Alzheimer Disease: Planel E

Baranov D, Bickler PE, Crosby GJ, Culley DJ, Eckenhoff MF, Eckenhoff RG, Hogan KJ, Jevtovic-Todorovic V, Palotás A, Perouansky M, Planel E, Silverstein JH, Wei H, Whittington RA, Xie Z, Zuo Z, Anonymous00067. · Department of Anesthesiology and Critical Care, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA. · Anesth Analg. · Pubmed #19372347 No free full text.

Abstract: In order to review the current status of the potential relationship between anesthesia and Alzheimer's disease, a group of scientists recently met in Philadelphia for a full day of presentations and discussions. This special article represents a consensus view on the possible link between Alzheimer's disease and anesthesia and the steps required to test this more definitively.

Bretteville A, Planel E. · Columbia University Medical Center, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, New York, NY 10032, USA. · J Alzheimers Dis. · Pubmed #18688094 No free full text.

Abstract: Alzheimer's disease brains are characterized by extracellular aggregates of the amyloid-beta peptide and intracellular neurofibrillary tangles, composed of aggregated hyperphosphorylated tau protein. The role of aggregated tau in neurodegeneration is still controversial, as evidence point to either a toxic or protective role in the disease. Here, we will first examine tau aggregation and its putative roles in Alzheimer's disease. We will then review the findings concerning different species of tau and their potential toxicity.

Planel E, Krishnamurthy P, Miyasaka T, Liu L, Herman M, Kumar A, Bretteville A, Figueroa HY, Yu WH, Whittington RA, Davies P, Takashima A, Nixon RA, Duff KE. · Taub Institute for Alzheimer's Disease Research, Department of Pathology, Columbia University Medical Center, New York, New York 10032, USA. · J Neurosci. · Pubmed #19036972 links to  free full text

Abstract: In Alzheimer's disease, tau is hyperphosphorylated, which is thought to detach it from microtubules (MTs), induce MT destabilization, and promote aggregation. Using a previously described in vivo model, we investigated whether hyperphosphorylation impacts tau function in wild-type and transgenic mice. We found that after anesthesia-induced hypothermia, MT-free tau was hyperphosphorylated, which impaired its ability to bind MTs and promote MT assembly. MT-bound tau was more resistant to hyperphosphorylation compared with free tau and tau did not dissociate from MTs in wild-type mice. However, 3-repeat tau detached from MT in the transgenic mice. Surprisingly, dissociation of tau from MTs did not lead to overt depolymerization of tubulin, and there was no collapse, or disturbance of axonal MT networks. These results indicate that, in vivo, a subpopulation of tau bound to MTs does not easily dissociate under conditions that extensively phosphorylate tau. Tau remaining on the MTs under these conditions is sufficient to maintain MT network integrity.

Liu L, Orozco IJ, Planel E, Wen Y, Bretteville A, Krishnamurthy P, Wang L, Herman M, Figueroa H, Yu WH, Arancio O, Duff K. · Department of Pathology, Taub Institute for Research on Alzheimer's Disease, Columbia University, Black Building #5-513, 650 West 168th Street, New York, NY 10032, USA. · Neurobiol Dis. · Pubmed #18504134 No free full text.

Abstract: In the last decade, multiple lines of transgenic APP overexpressing mice have been created that recapitulate certain aspects of Alzheimer's disease (AD). However, none of the previously reported transgenic APP overexpressing rat models developed AD-like beta-amyloid (Abeta) deposits, or age-related learning and memory deficits. In the present study, we have characterized a transgenic rat model overexpressing transgenes with three, familial AD mutations (two in APP and one in PS1) that were developed by Flood et al. [Flood, D.G., et al., Abeta deposition in a transgenic rat model of Alzheimer's disease. Society for Neuroscience 2003, Washington, DC, 2003]. From the age of 9 months, these rats develop Abeta deposits in both diffuse and compact forms, with the latter being closely associated with activated microglia and reactive astrocytes. Impaired long-term potentiation (LTP) was revealed by electrophysiological recordings performed on hippocampal slices from rats at 7 months of age, which is 2 months before the appearance of amyloid plaques. The deficit in LTP was accompanied by impaired spatial learning and memory in the Morris water maze, which became more pronounced in transgenic rats of 13 months of age. For Tg rats of both ages, there was a trend for cognitive impairment to correlate with total Abeta42 levels in the hippocampus. The rat model therefore recapitulates AD-like amyloid pathology and cognitive impairment. The advantage of the rat model over the available mouse models is that rats provide better opportunities for advanced studies, such as serial CSF sampling, electrophysiology, neuroimaging, cell-based transplant manipulations, and complex behavioral testing.

Muhammad A, Flores I, Zhang H, Yu R, Staniszewski A, Planel E, Herman M, Ho L, Kreber R, Honig LS, Ganetzky B, Duff K, Arancio O, Small SA. · Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA. · Proc Natl Acad Sci U S A. · Pubmed #18480253 links to  free full text

Abstract: Although deficiencies in the retromer sorting pathway have been linked to late-onset Alzheimer's disease, whether these deficiencies underlie the disease remains unknown. Here we characterized two genetically modified animal models to test separate but related questions about the effects that retromer deficiency has on the brain. First, testing for cognitive defects, we investigated retromer-deficient mice and found that they develop hippocampal-dependent memory and synaptic dysfunction, which was associated with elevations in endogenous Abeta peptide. Second, testing for neurodegeneration and amyloid deposits, we investigated retromer-deficient flies expressing human wild-type amyloid precursor protein (APP) and human beta-site APP-cleaving enzyme (BACE) and found that they develop neuronal loss and human Abeta aggregates. By recapitulating features of the disease, these animal models suggest that retromer deficiency observed in late-onset Alzheimer's disease can contribute to disease pathogenesis.

Matsuoka Y, Jouroukhin Y, Gray AJ, Ma L, Hirata-Fukae C, Li HF, Feng L, Lecanu L, Walker BR, Planel E, Arancio O, Gozes I, Aisen PS. · Department of Neurology, Georgetown University Medical Center, 4000 Reservoir Road N.W., Washington, DC 20057, USA. · J Pharmacol Exp Ther. · Pubmed #18199809 links to  free full text

Abstract: Neurofibrillary tangles composed of aggregated, hyperphosphorylated tau in an abnormal conformation represent one of the major pathological hallmarks of Alzheimer's disease (AD) and other tauopathies. However, recent data suggest that the pathogenic processes leading to cognitive impairment occur before the formation of classic tangles. In the earliest stages of tauopathy, tau detaches from microtubules and accumulates in the cytosol of the somatodendritic compartment of cells. Either as a cause or an effect, tau becomes hyperphosphorylated and aggregates into paired helical filaments that comprise the tangles. To assess whether an agent that modulates microtubule function can inhibit the pathogenic process and prevent cognitive deficits in a transgenic mouse model with AD-relevant tau pathology, we administered the neuronal tubulin-preferring agent, NAPVSIPQ (NAP). Three months of treatment with NAP at an early-to-moderate stage of tauopathy reduced the levels of hyperphosphorylated soluble and insoluble tau. A 6-month course of treatment improved cognitive function. Although nonspecific tubulin-interacting agents commonly used for cancer therapy are associated with adverse effects due to their anti-mitotic activity, no adverse effects were found after 6 months of exposure to NAP. Our results suggest that neuronal microtubule interacting agents such as NAP may be useful therapeutic agents for the treatment or prevention of tauopathies.

Tatebayashi Y, Planel E, Chui DH, Sato S, Miyasaka T, Sahara N, Murayama M, Kikuchi N, Yoshioka K, Rivka R, Takashima A. · Laboratory for Alzheimer's Disease, Brain Science Institute, The Institute of Physical and Chemical Research (RIKEN), Saitama, Japan. · FASEB J. · Pubmed #16478768 links to  free full text

Abstract: Tauopathies such as Alzheimer disease (AD) probably involve a type of phosphorylation imbalance causing the accumulation of abnormally hyperphosphorylated tau in neurons and/or glias. Investigation of R406W tau mutation may provide insight into such abnormal tau hyperphosphorylation, since this mutation causes AD-like dementia and tauopathy in humans and because it has the unique ability to reduce tau phosphorylation in vitro and in cultured cells. Here we show that R406W mutation primarily disrupts tau phosphorylation at Ser404, a priming phosphorylation site of glycogen synthase kinase-3beta (GSK-3beta), thereby reducing subsequent GSK-3beta-mediated phosphorylation at the PHF-1 site (mostly Ser396). In contrast, c-jun N-terminal kinase (JNK) as activated in the mitotic phase directly hyperphosphorylates R406W tau at the PHF-1 site. This was confirmed by PHF-1 hyperphosphorylation of R406W tau in mitotic cells, its association with cytoplasmic JNK activation, and its inhibition by a JNK inhibitor, SP600125. These data unveil the unknown mechanisms of physiological tau phosphorylation at the PHF-1 site and suggest that cytoplasmic JNK activation may play an important role in the abnormal tau hyperphosphorylation associated with R406W tau mutation and in AD.

Planel E, Miyasaka T, Launey T, Chui DH, Tanemura K, Sato S, Murayama O, Ishiguro K, Tatebayashi Y, Takashima A. · Laboratory for Alzheimer's Disease, The Institute of Physical and Chemical Research, Wako-shi, Saitama 351-0198, Japan. · J Neurosci. · Pubmed #15014115 links to  free full text

Abstract: Alzheimer's disease (AD) brains contain neurofibrillary tangles (NFTs) composed of abnormally hyperphosphorylated tau protein. Regional reductions in cerebral glucose metabolism correlating to NFT densities have been reported in AD brains. Assuming that reduced glucose metabolism might cause abnormal tau hyperphosphorylation, we induced in vivo alterations of glucose metabolism in mice by starvation or intraperitoneal injections of either insulin or deoxyglucose. We found that the treatments led to abnormal tau hyperphosphorylation with patterns resembling those in early AD brains and also resulted in hypothermia. Surprisingly, tau hyperphosphorylation could be traced down to a differential effect of low temperatures on kinase and phosphatase activities. These data indicate that abnormal tau hyperphosphorylation is associated with altered glucose metabolism through hypothermia. Our results imply that serine-threonine protein phosphatase 2A plays a major role in regulating tau phosphorylation in the adult brain and provide in vivo evidence for its crucial role in abnormal tau hyperphosphorylation in AD.

Tatebayashi Y, Miyasaka T, Chui DH, Akagi T, Mishima K, Iwasaki K, Fujiwara M, Tanemura K, Murayama M, Ishiguro K, Planel E, Sato S, Hashikawa T, Takashima A. · Laboratory for Alzheimer's Disease and Neural Architecture, Brain Science Institute, Institute of Physical and Chemical Research (RIKEN), 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan. · Proc Natl Acad Sci U S A. · Pubmed #12368474 links to  free full text

Abstract: The R406W tau mutation found in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) causes a hereditary tauopathy clinically resembling Alzheimer's disease. Expression of modest levels of the longest human tau isoform with this mutation under the control of the alpha-calcium-calmodulin-dependent kinase-II promoter in transgenic (Tg) mice resulted in the development of congophilic hyperphosphorylated tau inclusions in forebrain neurons. These inclusions appeared as early as 18 months of age. As with human cases, tau inclusions were composed of both mutant and endogenous wild-type tau, and were associated with microtubule disruption and flame-shaped transformations of the affected neurons. Straight tau filaments were recovered from Sarkosyl-insoluble fractions from only the aged Tg brains. Behaviorally, aged Tg mice had associative memory impairment without obvious sensorimotor deficits. Therefore, these mice that exhibit a phenotype mimicking R406W FTDP-17 provide an animal model for investigating the adverse properties associated with this mutation, which might potentially recapitulate some etiological events in Alzheimer's disease.

Sato S, Tatebayashi Y, Akagi T, Chui DH, Murayama M, Miyasaka T, Planel E, Tanemura K, Sun X, Hashikawa T, Yoshioka K, Ishiguro K, Takashima A. · Laboratory for Alzheimer's Disease, Brain Science Institute, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan. · J Biol Chem. · Pubmed #12191990 links to  free full text

Abstract: Neurofibrillary tangles (NFTs) are found in a wide range of neurodegenerative disorders, including Alzheimer's disease. The major component of NFTs is aberrantly hyperphosphorylated microtubule-associated protein tau. Because appropriate in vivo models have been lacking, the role of tau phosphorylation in NFTs formation has remained elusive. Here, we describe a new model in which adenovirus-mediated gene expression of tau, DeltaMEKK, JNK3, and GSK-3beta in COS-7 cells produces most of the pathological phosphorylation epitopes of tau including AT100. Furthermore, this co-expression resulted in the formation of tau aggregates having short fibrils that were detergent-insoluble and Thioflavin-S-reactive. These results suggest that aberrant tau phosphorylation by the combination of these kinases may be involved in "pretangle," oligomeric tau fibril formation in vivo.

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.