Journal of Alzheimer's Disease - Volume 20, issue 4

Authors: Rattray, Ivan | Pitiot, Alain | Lowe, James | Auer, Dorothee P. | Lima, Sarah-Jane | Schubert, Mirjam I. | Prior, Malcolm J.W. | Marsden, Charles A. | Diaz, Fernando Pérez | Kendall, David A. | Pardon, Marie-Christine

Article Type: Research Article

Abstract: We have previously shown that repeated exposure to mild novel cage stress prevents the onset of recent contextual fear memory deficits and attenuated amyloid deposition in the TASTPM mouse model of Alzheimer's disease. Here, we extended this investigation to remote contextual fear memory and extinction. TASTPM and wild-type mice acquired contextual fear at 4 months of age. Retention and extinction of contextual fear were assessed at 5.5 months prior to in vivo MRI assessment of regional T2 relaxation times and brain volumes followed by immunostaining to determine amyloid plaque load. Remote contextual fear memory was preserved in TASTPM mice …regardless of the stress condition. Stress impaired extinction in wild-type mice but facilitated this process in TASTPM mice. Genotype-dependent effects of stress were observed on regional T2 times which were prolonged in the subiculum and thalamus of stressed TASTPM, possibly reflecting reduced amyloid pathology. Amyloid plaque load was particularly decreased in the retrosplenial cortex of stressed TASTPM mice, which also showed an overall reduction in the number of diffuse plaques. These findings support the hypothesis that repeated mild levels of stress induced by novel activities can delay the progression of pathological changes relevant to Alzheimer's disease. Show more

Keywords: Alzheimer's disease, amyloid-β, extinction, memory, MRI, stress, transgenic

DOI: 10.3233/JAD-2010-091354

Citation: Journal of Alzheimer's Disease, vol. 20, no. 4, pp. 1049-1068, 2010

Authors: Agholme, Lotta | Lindström, Tobias | Kågedal, Katarina | Marcusson, Jan | Hallbeck, Martin

Article Type: Research Article

Abstract: Neuroscience, including research on Alzheimer's disease, is hampered by the lack of suitable in vitro models to study the human nervous system. To counteract this, many attempts to differentiate cell lines into more neuron-like cells have been performed, resulting in partial expression of neuronal features. Furthermore, it has been reported that neuroblastoma cell lines lack mature isoforms of tau. Our aim was to develop an improved in vitro model, generating sustainable cells with morphology and biochemistry of human, mature neurons. To obtain cells with neuronal differentiation and function, we investigated the effect of combining three-dimensional culturing of SH-SY5Y cells in …extracellular matrix (ECM) gel with several factors reported to have neuro-differentiating effects. This resulted in cells with apparent neuronal morphology with long, extensively branched neurites. Further investigation revealed expression of several neurospecific markers including synapse protein Sv2 and nuclear marker NeuN, as well as the presence of synapses and axonal vesicle transport. In addition, these cells expressed mature tau isoforms, and tau protein expression was significantly increased compared to undifferentiated cells, reaching levels found in adult human brain. In conclusion, we found that pre-treatment with retinoic acid followed by ECM gel culturing in combination with brain derived neurotrophic factor, neuregulin β1, nerve growth factor, and vitamin D3 treatment generated sustainable cells with unambiguous resemblance to adult neurons. These cells also expresses adult splicing forms of tau with neuronal localization, making this cellular in vitro model useful in many areas of neuroscience research, particularly the Alzheimer's disease field. Show more

Keywords: Alzheimer's disease, differentiation, in vitro model, neuroblastoma, tau

DOI: 10.3233/JAD-2010-091363

Citation: Journal of Alzheimer's Disease, vol. 20, no. 4, pp. 1069-1082, 2010

Authors: Kester, Maartje I. | van der Flier, Wiesje M. | Mandic, Gorana | Blankenstein, Marinus A. | Scheltens, Philip | Muller, Majon

Article Type: Research Article

Abstract: We examined the impact of hypertension on cerebrospinal fluid (CSF) biomarkers amyloid-β1-42 (Aβ42 ), total tau (tau), and phosphorylated tau at threonine 181 (ptau-181), and assessed the modifying role of APOE genotype in this relation in 546 patients (mean age 65 ± 10, 47% female) from our memory-clinic. Of these patients 150 had subjective complaints, 140 were diagnosed with mild cognitive impairment, and 256 with Alzheimer's disease. Linear regression analyses adjusted for age, gender, and diagnosis showed that the association of hypertension with tau and ptau-181 was modified by APOE genotype (p-values for interaction p< 0.05). In APOE ε4 …homozygotes (n=74), and to a lesser extent in APOE ε4 heterozygotes, hypertension was associated with higher tau and ptau-181 levels; β (95%CI) were 188 (11; 364) pg/mL and 22 (3; 42) pg/mL for the APOE ε4 homozygotes. Hypertension was not associated with Aβ42 levels, and APOE genotype did not modify this relation. Our findings suggest that hypertension is directly related to tau pathology in APOE ε4 homozygous carriers. Show more

Keywords: Alzheimer's disease, APOE genotype, CSF biomarkers, hypertension

DOI: 10.3233/JAD-2010-091198

Citation: Journal of Alzheimer's Disease, vol. 20, no. 4, pp. 1083-1090, 2010

Authors: Yu, Jia | Sun, Miao | Chen, Zheng | Lu, Jiangyang | Liu, Yi | Zhou, Liang | Xu, Xuemin | Fan, Dongsheng | Chui, Dehua

Article Type: Research Article

Abstract: Alzheimer's disease (AD), the most common form of dementia, is characterized by the presence of excessive deposits of aggregated amyloid-β (Aβ), which is derived from the amyloid-β protein precursor (AβPP) following processing by β- and γ-secretase. Metal elements are implicated in the pathophysiology of AD. Magnesium affects many biochemical mechanisms vital for neuronal properties and synaptic plasticity, and magnesium levels were reported to be decreased in various tissues including brain of AD patients. However, the exact role of magnesium in the neurodegenerative process of AD remains elusive. In this study, we investigated the effects of physiological (0.8 mM, as normal …control), low (0–0.4 mM), and high (1.2–4.0 mM) concentrations of extracellular magnesium ([Mg2+ ]o ) on AβPP processing and Aβ secretion. Here we show the effects of varying [Mg2+ ]o on AβPP processing is time- and dose-dependent. After 24 h treatment, high [Mg2+ ]o increased C-terminal fragment-α (CTFα) levels and soluble α-secretase cleaved AβPP (sAβPPα) release via enhancing retention of AβPP on plasma membrane. In contrast, low [Mg2+ ]o enhanced CTFβ accumulation and Aβ secretion, and reduced cell surface AβPP level. Varying [Mg2+ ]o did not alter protein contents of full length AβPP. However, decreased total intracellular magnesium level by magnesium deprivation over 24 hr impaired cell viability. Normal AβPP processing could be restored when magnesium was adjusted back to physiological concentration. These data demonstrate that AβPP processing can be modulated by magnesium and at high [Mg2+ ]o , AβPP processing favors the α-secretase cleavage pathway. Our findings suggest that supplementation of magnesium has a therapeutic potential for preventing AD. Show more

Keywords: Alzheimer's disease, amyloid-β, amyloid-β protein precursor, magnesium

DOI: 10.3233/JAD-2010-091444

Citation: Journal of Alzheimer's Disease, vol. 20, no. 4, pp. 1091-1106, 2010

Authors: Lambert, Jean-Charles | Grenier-Boley, Benjamin | Chouraki, Vincent | Heath, Simon | Zelenika, Diana | Fievet, Nathalie | Hannequin, Didier | Pasquier, Florence | Hanon, Olivier | Brice, Alexis | Epelbaum, Jacques | Berr, Claudine | Dartigues, Jean-Francois | Tzourio, Christophe | Campion, Dominique | Lathrop, Mark | Amouyel, Philippe

Article Type: Research Article

Abstract: The results of several genome-wide association studies (GWASs) in the field of Alzheimer's disease (AD) have recently been published. Although these studies reported in detail on single-nucleotide polymorphisms (SNPs) and the neighboring genes with the strongest evidence of association with AD, little attention was paid to the rest of the genome. However, complementary statistical and bio-informatics approaches now enable the extraction of pertinent information from other SNPs and/or genes which are only nominally associated with the disease risk. Two different tools (the ALIGATOR and GenGen/KEGG software packages) were used to analyze a large GWAS dataset containing 2,032 AD cases and …5,328 controls. Convergent outputs from the two gene set enrichment approaches suggested an immune system dysfunction in AD. Furthermore, although these statistical approaches did not adopt a priori hypotheses concerning a biological function's putative role in the disease process, genes associated with AD risk were overrepresented in the "Alzheimer's disease" KEGG pathway. In conclusion, a systematic search for biological pathways using GWAS data set seems to comfort the primary causes already suspected but may specifically highlight the importance of the immune system in AD. Show more

Keywords: Alzheimer's disease, APOE, Ca2+, gene, GWAS, immunity, MHC, pathway, polymorphism

DOI: 10.3233/JAD-2010-100018

Citation: Journal of Alzheimer's Disease, vol. 20, no. 4, pp. 1107-1118, 2010

Authors: Espuny-Camacho, Ira | Dominguez, Diana | Merchiers, Pascal | Rompaey, Luc Van | Selkoe, Dennis | Strooper, Bart De

Article Type: Research Article

Abstract: Peroxisome proliferator-activated receptor gamma (PPARγ) activation results in an increased rate of amyloid-β (Aβ) clearance from the media of diverse cells in culture, including primary neurons and glial cells. Here, we further investigate the mechanism for Aβ clearance and found that PPARγ activation modulates a cell surface metalloprotease that can be inhibited by metalloprotease inhibitors, like EDTA and phenanthroline, and also by the peptide hormones insulin and glucagon. The metalloprotease profile of the Aβ-degrading mechanism is surprisingly similar to insulin-degrading enzyme (IDE). This mechanism is maintained in hippocampal and glia primary cultures from IDE loss-of-function mice. We conclude that PPARγ …activates an IDE-like Aβ degrading activity. Our work suggests a drugable pathway that can clear Aβ peptide from the brain. Show more

Keywords: Amyloid-β (Aβ) clearance, insulin-degrading enzyme (IDE), metalloprotease, peroxisome proliferator-activated receptor gamma (PPARγ)

DOI: 10.3233/JAD-2010-091633

Citation: Journal of Alzheimer's Disease, vol. 20, no. 4, pp. 1119-1132, 2010

Authors: Lenzken, Silvia C. | Stanga, Serena | Lanni, Cristina | De Leonardis, Fabio | Govoni, Stefano | Racchi, Marco

Article Type: Research Article

Abstract: The amyloid-β protein precursor (AβPP) is an integral membrane protein subjected to constitutive and regulated proteolytic processing. We have previously demonstrated that protein kinase C ε (PKCε) plays a key role in the regulation of AβPP metabolism via cholinergic receptors. The purpose of the present work is to clarify whether other putative signaling systems are involved in the same pharmacological pathway. We focused particularly on casein kinase 2 (CK2), demonstrating a direct interaction between PKCε and CK2 following cholinergic stimulation. Treatment of human neuroblastoma SH-SY5Y cells with a selective inhibitor of CK2 reduced the effect of carbachol on the release …of sAβPPα. This treatment did not influence the activation and translocation of PKCε suggesting that the latter is located upstream of CK2. On the basis of our results, we add another player to the complex cellular mechanisms regulating non-amyloidogenic processing of AβPP. Show more

Keywords: Alzheimer's disease, amyloid-β protein precursor, casein kinase 2, cholingergic, neuroblastoma, protein kinase C, signal transduction

DOI: 10.3233/JAD-2010-090232

Citation: Journal of Alzheimer's Disease, vol. 20, no. 4, pp. 1133-1141, 2010

Authors: Cheng, Yong | Yu, Long-Chuan

Article Type: Research Article

Abstract: The neuropeptide galanin and its receptors are found to be upregulated in brain associated with Alzheimer's disease (AD), while the role of galanin in AD is still unclear. The present study was performed to explore the neuroprotective role of galanin both in vitro and in vivo. Our results demonstrated that galanin inhibited the neurotoxicity induced by amyloid-β25-35 (Aβ25-35 ) or Aβ1-42 in primary cultured hippocampal neurons of rats. Moreover, Gal2-11 (an agonist of GalR2/3) also inhibited the neurotoxicity induced by Aβ25-35 in the cultured neurons. We further found that galanin inhibited the activation of p53, Bax, and …caspase-3 induced by Aβ25-35 in the cultured hippocampal neurons. Moreover, galanin reversed the down regulation of Bcl-2 induced by Aβ25-35 in the cultured neurons. Interestingly, in the Morris water maze task we found that intra-CA1 injection of Aβ25-35 -induced spatial learning deficits in rats were blocked by galanin. In addition, galanin inhibited the Aβ25-35 -induced dysregulation of p53, Bax, and MAP2 in rat hippocampus. Our results strongly demonstrate that galanin plays neuroprotective roles in nerve cells and in AD-induced learning and memory deficits. Show more

Keywords: Amyloid-β, Bax, Bcl-2, caspase-3, Gal2-11, galanin, galanin receptor 2, hippocampal neuron, MAP2, Morris water maze, neuroprotective effect, p53

DOI: 10.3233/JAD-2010-091234

Citation: Journal of Alzheimer's Disease, vol. 20, no. 4, pp. 1143-1157, 2010

Authors: Exley, Christopher | House, Emily | Collingwood, Joanna F. | Davidson, Mark R. | Cannon, Danielle | Donald, Athene M.

Article Type: Research Article

Abstract: Several amyloidogenic proteins including insulin, β-lactoglobulin, and albumin form spherulites in vitro under non-physiological conditions. These micrometer-sized, roughly spherical structures are composed of ordered arrays of amyloid fibrils in radial arrangements which, characteristically, show a typical Maltese cross pattern of light extinction under the polarizing microscope. The physiological significance of amyloid spherulites is unknown though in Alzheimer's disease, senile plaques composed primarily of β sheets of amyloid-β (Aβ)42 have, very occasionally, been shown to give a Maltese cross pattern of light extinction under crossed polarizers. Herein we describe the first observation of the formation in vitro of spherulites of …Aβ42 . They were formed under near-physiological conditions in which the β sheet conformation of pre-formed aggregates of Aβ42 had been abolished following the addition of an excess of copper. Incubation of these preparations at 37°C for up to 9 months resulted in the formation of globular structures, 5–20 μm in diameter, which exhibited a Maltese cross pattern of light extinction typical of spherulites. Near-identical spherulitic structures were also observed in abundance in 30 μm thick sections of Alzheimer's disease brain tissue. Synchrotron x-ray fluorescence showed that the location of these spherulites in AD tissue coincided with locally elevated concentrations of tissue copper. The formation in vitro of spherulites of Aβ42 which morphologically appeared analogous to spherulitic structures observed in vivo strongly supports the hypothesis that spherulites and senile plaques in AD tissue are one and the same structures and that their ultimate formation may involve copper. Show more

Keywords: Aβ42, Alzheimer's disease, amyloid, copper, senile or neuritic plaque, spherulite

DOI: 10.3233/JAD-2010-091630

Citation: Journal of Alzheimer's Disease, vol. 20, no. 4, pp. 1159-1165, 2010

Authors: Willis, Michael | Kaufmann, Walter A. | Wietzorrek, Georg | Hutter-Paier, Birgit | Moosmang, Sven | Humpel, Christian | Hofmann, Franz | Windisch, Manfred | -Günther Knaus, Hans | Marksteiner, Josef

Article Type: Research Article

Abstract: Cumulative evidence indicates that amyloid-β peptides exert some of their neurodegenerative effects through modulation of L-type voltage gated calcium channels, which play key roles in a diverse range of CNS functions. In this study we examined the expression of CaV 1.2 L-type voltage gated calcium channels in transgenic mice overexpressing human AβPP751 with the London (V717I) and Swedish (K670M/N671L) mutations by immunohistochemistry in light and electron microscopy. In hippocampal layers of wild type and transgenic mice, CaV 1.2 channels were predominantly localized to somato-dendritic domains of neurons, and to astrocytic profiles with an age-dependent increase in labeling density. In transgenic …animals, CaV 1.2-like immunoreactive clusters were found in neuronal profiles in association with amyloid-β plaques. Both the number and density of these clusters depended upon age of animals and number of plaques. The most striking difference between wild type and transgenic mice was the age-dependent expression of CaV 1.2 channels in reactive astrocytes. At the age of 6 month, CaV 1.2 channels were rarely detected in reactive astrocytes of transgenic mice, but an incremental number of CaV 1.2 expressing reactive astrocytes was found with increasing age of animals and number of amyloid-β plaques. This study demonstrates that CaV 1.2 channels are highly expressed in reactive astrocytes of 12-months of age transgenic mice, which might be a consequence of the increasing amyloid burden. Further studies should clarify which functional implications are associated with the higher availability of CaV 1.2 channels in late stage Alzheimer's disease. Show more

Keywords: Alpha1C, Alzheimer's disease, amyloid, astrocytes, dendrites

DOI: 10.3233/JAD-2010-091117

Citation: Journal of Alzheimer's Disease, vol. 20, no. 4, pp. 1167-1180, 2010