Alzheimer Disease: Fujita SC

Fujio J, Hosono H, Ishiguro K, Ikegami S, Fujita SC. · Mitsubishi Kagaku Institute of Life Sciences, 11 Minamiooya, Machida, Tokyo 194-8511, Japan. · Neurochem Int. · Pubmed #17597257 No free full text.

Abstract: Stress response is intimately involved in memory formation. Stress has been shown to cause reversible Alzheimer-like tau phosphorylation in the brain of experimental animals, but it is not known whether tau phoshorylation takes place during memory acquisition. As an initial investigation we chose contextual fear conditioning paradigm involving electric shocks, and studied tau phosphorylation in the hippocampus and a neighboring limbic region of the mouse brain. Quantitative immunoblot analyses of tissue extracts rapidly prepared from animals undergoing the conditioning showed statistically significant increases in the phosphorylation level at Thr231/Ser235 of tau in both tissues. The reaction reached statistical significance after 10 but not 3 shocks of 0.8mA. Ten shocks of 0.2mA were ineffective. Concurrent increases in phosphorylation of protein kinase TPKI/GSK3beta at Ser9 and of CaMKIIalpha at Thr286 were observed. These results suggest involvement of tau and TPKI/GSK3beta phosphorylation in an early phase of memory formation in the hippocampus and amygdala, raising a possibility that a dysregulation of tau phosphorylation may underlie memory impairment in incipient Alzheimer's disease.

Ikeda Y, Ishiguro K, Fujita SC. · Mitsubishi Kagaku Institute of Life Sciences, 11 Minamiooya, Machida, Tokyo 194-8511, Japan. · FEBS Lett. · Pubmed #17289030 No free full text.

Abstract: Tau is reversibly hyperphosphorylated in the mouse brain by starvation or cold water swimming. Here, we report tau phosphorylation in the hippocampus of normal mouse after ether anesthesia, known to trigger typical stress reactions. Robust phosphorylation of tau was observed immediately and 10min after ether vapor exposure at Ser202/Thr205 and Thr231/Ser235, sites typically phosphorylated in Alzheimer brains. The phosphorylation levels returned to baseline by 1h. The most conspicuous and consistent change in the protein kinases studied was the inactivating phosphorylation of Ser9 of TPKI/GSK3beta in close correspondence with tau phosphorylation. These findings show that tau phosphorylation is a rapid physiological process integral to stress response system, and suggest involvement therein of TPKI/GSK3beta.

Hayashi H, Igbavboa U, Hamanaka H, Kobayashi M, Fujita SC, Wood WG, Yanagisawa K. · Department of Dementia Research, National Institute for Longevity Sciences, 36-3 Gengo, Morioka, Obu 474-8522, Japan. · Neuroreport. · Pubmed #11930145 No free full text.

Abstract: Inheritance of the apolipoprotein (apoE) epsilon4 allele is a risk factor for developing Alzheimer's disease (AD). The purpose of the present study was to determine effects of apoE-isoforms on the transbilayer distribution of cholesterol in synaptic plasma membranes (SPM) using mice expressing human apoE3 and apoE4. Total SPM cholesterol levels did not differ among the wild-type and apoE3 and apoE4 knock-in mice. However, a striking difference was observed in the transbilayer distribution of SPM cholesterol. ApoE4 knock-in mice showed an approximately 2-fold increase in exofacial leaflet cholesterol compared with apoE3 knock-in mice and wild-type mice. The results of this study suggest that pathogenic effects of apoE4 on AD development could be closely linked to alteration of cholesterol distribution in SPM.

Planel E, Yasutake K, Fujita SC, Ishiguro K. · Mitsubishi Kasei Institute of Life Sciences, 11 Minamiooya, Machida, Tokyo 194-8511, Japan. · J Biol Chem. · Pubmed #11441005 links to  free full text

Abstract: Hyperphosphorylated tau is the major component of paired helical filaments in neurofibrillary tangles found in Alzheimer's disease (AD) brain. Starvation of adult mice induces tau hyperphosphorylation at many paired helical filaments sites and with a similar regional selectivity as those in AD, suggesting that a common mechanism may be mobilized. Here we investigated the mechanism of starvation-induced tau hyperphosphorylation in terms of tau kinases and Ser/Thr protein phosphatases (PP), and the results were compared with those reported in AD brain. During starvation, tau hyperphosphorylation at specific epitopes was accompanied by decreases in tau protein kinase I/glycogen synthase kinase 3 beta (TPKI/GSK3 beta), cyclin-dependent kinase 5 (cdk5), and PP2A activities toward tau. These results demonstrate that the activation of TPKI/GSK3 beta and cdk5 is not necessary to obtain hyperphosphorylated tau in vivo, and indicate that inhibition of PP2A is likely the dominant factor in inducing tau hyperphosphorylation in the starved mouse, overriding the inhibition of key tau kinases such as TPKI/GSK3 beta and cdk5. Furthermore, these data give strong support to the hypothesis that PP2A is important for the regulation of tau phosphorylation in the adult brain, and provide in vivo evidence in support of a central role of PP2A in tau hyperphosphorylation in AD.

Yanagisawa M, Planel E, Ishiguro K, Fujita SC. · Mitsubishi Kasei Institute of Life Sciences, 11 Minamiooya, Machida, Tokyo, Japan. · FEBS Lett. · Pubmed #10567721 No free full text.

Abstract: Hyperphosphorylated tau is the major component of paired helical filaments in neurofibrillary tangles found in Alzheimer's disease brains, and tau hyperphosphorylation is thought to be a critical event in the pathogenesis of this disease. The objective of this study was to reproduce tau hyperphosphorylation in an animal model by inducing hypoglycemia. Food deprivation of mice for 1 to 3 days progressively enhanced tau hyperphosphorylation in the hippocampus, to a lesser extent in the cerebral cortex, but the effect was least in the cerebellum, in correspondence with the regional selectivity of tauopathy in Alzheimer's disease. This hyperphosphorylation was reversible by refeeding for 1 day. We discuss possible mechanisms of this phenomenon, and propose the starved mouse as a simple model to study in vivo tau phosphorylation and dephosphorylation which are altered in Alzheimer's disease.