSE: - 0.6 points / year), in patients with moderate dementia at approximately twice the rate. However, this progression rate is dramatically lower than data reported for untreated patients or patients on choline-esterase inhibitors in the second year of long-term studies. Despite the fact that this study was not double-blinded, placebo-controlled and randomized, our data suggest that treatment with a-lipoic acid might be a successful 'neuroprotective' therapy option for AD (Hager et al., 2007). However, a state-of-theart phase II trial is needed urgently.
Publications
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Einfluß aggregierter Proteine auf den Zellzyklus von Neuronen bei der Alzheimerschen Erkrankung
Angela Schmitt
