Alzheimer Disease: Götz ME

Wruck CJ, Götz ME, Herdegen T, Varoga D, Brandenburg LO, Pufe T. · Department of Anatomy and Cell Biology, RWTH Aachen, Wendlingweg 2, 52074 Aachen, Germany. · Mol Pharmacol. · Pubmed #18334601 links to  free full text

Abstract: One hallmark of Alzheimer's disease is the accumulation of amyloid beta-peptide (AP), which can initiate a cascade of oxidative events that may result in neuronal death. Because nuclear factor erythroid 2-related factor 2 (Nrf2) is the major regulator for a battery of genes encoding detoxifying and antioxidative enzymes via binding to the antioxidant response element (ARE), it is of great interest to find nontoxic activators of Nrf2 rendering neuronal cells more resistant to AP toxicity. Using ARE-luciferase assay and Western blot, we provide evidence that the kavalactones methysticin, kavain, and yangonin activate Nrf2 time- and dose-dependently in neural PC-12 and astroglial C6 cells and thereby up-regulate cytoprotective genes. Viability and cytotoxicity assays demonstrate that Nrf2 activation is able to protect neural cells from amyloid beta-(1-42) induced neurotoxicity. Down-regulation of Nrf2 by small hairpin RNA as well as extracellular signal-regulated kinase 1/2 inhibition abolishes cytoprotection. We further give evidence that kavalactone-mediated Nrf2 activation is not dependent on oxidative stress production. Our results demonstrate that kavalactones attenuate amyloid beta-peptide toxicity by inducing protective gene expression mediated by Nrf2 activation in vitro. These findings indicate that the use of purified kavalactones might be considered as an adjunct therapeutic strategy to combat neural demise in Alzheimer disease and other oxidative stress-related diseases.

Völkel W, Sicilia T, Pähler A, Gsell W, Tatschner T, Jellinger K, Leblhuber F, Riederer P, Lutz WK, Götz ME. · Department of Toxicology, University of Würzburg, Würzburg, Germany. · Neurochem Int. · Pubmed #16483694 No free full text.

Abstract: In the last decade an important role for the progression of neuronal cell death in Alzheimer's disease (AD) has been ascribed to oxidative stress. trans-4-Hydroxy-2-nonenal, a product of lipid peroxidation, forms conjugates with a variety of nucleophilic groups such as thiols or amino moieties. Here we report for the first time the quantitation of glutathione conjugates of trans-4-hydroxy-2-nonenal (HNEGSH) in the human postmortem brain using the specific and very sensitive method of electrospray ionization triple quadrupole mass spectrometry (ESI-MS-MS). Levels of HNEGSH conjugates calculated as the sum of three chromatographically separated diastereomers were determined in hippocampus, entorhinal cortex, substantia innominata, frontal and temporal cortex, as well as cerebellum from patients with AD and controls matched for age, gender, postmortem delay and storage time. Neither age, nor postmortem delay, nor storage time did correlate with levels of HNEGSH conjugates which ranged between 1 and 500 pmol/g fresh weight in the brain areas examined. The brain specimen from patients with clinically and neuropathologically probable AD diagnosed according to criteria of the consortium to establish a registry for AD (CERAD) show increased levels of HNEGSH in the temporal and frontal cortex, as well as in the substantia innominata. Classification of disease severity according to Braak and Braak, which takes into consideration the amount of neurofibrillary tangles and neuritic plaques, revealed highest levels of HNEGSH in the substantia innominata and the hippocampus, two brain regions known to be preferentially affected in AD. These results substantiate the link between conjugates of glutathione with a product of lipid peroxidation and Alzheimer's disease and justify further studies to evaluate the role of HNE metabolites as potential biomarkers for disease progression in AD.

Frölich L, Götz ME, Weinmüller M, Youdim MB, Barth N, Dirr A, Gsell W, Jellinger K, Beckmann H, Riederer P. · Division of Geriatric Psychiatry, Central Institute of Mental Health Mannheim, University of Heidelberg, Germany. · J Neural Transm. · Pubmed #14991456 No free full text.

Abstract: In dementia of Alzheimer type (DAT), cerebral glucose metabolism is reduced in vivo, and enzymes involved in glucose breakdown are impaired in post-mortem brain tissue. Pyruvate dehydrogenase complex activity (PDHc) is one of the enzymes known to be reduced, while succinate dehydrogenase activity (SDH), another enzyme of oxidative glucose metabolism is unchanged. In dementia of vascular type (DVT), variable changes in glucose metabolism have been demonstrated in vivo, while changes of enzyme activities in post-mortem brain tissue are unknown. Here, PDHc and SDH activity were stimulated with each of the two stereoisomers of alpha lipoic acid in post-mortem parietal brain cortex of patients with DAT, DVT, and one case of Pick's disease and compared to stimulation effects in a control group, matched for age, sex, post-mortem delay, and storage time of brain tissue. PDHc in DAT and DVT, but not in Pick's disease was reduced. PDHc activity could be slightly stimulated by 10 micro M of the physiological stereoisomer (r)-alpha-lipoic acid, in controls and DVT (possibly also in Pick's disease), but not in DAT. In all groups investigated SDH was activated by 100 micro M and 1 mM of both isomers of alpha-lipoic acid, whereas 10 mM of both stereoisomers of alpha-lipoic acid caused an inhibition of both, PDHc and SDH activity. The loss of basal and of (r)-alpha-lipoic acid stimulated PDHc activity indicate that a functional or structural impairment of PDHc may exist in DAT and DVT which is not merely attributable to loss of mitochondria since basal and stimulated SDH activities are similar in controls, DVT and DAT, thus indicating selective vulnerability of PDHc.

Götz ME, Wacker M, Luckhaus C, Wanek P, Tatschner T, Jellinger K, Leblhuber F, Ransmayr G, Riederer P, Eder E. · Department of Toxicology, University of Würzburg, Germany. · Neurosci Lett. · Pubmed #11983292 No free full text.

Abstract: In recent years, an important role for the pathogenesis of Alzheimer's disease (AD) has been ascribed to oxidative stress. Trans-4-hydroxy-2-nonenal, a product of lipid peroxidation, forms stable adducts with a variety of nucleophilic substituents such as thiols or amino moieties. Here, we report the quantification of 1,N2-propanodeoxyguanosine adducts of trans-4-hydroxy-2-nonenal (HNE-dGp) using the specific and very sensitive method of 32P-postlabeling of deoxyguanosine adducts derived from nuclear DNA in neuron rich areas of the hippocampus, the parietal cortex, and the cerebellum of postmortem brains from patients with AD and age matched controls. Adduct levels were highest in the hippocampus, followed by the cerebellum and parietal cortex irrespective of the disease. Neither age, postmortem delay time, gender, nor the extent of neurofibrillary deposits affected tissue adduct levels in the brain areas examined. Although distinctively present in the human brain, the level of HNE-dGp adducts appears not to be useful as a biomarker for AD.

Yamamoto M, Götz ME, Ozawa H, Luckhaus C, Saito T, Rösler M, Riederer P. · Department of Psychiatry and Psychotherapy, University of Würzburg, Germany. · Biochim Biophys Acta. · Pubmed #11113632 No free full text.

Abstract: Previous studies reported disruption of adenylyl cyclase (AC)-cyclic AMP (cAMP) signal transduction in brain of Alzheimer's disease (AD). We also demonstrated that basal and stimulated AC activities in the presence of calcium and calmodulin (Ca(2+)/CaM) were significantly decreased in AD parietal cortex. In the present study, we examined the amounts of Ca(2+)/CaM-sensitive types I and VIII AC, and Ca(2+)/CaM-insensitive type VII AC in the postmortem hippocampi from AD patients and age-matched controls using immunoblotting. The specificities of the anti-type VII and VIII AC antibodies were confirmed by preabsorption with their specific blocking peptides. We observed a significant decrease in the level of type I AC and a tendency to decrease in the level of type VIII AC in AD hippocampus. On the other hand, the level of type VII AC showed no alteration between AD and controls. A body of evidence from the studies with invertebrates and vertebrates suggests that types I and VIII AC may play an essential role in learning and memory. Our finding thus firstly demonstrated that a specific disruption of the Ca(2+)/CaM-sensitive AC isoforms is likely involved in the pathophysiology in AD hippocampus.