Journal of Alzheimer's Disease - Volume 19, issue 3

Authors: Marwarha, Gurdeep | Dasari, Bhanu | Prasanthi, Jaya R.P. | Schommer, Jared | Ghribi, Othman

Article Type: Research Article

Abstract: Accumulation of amyloid-β (Aβ) peptide and deposition of hyperphosphorylated tau protein are two major pathological hallmarks of Alzheimer's disease (AD). We have shown that cholesterol-enriched diets and its metabolite 27-hydroxycholesterol (27-OHC) increase Aβ and phosphorylated tau levels. However, the mechanisms by which cholesterol and 27-OHC regulate Aβ production and tau phosphorylation remain unclear. Leptin, an adipocytokine involved in cell survival and in learning, has been demonstrated to regulate Aβ production and tau hyperphosphorylation in transgenic mice for AD. However, the involvement of leptin signaling in cholesterol and cholesterol metabolites-induced Aβ accumulation and tau hyperphosphorylation are yet to be examined. In …this study, we determined the effect of high cholesterol diet and 27-OHC on leptin expression levels and the extent to which leptin treatment affects 27-OHC-induced AD-like pathology. Our results show that feeding rabbits a 2% cholesterol-enriched diet for 12 weeks reduces the levels of leptin by ∼80% and incubating organotypic slices from adult rabbit hippocampus with 27-OHC reduced leptin levels by ∼30%. 27-OHC induces a 1.5-fold increase in Aβ40 and a 3-fold increase in Aβ42 and in phosphorylated tau. Treatment with leptin reversed the 27-OHC-induced increase in Aβ and phosphorylated tau by decreasing the levels of BACE-1 and GSK-3β respectively. Our results suggest that cholesterol-enriched diets and cholesterol metabolites induce AD-like pathology by altering leptin signaling. We propose that leptin administration may prevent the progression of sporadic forms of AD that are related to increased cholesterol and oxidized cholesterol metabolite levels. Show more

Keywords: BACE-1, cholesterol, GSK-3β, hippocampus, 27-hydroxycholesterol, leptin, organotypic slices, tau

DOI: 10.3233/JAD-2010-1298

Citation: Journal of Alzheimer's Disease, vol. 19, no. 3, pp. 1007-1019, 2010

Authors: Auffret, Alexandra | Gautheron, Vanessa | Mattson, Mark P. | Mariani, Jean | Rovira, Catherine

Article Type: Research Article

Abstract: Presenilin 1 (PS1) mutations are responsible for many early-onset familial Alzheimer's disease (FAD) cases. While increasing evidence points to impaired synaptic plasticity as an early event in AD, PS1 mutant mice exhibit a paradoxical increase in hippocampal long-term potentiation (LTP). Among PS1 mouse models, PS1 M146V mutant knock-in mice (PS1KI) are particularly interesting in that they exhibit memory impairment in spatial tasks. Here we investigated the effects of aging on two forms of LTP in PS1KI mice, the widely-studied early phase of LTP (E-LTP) and a particular form of LTP called late-LTP (L-LTP) which requires transcription and protein synthesis. L-LTP …is thought to be critical for long-term memory. We found a lower L-LTP maintenance phase in PS1KI mice compared to wild type littermates at 3 months of age. As the mice age, they exhibit impairment of both the induction and maintenance phases of LTP. When E-LTP and NMDA receptor-mediated transmission were analyzed, PS1KI mice displayed an increase at 3 months compared to wild type littermates; this difference did not persist at older ages and finally decreased at 12 months. These results reveal an L-LTP decrease in PS1 mutant mice at an early stage, which occurs coincidently with a paradoxical enhancement of E-LTP. The observation of a decrease in both forms of LTP during aging supports the view that PS1KI mice are a valuable model for the study of age-dependent synaptic dysfunction and cognitive decline in AD. Show more

Keywords: Aging, Alzheimer's disease, hippocampus, long-term potentiation, presenilin 1

DOI: 10.3233/JAD-2010-1302

Citation: Journal of Alzheimer's Disease, vol. 19, no. 3, pp. 1021-1033, 2010

Authors: Tabaton, Massimo | Odetti, Patrizio | Cammarata, Sergio | Borghi, Roberta | Monacelli, Fiammetta | Caltagirone, Carlo | Bossù, Paola | Buscema, Massimo | Grossi, Enzo

Article Type: Research Article

Abstract: The search for markers that are able to predict the conversion of amnestic mild cognitive impairment (aMCI) to Alzheimer's disease (AD) is crucial for early mechanistic therapies. Using artificial neural networks (ANNs), 22 variables that are known risk factors of AD were analyzed in 80 patients with aMCI, for a period spanning at least 2 years. The cases were chosen from 195 aMCI subjects recruited by four Italian Alzheimer's disease units. The parameters of glucose metabolism disorder, female gender, and apolipoprotein E ε3/ε4 genotype were found to be the biological variables with high relevance for predicting the conversion of aMCI. …The scores of attention and short term memory tests also were predictors. Surprisingly, the plasma concentration of amyloid-β42 had a low predictive value. The results support the utility of ANN analysis as a new tool in the interpretation of data from heterogeneous and distinct sources. Show more

Keywords: Alzheimer's disease, artificial neural networks, biological markers, mild cognitive impairment

DOI: 10.3233/JAD-2010-1300

Citation: Journal of Alzheimer's Disease, vol. 19, no. 3, pp. 1035-1040, 2010

Authors: Mura, Elisa | Preda, Stefania | Govoni, Stefano | Lanni, Cristina | Trabace, Luigia | Grilli, Massimo | Lagomarsino, Federica | Pittaluga, Anna | Marchi, Mario

Article Type: Research Article

Abstract: We previously demonstrated that amyloid-β (Aβ) has a neuromodulatory action in the nucleus accumbens (NAc). In this area of the brain, the peptide disrupts the cholinergic control of dopamine (DA) release both in vivo and in vitro. The aim of the present work was to extend the research on the neuromodulatory effect of Aβ1-40 on DA transmission to different release stimuli and to another dopaminergic brain area, the caudate putamen (CPu), in order to clarify whether the effect of the peptide is stimulus- or brain area-selective. We performed both in vivo (microdialysis associated to HPLC) and in vitro studies …(synaptosomes in superfusion). Both in NAc and in CPu and both in vivo and in vitro, Aβ did not affect either basal or potassium-stimulated DA release. In CPu, the Aβ ability to impair the DA release evoked by the cholinergic agonist carbachol, observed in NAc, was confirmed only in vitro. Moreover, in vitro Aβ affected a specific component of the DA overflow evoked by the non-selective metabotropic glutamate receptors agonist t-ACPD. Altogether, these results show that Aβ may have different neuromodulatory actions depending upon the secretory stimulus and, in vivo, the brain area investigated. Show more

Keywords: Amyloid-β, dopamine, microdialysis, nucleus accumbens, striatum, synaptosomes

DOI: 10.3233/JAD-2010-1299

Citation: Journal of Alzheimer's Disease, vol. 19, no. 3, pp. 1041-1053, 2010

Authors: Juhász, Gábor | Barkóczi, Balázs | Vass, Gabriella | Datki, Zsolt | Hunya, Ákos | Fülöp, Lívia | Budai, Dénes | Penke, Botond | Szegedi, Viktor

Article Type: Research Article

Abstract: The aggregated form of amyloid-β (Aβ)1-42 has been shown to increase N-methyl-D-aspartic acid (NMDA) evoked neuronal activity in vivo. Here we further characterized this phenomenon by investigating the role of integrin activation and downstream Src kinase activity using in vivo electrophysiology and in vitro intracellular Ca2+ measurements. Pretreatment of differentiated SH-SY5Y cells with fibrillar Aβ1-42 markedly enhanced the intracellular calcium increases caused by NMDA receptor (NMDA-R) stimulation. Function blocking antibody against β1 integrin depressed the facilitatory effects of Aβ1-42 . Similarly, Aβ1-42 facilitated NMDA-R driven firing of hippocampal neurons in vivo, and this effect was reduced …by neutralizing antibody against β1 integrins. The positive action of Aβ1-42 on NMDA-R dependent responses was also depressed by an inhibitor known to block Src kinase. These results support the hypothesis that aggregated Aβ1-42 is recognized by the β1 subunit containing integrins and may induce a Src kinase dependent NMDA receptor phosphorylation. Show more

Keywords: Alzheimer's disease, amyloid-β, calcium influx, integrin, NMDA receptor, single-unit, Src kinase

DOI: 10.3233/JAD-2010-1301

Citation: Journal of Alzheimer's Disease, vol. 19, no. 3, pp. 1055-1067, 2010

Authors: Fernandez, Liana Lisboa | Carmona, Marga | Portero-Otin, Manuel | Naudi, Alba | Pamplona, Reinald | Schröder, Nadja | Ferrer, Isidro

Article Type: Research Article

Abstract: The present study was aimed to investigate neuropathological changes in AβPP/PS1 transgenic mice (Tg), as a model of Alzheimer's disease, subjected to supplementary iron administration in a critical postnatal period, in order to reveal the interaction of genetic and environmental risk factors in the pathogenesis of the disease. Twelve Tg and 10 wild-type (Wt) littermates were administered iron between the 12th and 14th post-natal days (TgFe, WtFe); 11 Tg and 15 Wt received vehicle (sorbitol 5%) alone in the same period (TgSb, WtSb). Mice were killed at the age of six months and processed for morphological and biochemical studies. No …modifications in amyloid-β burden were seen in iron-treated and non-iron-treated AβPP/PS1 mice. No differences in microglial reactions were observed when comparing the four groups of mice. Yet increased astrocytosis, as revealed by densitometry of GFAP-immunoreactive astrocytes, and increased expression levels of GFAP, as revealed by gel electrophoresis and western blotting, were found in iron-treated mice (both Tg and Wt) when compared with TgSb and WtSb. This was accompanied by significant changes in brain fatty acid composition in AβPP/PS1 mice that led to a lower membrane peroxidizability index and to reduced protein oxidative damage, as revealed by reduced percentages of the oxidative stress markers: glutamic semialdehyde, aminoadipic semialdehyde, Nε -carboxymethyl-lysine, Nε -carboxyethyl-lysine, and Nε -malondialdehyde-lysine. These findings demonstrate that transient dietary iron supplementation during the neonatal period is associated with cellular and metabolic imprinting in the brain in adult life, but it does not interfere with the appearance of amyloid plaques in AβPP/PS1 transgenic mice. Show more

Keywords: AβPP/PS1 transgenic mice, Alzheimer's disease, docosahexaenoic acid, docosapentaenoic acid, GFAP, iron, neurodegeneration, peroxidizability index, protein oxidation

DOI: 10.3233/JAD-2010-1304

Citation: Journal of Alzheimer's Disease, vol. 19, no. 3, pp. 1069-1080, 2010

Authors: Mueller, Claudius | Zhou, Weidong | VanMeter, Amy | Heiby, Michael | Magaki, Shino | Ross, Mark M. | Espina, Virginia | Schrag, Matthew | Dickson, Cindy | Liotta, Lance A. | Kirsch, Wolff M.

Article Type: Research Article

Abstract: One of the remaining challenges in Alzheimer's disease (AD) research is the establishment of biomarkers for early disease detection. As part of a prospective study spanning a period of five years, we have collected serial serum samples from cognitively normal, mild cognitively impaired (MCI), and mild AD participants, including same patient samples before and after cognitive decline. Using mass spectrometry we identified several promising leads for biomarker development, such as prosaposin, phospholipase D1, biliverdin reductase B, and S100 calcium binding protein A7. Selected candidate markers were verified using reverse phase protein microarray assays. Of 15 protein/protein abundance ratios that were …significantly altered in sera from subjects with mild AD compared to Normal or MCI subjects, 14 were composed of ratios containing heme oxygenase-1, biliverdin reductase A, or biliverdin reductase B. Moreover, an increase in the protein abundance ratio of matrix metallopeptidase 9/biliverdin reductase differentiated stable MCI subjects from MCI subjects progressing into mild AD before the onset of cognitive decline. These findings strongly implicate the heme degradation pathway as a promising source of protein biomarkers for the early detection of AD. Show more

Keywords: Alzheimer's disease, biomarker, BLVR, BVR, complement factor H, heme, heme oxyengase-1, phospholipase D1, prosaposin, S100A7, serum

DOI: 10.3233/JAD-2010-1303

Citation: Journal of Alzheimer's Disease, vol. 19, no. 3, pp. 1081-1091, 2010

Authors: Dance, Amber | Landhuis, Esther

Article Type: Editorial

DOI: 10.3233/JAD-2010-1320

Citation: Journal of Alzheimer's Disease, vol. 19, no. 3, pp. 1093-1097, 2010

Article Type: Announcement

DOI: 10.3233/JAD-2010-1305

Citation: Journal of Alzheimer's Disease, vol. 19, no. 3, pp. 1099-1100, 2010