Journal of Alzheimer's Disease - Volume 19, issue 2

Authors: Cheng, Xin | Yang, Libang | He, Ping | Li, Rena | Shen, Yong

Article Type: Research Article

Abstract: We reported that tumor necrosis factor receptor I (TNFRI) is required for neuronal death induced by amyloid-β protein in the Alzheimer's disease (AD) brain. However, whether TNF receptor subtypes are expressed and activated differentially in AD brains compared to non-demented brains remains unclear. Our studies on Western blot and ELISA measurements demonstrated that TNFRI levels are increased whereas TNFRII levels are decreased in AD brains compared to non-demented brains (p < 0.05). Immunohistochemical results demonstrated that both TNFRI and TNFRII are expressed in neurons in AD and non-demented brains. However, in situ hybridization studies showed little change in the mRNA …levels of either type of TNF receptor in the neurons of AD brains compared to non-demented brains. To examine whether different levels of TNF receptors in AD brains are correlated with the alteration of functional binding of TNF receptors, by using 125 I-TNF-α binding technique, we found that, in AD brains, 125 I-TNF-α binding affinity to TNFRI is increased, whereas binding affinity to TNFRII is decreased (p < 0.01). These studies reveal a novel observation of abnormal TNF receptor activation in AD brains. Differential TNF receptor protein levels and binding affinities suggest distinct pathogenic mechanisms of neurodegeneration in the AD brain. Show more

Keywords: Alzheimer's disease, amyloid-β, neurodegeneration, receptor binding, TNF-α, TNFRI, TNFRII

DOI: 10.3233/JAD-2010-1253

Citation: Journal of Alzheimer's Disease, vol. 19, no. 2, pp. 621-630, 2010

Authors: Cocks, Graham | Wilde, Jonathan I. | Graham, Simon J | Bousgouni, Vicky | Virley, David | Lovestone, Simon | Richardson, Jill

Article Type: Research Article

Abstract: In a recent clinical study, the thiazolidinedione (TZD) pioglitazone (Actos™ was reported to preserve cognitive function in patients with mild to moderate Alzheimer's disease and type II diabetes mellitus. TZDs are agonists of the nuclear hormone receptor peroxisome proliferator-activated receptor-γ (PPARγ), are peripheral insulin sensitizers, and have recently been reported to increase mitochondrial biogenesis in the central nervous system and dendritic spine density. We report a transcriptional profile of the TZD pioglitazone and the non-TZD PPARγ agonist GW347845 in primary cortical culture. We observed that pioglitazone, but not GW347845, increased cholesterol biosynthetic and lipogenic gene expression after 6 h, and …the expression of the cholesterol efflux transporters Abca1 and Abcg1 after 24 h. Co-treatment of pioglitazone with the PPARγ antagonist GW9662 did not significantly reduce these effects, suggesting a PPARγ-independent mechanism. These findings suggest a novel effect of TZDs in neurons that may be of relevance as a novel approach against Alzheimer's disease. Show more

Keywords: ABCA1, Alzheimer's disease, cholesterol biosynthesis, thiazolidinediones

DOI: 10.3233/JAD-2010-1266

Citation: Journal of Alzheimer's Disease, vol. 19, no. 2, pp. 631-646, 2010

Authors: Kim, WonHee | Lee, Sangmook | Jung, Cheolwha | Ahmed, Ambar | Lee, Gloria | Hall, Garth F.

Article Type: Research Article

Abstract: The mechanisms by which tau-containing lesions are propagated between adjacent and synaptically interconnected parts of the brain are a potentially important but poorly understood component of human tauopathies such as Alzheimer's disease, Pick's disease, and corticobasal degeneration. Since the utility of currently available transgenic models for studying intercellular aspects of tauopathy is limited by their broad patterns of tau expression in the central nervous system, we used an in situ tauopathy model that replicates tau-induced cytodegeneration in identified neurons on a tau-negative background to determine whether tau secretion or interneuronal transfer might play a role in lesion propagation. We found …that the N-terminal half of tau is required for tau secretion and is efficiently exported to the extracellular space and adjacent neurons at relatively low levels of overexpression. By contrast, full-length tau is secreted by a separate mechanism that is correlated with phosphorylation of tau at tyrosine 18 and dendritic degeneration, is exacerbated by tauopathy mutations, and blocked by mutations that inhibit tau:tau interactions. Anterograde transneuronal tau movement occurred with the expression of tau containing the P301L tauopathy mutant, but not with wild type tau isoforms. Our results are consistent with recent studies suggesting a role for molecular “templating” in the propagation of neurofibrillary lesions and provide a novel conceptual and experimental basis for studying the mechanisms of interneuronal propagation and toxicity in human neurodegenerative disease. Show more

Keywords: Pseudophosphorylation, secretion, tau, tauopathy, transneuronal tau movement, tyrosine phosphorylation

DOI: 10.3233/JAD-2010-1273

Citation: Journal of Alzheimer's Disease, vol. 19, no. 2, pp. 647-664, 2010

Authors: Hernandez, Santiago | McClendon, McKee J. | Zhou, Xiao-Hua Andrew | Sachs, Michael | Lerner, Alan J.

Article Type: Research Article

Abstract: Existing research shows differences in medication use for Alzheimer's disease (AD) based on demographics such as race, ethnicity, and geographical location. To determine individual and community characteristics associated with differences in acetylcholinesterase inhibitor (AChEI) and memantine use in AD, 3,049 AD subjects were drawn from 30 centers and evaluated using the Uniform data set (UDS). Cases were evaluated at the individual level within the context of 31 communities (one center encompassed two separate geographical regions). Multivariate analysis was used to determine the significance of individual variables on medication use. Compared to non-Hispanic Whites, Blacks were less likely to use AChEI …and memantine with odds ratios (OR) of 0.59 (95% CI 0.46–0.76) and 0.43 (95% CI 0.32–0.57), respectively. Compared to non-Hispanic Whites, non-Black Hispanics were less likely to use memantine (OR = 0.69 (95% CI 0.49–0.98)). No association was found between the proportion of Blacks or non-Black Hispanics versus non-Hispanic Whites at an Alzheimer Disease Center and individual use of AChEI or memantine. Other significant variables include gender, age, marital status, dementia severity, source of referral, AChEI use, and education. Education and age somewhat mitigated disparity. Significant racial and ethnic differences in AChEI and memantine use exist at the individual level regardless of the racial and ethnic composition of the individual's community. Research and initiatives at the societal level may be an important consideration toward addressing these differences. Show more

Keywords: Acetylcholinesterase inhibitor, Alzheimer's disease, disparity, ethnicity, memantine, race

DOI: 10.3233/JAD-2010-1269

Citation: Journal of Alzheimer's Disease, vol. 19, no. 2, pp. 665-672, 2010

Authors: van Dijk, Marie | van Bezu, Jan | Poutsma, Ankie | Veerhuis, Robert | Rozemuller, Annemieke J. | Scheper, Wiep | Blankenstein, Marinus A. | Oudejans, Cees B.

Article Type: Research Article

Abstract: Pre-eclampsia and late-onset Alzheimer's disease (LOAD) share no clinical features. In contrast to these clinical dissimilarities, striking parallels exist between the (epi)genetic features associated with pre-eclampsia and LOAD for the genes located on 10q22. The parallels in identity between the 10q22 genes involved and active in the organs (placenta, brain) primarily affected in the respective diseases led us to explore, if the pre-eclampsia susceptibility gene STOX1 is functionally involved in LOAD. We demonstrate that isoform A of STOX1 is abundantly expressed in the brain, correlates with severity of disease, and selectively transactivates LRRTM3 in neural cells with increased amyloid-β protein …precursor processing. Similar in vitro results were seen in trophoblast. Our data indicate that STOX1 controls a conserved pathway shared between placenta and brain with overexpression in LOAD. Show more

Keywords: Alzheimer's disease, amyloid-β protein precursor processing, LRRTM3, neuron, pre-eclampsia, STOX1, trophoblast

DOI: 10.3233/JAD-2010-1265

Citation: Journal of Alzheimer's Disease, vol. 19, no. 2, pp. 673-679, 2010

Authors: Dosanjh, Laura E. | Brown, Marishka K. | Rao, Gautam | Link, Christopher D. | Luo, Yuan

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is rapidly reaching epidemic proportions in the United States, currently affecting more than 5 million individuals and predicted to affect 14 million by 2050. Despite a general consensus that the amyloid-β (Aβ) protein plays a significant role in disease progression, the underlying pathology of the disease is not entirely clear. Caenorhabditis elegans is a simple organism that has been used as a model for basic mechanistic studies on the underlying pathological processes involved in AD. Previous studies from our labs demonstrated that transgenic C. elegans with muscle specific expression of human Aβ undergo rapid paralysis, and worms …with neuronal expression of Aβ show deficits in chemotaxis to volatile chemicals. In this study, we evaluate the effect of neuron specific expression of Aβ on multiple neuronally controlled behaviors in a transgenic C. elegans. These worms demonstrate deficits in odorant preference associative learning behavior, and the serotonin-controlled behaviors experience-dependent learning and egg laying. These newly identified learning-deficit behavioral phenotypes in the neuronal Aβ C. elegans suggest that the model may be used to elucidate underlying pathological events related to development of AD and for pharmaceutical intervention. Show more

Keywords: Amyloid toxicity, C. elegans, genotyping, neurological behavioral

DOI: 10.3233/JAD-2010-1267

Citation: Journal of Alzheimer's Disease, vol. 19, no. 2, pp. 681-690, 2010

Authors: Plaschke, Konstanze | Kopitz, Juergen | Siegelin, Markus | Schliebs, Reinhard | Salkovic-Petrisic, Melita | Riederer, Peter | Hoyer, Siegfried

Article Type: Research Article

Abstract: For studying rare hereditary Alzheimer's disease (AD), transgenic (Tg) animal models overexpressing amyloid-β protein precursor (AβPP) followed by increased amyloid-β (Aβ) formation are used. In contrast, sporadic AD has been proposed to start with an insulin-resistant brain state (IRBS). We investigated the effect of IRBS induced by intracerebroventricularly (icv) administered streptozotocin (STZ) on behavior, glycogen synthase kinase-3 (GSK)α/β content, and the formation of AD-like morphological hallmarks Aβ and tau protein in AβPP Tg2576 mice. Nine-month-old Tg mice were investigated 6 months after a single icv injection of STZ or placebo. Spatial cognition was analyzed using the Morris water maze test. …Soluble and aggregated Aβ40/42 fragments, total and phosphorylated tau protein, and GSK-3α/β were determined by ELISA. Cerebral (immuno)histological analyses were performed. In Tg mice, STZ treatment increased mortality, reduced spatial cognition, and increased cerebral aggregated Aβ fragments, total tau protein, and congophilic amyloid deposits. These changes were associated with decreased GSK-3α/β ratio (phosphorylated/total). A linear negative correlation was detected between Aβ42 and cognition, and between GSK-3α/β ratio and aggregated Aβ40+42 . No marked necrotic and apoptotic changes were observed. In conclusion, IRBS may aggravate AD-like changes such as behavioral and increase the formation of pathomorphological AD hallmarks via GSK-3α/β pathway in AβPP-overexpressing mice. Show more

Keywords: Amyloid-β, glycogen synthase kinase-3, insulin, sporadic Alzheimer's disease, streptozotocin, transgenic 2576 mice, tau

DOI: 10.3233/JAD-2010-1270

Citation: Journal of Alzheimer's Disease, vol. 19, no. 2, pp. 691-704, 2010

Authors: Leroy, Karelle | Ando, Kunie | Héraud, Céline | Yilmaz, Zehra | Authelet, Michèle | Boeynaems, Jean-Marie | Buée, Luc | De Decker, Robert | Brion, Jean-Pierre

Article Type: Research Article

Abstract: Neurofibrillary tangles (NFTs) made of phosphorylated tau proteins are a key lesion of Alzheimer's disease and other neurodegenerative diseases, and previous studies have indicated that lithium can decrease tau phosphorylation in tau transgenic models. In this study, we have reassessed the effectiveness of treatment per os with lithium on the prevention, the arrest, or the reversal of NFT development in a tau transgenic line (Tg30tau) developing severe neurofibrillary pathology in the brain and the spinal cord. Wild-type and Tgtau30 mice were treated per os with lithium carbonate or with natrium carbonate by chronic chow feeding for 8 months starting at …the age of 3 months (to test for a preventive effect on NFT formation) or by oral gavage for 1 month starting at the age of 9 months (after development of NFTs). In mice treated by oral gavage, a decrease of tau phosphorylation and of Sarkosyl-insoluble aggregated tau was observed in the brain and in the spinal cord. The density of NFTs identified by Gallyas staining in the hippocampus and in the spinal cord was also significantly reduced and was similar to that observed at the beginning of the lithium treatment. In these animals, the level of brain β-catenin was increased probably as a result of its stabilization by glycogen synthase kinase-3β inhibition. Despite this inhibitory effect of lithium on NFT development, the motor and working memory deficits were not significantly rescued in these aged animals. Chronic chow feeding with lithium did not alter the development of NFT. Nevertheless, this study indicates that even a relatively short-term per os treatment leading to high blood concentration of lithium is effective in arresting the formation of NFTs in the hippocampus and the spinal cord of a tau transgenic model. Show more

Keywords: Lithium, neurofibrillary tangles, phosphorylation, tau, transgenic mouse, treatment

DOI: 10.3233/JAD-2010-1276

Citation: Journal of Alzheimer's Disease, vol. 19, no. 2, pp. 705-719, 2010

Authors: Tremblay, Matthew A. | Acker, Christopher M. | Davies, Peter

Article Type: Research Article

Abstract: Tau is a microtubule-associated protein and a main component of neurofibrillary tangles, one of the pathologic hallmarks of Alzheimer's disease. The paired helical filaments (PHF) that comprise neurofibrillary tangles contain an abnormally hyperphosphorylated form of tau. Historically, most of the tau phosphorylation sites that have been characterized are serine and threonine residues. Recent reports state that tau can be phosphorylated at tyrosine residues by kinases including Fyn, Syk, and c-abl (Abl). Proteomic analyses show that tau phosphorylated at tyrosine 394 (Y394) exists within PHF samples taken from Alzheimer's disease brains. This study also confirms phosphorylation of Y394 as an Alzheimer's …disease-specific event by immunohistochemistry. To date, only Abl is known to phosphorylate this particular site on tau. We report, for the first time, that Arg, the other member of the Abl family of tyrosine kinases, also phosphorylates tau at Y394 in a manner independent of Abl activity. Given the reported role of Arg in oxidative stress response and neural development, the ability to phosphorylate tau at Y394 implicates Arg as a potential player in the pathogenesis of Alzheimer's disease and other tauopathies. Show more

Keywords: Abl2, Alzheimer's disease, Arg, phosphorylation, tangle, tau, tyrosine

DOI: 10.3233/JAD-2010-1271

Citation: Journal of Alzheimer's Disease, vol. 19, no. 2, pp. 721-733, 2010

Authors: Yin, Yang-Yang | Liu, Hao | Cong, Xiao-Bin | Liu, Zhao | Wang, Qun | Wang, Jian-Zhi | Zhu, Ling-Qiang

Article Type: Research Article

Abstract: Tau hyperphosphorylation and memory deficit are characteristic alterations of Alzheimer's disease (AD). Protein phosphatases (PP) 2A plays a crucial role in AD-like lesions. Inhibition of PP2A through hippocampal injection of okadaic acid (OA) induces tau hyperphosphorylation and memory impairment of rats. By using this model, we explored in the present study the effects of acetyl-L-carnitine (ALCAR), a constituent of the inner mitochondrial membrane, on the memory retention, tau phosphorylation, and oxidative stress in rats. We found that pre-treatment of ALCAR (50 mg/d · rat, per os) for two weeks efficiently improved the OA-induced spatial memory retention impairment of the rats. …ALCAR antagonized tau hyperphosphorylation at multiple AD sites and it abated the OA-induced PP2A inhibition and oxidative stress. Our study provides the first in vivo evidence that ALCAR can attenuate AD-like PP2A inhibition, tau hyperphosphorylation, and spatial memory deficit of the rats. It suggests that ALCAR may hold potential in AD treatment. Show more

Keywords: Acetyl-L-carnitine, Alzheimer's disease, hyperphosphorylation, okadaic acid, spatial memory, tau

DOI: 10.3233/JAD-2010-1272

Citation: Journal of Alzheimer's Disease, vol. 19, no. 2, pp. 735-746, 2010