Journal of Alzheimer's Disease - Volume 18, issue 4

Authors: Valente, Tony | Hidalgo, Juan | Bolea, Irene | Ramirez, Bartolomé | Anglés, Neus | Reguant, Jordi | Morelló, José Ramón | Gutiérrez, Cristina | Boada, Mercè | Unzeta, Mercedes

Article Type: Research Article

Abstract: At present it is widely accepted that there are at least two neurogenic sites in the adult mammalian brain: the subventricular zone (SVZ) of lateral ventricles and the subgranular zone (SGZ) of the hippocampus dentate gyrus. The adult proliferation rate declines with aging and is altered in several neurodegenerative pathologies including Alzheimer's disease. The aim of this work was to study whether a natural diet rich in polyphenols and polyunsaturated fatty acids (LMN diet) can modulate neurogenesis in adult mice and give insight into putative mechanisms. Results with BrdU and PCNA demonstrated that the LMN fed mice had more newly …generated cells in the SVZ and SGZ, and those with DCX (undifferentiated neurons) and tyrosine hydroxylase, calretinin, and calbindin (differentiated neurons) immunostainings and western blots demonstrated a significant effect on neuronal populations, strongly supporting a positive role of the LMN diet on adult neurogenesis. In primary rat neuron cultures, the LMN cream dramatically protected against damage caused by both hydrogen peroxide and Aβ1-42 , demonstrating a potent antioxidant effect that could play a major role in the normal adult neurogenesis and, moreover, the LMN diet could have a significant effect combating the cognitive function decline during both aging and neurodegenerative diseases such as Alzheimer's disease. Show more

Keywords: 129S1/SvImJ mice, adult neurogenesis, diet, hippocampus, olfactory bulb, polyphenols, polyunsaturated fatty acids

DOI: 10.3233/JAD-2009-1188

Citation: Journal of Alzheimer's Disease, vol. 18, no. 4, pp. 849-865, 2009

Authors: Borroni, Barbara | Grassi, Mario | Archetti, Silvana | Costanzi, Chiara | Bianchi, Marta | Caimi, Luigi | Caltagirone, Carlo | Di Luca, Monica | Padovani, Alessandro

Article Type: Research Article

Abstract: The gene encoding the brain-derived neurotrophic factor (BDNF) has been demonstrated as a candidate for Alzheimer's disease-related depression (AD-D) susceptibility. Additionally, an association between AD-D and the functional valine to methionine (Val66Met) polymorphism has been reported. The aim of this study was to assess the genetic contribution of other BDNF variants to AD-D. Two-hundred forty-five AD patients were divided into two subgroups according to the presence (AD-D) or the absence (AD-nD) of depressive symptoms. Four single-nucleotide polymorphisms within BDNF gene were considered, i.e., C270T, rs2049045 C/G, G196A (Val66Met), and G11757C. In our sample, 35.5% of patients (n = 87) reported …AD-related depressive symptoms. The individual SNP analysis showed an association between G196A and G11757C genotypes and AD-D. Accordingly, considering the allele frequencies, BDNF 196*A allele was significantly overrepresented in AD-D compared to AD-nD (OR = 1.80, 95% CI = 1.19–2.72), as well as BDNF 11757*C allele (OR = 1.90, 95% CI = 1.25–2.90). Haplotype analyses revealed that the alleles at four loci (C270T, rs2049045 C/G, G196A, G11757C) interacted to further increase the risk of AD-D. Compared to the most common not-at-risk C-C-G-G haplotype, C-G-A-C (OR = 3.55, 95% CI = 1.44–8.76, P = 0.006) and C-C-A-C haplotypes (OR = 1.72, 95% CI = 1.03–2.87, P = 0.037) were overrepresented in AD-D. This study suggests that BDNF genetic variations play a role in the susceptibility to AD-related depression. Show more

Keywords: Alzheimer's disease, brain-derived neurotrophic factor (BDNF), depression, genetics, haplotype, polymorphism

DOI: 10.3233/JAD-2009-1191

Citation: Journal of Alzheimer's Disease, vol. 18, no. 4, pp. 867-875, 2009

Authors: Tomàs, Marta | Garcia, Neus | Santafé, Manuel M. | Lanuza, Maria | Tomàs, Josep

Article Type: Research Article

Abstract: Using intracellular recording of the diaphragm muscle of adult rats, we have investigated the short-term functional effects of amyloid-β (Aβ)25-35 peptide aggregates on the modulation of acetylcholine (ACh) release and the involvement of protein kinase C (PKC). The non-aggregated form of this peptide does not change the evoked and spontaneous transmitter release parameters on the neuromuscular synapse. However, the aggregated form of Aβ25-35 acutely interferes with evoked quantal ACh release (∼40% reduction) when synaptic activity in the ex vivo neuromuscular preparation is maintained by low frequency (1 Hz) electrical stimulation. This effect is partially dependent on the activity …of PKC that may have a permissive action. The end result of Aβ25-35 is in opposition to the PKC-dependent maintenance effect on ACh release manifested in active synapses. Show more

Keywords: Acetylcholine release, amyloid-β, amyloid-β protein precursor, motor nerve terminals, protein kinase C

DOI: 10.3233/JAD-2009-1195

Citation: Journal of Alzheimer's Disease, vol. 18, no. 4, pp. 877-884, 2009

Authors: Counts, Scott E. | He, Bin | Che, Shaoli | Ginsberg, Stephen D. | Mufson, Elliott J.

Article Type: Research Article

Abstract: Fibers containing galanin (GAL) hyperinnervate cholinergic basal forebrain (CBF) nucleus basalis neurons in late stage Alzheimer's disease (AD), yet the molecular consequences of this phenomenon are unknown. To determine whether GAL alters the expression of genes critical to CBF cell survival in AD, single cell microarray analysis was used to determine mRNA levels within nucleus basalis neurons lacking GAL innervation from subjects who died with a clinical diagnosis of no cognitive impairment (NCI) compared to nucleus basalis neurons from AD cases either lacking GAL hyperinnervation (AD/GAL-) or those displaying prominent GAL hyperinnervation (AD/GAL+). Levels of mRNAs encoding putatively neuroprotective proteins …such as the GluR2 Ca2+ -impermeable glutamate receptor subunit, superoxide dismutase 2, and the GLUT2 glucose transporter were significantly decreased in AD/GAL- nucleus basalis neurons compared to NCI and AD/GAL+ neurons. By contrast, mRNAs encoding calpain catalytic and regulatory subunits, which may contribute to cell death in AD, were increased in AD/GAL- compared to NCI and AD/GAL+ neurons. Hence, GAL fiber hyperinnervation appears to preserve the expression of genes subserving multiple neuroprotective pathways suggesting that GAL overexpression regulates CBF neuron survival in AD. Show more

Keywords: Alzheimer's disease, antioxidant, calcium, calpain, cholinergic basal forebrain, galanin, glucose transporter, glutamate receptor, nucleus basalis, ubiquitin

DOI: 10.3233/JAD-2009-1196

Citation: Journal of Alzheimer's Disease, vol. 18, no. 4, pp. 885-896, 2009

Authors: Kovac, Andrej | Zilkova, Monika | Deli, Maria A. | Zilka, Norbert | Novak, Michal

Article Type: Research Article

Abstract: Recent findings showed that vascular dysfunction is an integral part of Alzheimer's disease pathology. Increased microvascular permeability is mainly associated with cerebrovascular amyloid-β deposits. In contrast, little is known about the relationship between functional impairment of the blood-brain barrier and misfolded tau. In the present study, we examined whether human truncated tau is able to impair the blood-brain barrier in an in vitro model. We have found that truncated tau induced a very strong polarity-dependent effect in the rat blood-brain barrier model. When the tau was added to the upper compartment of the model containing endothelial cells (apical treatment), no …effect was observed. However, the application of tau to the lower compartment (basolateral treatment), consisting of astrocyte-microglia culture, triggered significant decrease of transendothelial electrical resistance and increase of endothelial permeability for mannitol. Further, we found that truncated tau showed cytotoxic effects on astrocyte-microglia culture manifested by increased extracellular adenylate kinase levels. Molecular analysis of underlying mechanisms of tau-induced blood-brain barrier damage revealed the contribution of pro-inflammatory cytokine tumor necrosis factor-α and chemokine MCP-1 released from activated microglial cells. This study for the first time uncovers a novel toxic gain of function of misfolded tau that could contribute to the cerebral microvascular damage in human tauopathies. Show more

Keywords: Alzheimer's disease, blood-brain barrier, microglia, truncated tau protein, tumor necrosis factor-α (TNF-α)

DOI: 10.3233/JAD-2009-1197

Citation: Journal of Alzheimer's Disease, vol. 18, no. 4, pp. 897-906, 2009

Authors: Lin, Yuh-Te | Cheng, Jiin-Tsuey | Yao, Yun-Chin | Juo, | Lo, Yuk-Keung | Lin, Ching-Hwung | Ger, Luo-Ping | Lu, Pei-Jung

Article Type: Research Article

Abstract: Given the need for tools for early and accurate diagnosis, prediction of disease progression, and monitoring efficacy of therapeutic agents for AD, the study of cerebrospinal fluid (CSF) biomarkers has become a rapidly growing field of research. Several studies have reported conflicting data regarding the relationships between CSF biomarkers and dementia severity. In this study, we have focused on the identification of CSF biomarkers and their correlations with the impairment of different cognitive domains measured using the Cognitive Abilities Screening Instrument (CASI). Patients with AD (n=28), non-AD dementia (n=16), other neurological disorders (OND, n=14), and healthy controls (HC, n=21) were …enrolled. Our results revealed significantly higher CSF total tau (t-tau) and lower amyloid-β42 levels in AD patients compared with those in HC and OND groups. Moreover, our data show that CSF t-tau levels, but not Aβ42 levels, have an inverse correlation with the score of short-term memory in CASI for patients with AD (Spearman: r=−0.444; p=0.018). This data might indicate that the higher CSF t-tau level is associated with more NFT pathology and more severe impairment of short-term memory in AD patients. Show more

Keywords: Alzheimer's disease, beta-amyloid, cerebrospinal fluid, cognition, memory, tau

DOI: 10.3233/JAD-2009-1214

Citation: Journal of Alzheimer's Disease, vol. 18, no. 4, pp. 907-918, 2009

Authors: Campos-Peña, Victoria | Tapia-Ramírez, José | Sánchez-Torres, Carmen | Meraz-Rios, Marco Antonio

Article Type: Research Article

Abstract: The hallmark of Alzheimer's disease is the pathological aggregation of tau proteins into paired helical filaments and neurofibrillary tangles. This paper evaluates the abnormal expression and localization of chimeric tau molecules at the plasma membrane of COS-7 cells and its relationship with tau polymerization. Overexpression of these proteins, in combination with either tau441 or tau391, induces tau to assemble into β-pleated sheets that are recognized by Thiazin red. Immunoelectromicroscopy analysis revealed the presence of filaments close to the plasma membrane resembling those found in Alzheimer's disease. The capacity of plasma membrane-associated chimeric tau proteins to capture full length tau was …increased in the presence of H2 O2 or okadaic acid treatments. This suggests that hyperphosphorylation or an oxidative environment could both influence the biochemical properties of the cell that lead to assembly of paired helical filaments. The altered localization of tau protein at the plasma membrane could play a key role in the assembly of pathological tau. Show more

Keywords: Alzheimer's disease, β-pleated sheet, membrane localization, paired helical filaments, tau aggregation

DOI: 10.3233/JAD-2009-1198

Citation: Journal of Alzheimer's Disease, vol. 18, no. 4, pp. 919-933, 2009

Authors: Cimini, AnnaMaria | Moreno, Sandra | D'Amelio, Marcello | Cristiano, Loredana | D'Angelo, Barbara | Falone, Stefano | Benedetti, Elisabetta | Carrara, Paolo | Fanelli, Francesca | Cecconi, Francesco | Amicarelli, Fernanda | Cerù, Maria Paola

Article Type: Research Article

Abstract: The central role of peroxisomes in reactive oxygen species and lipid metabolism and their importance in brain functioning are well established. The aim of this work has been to study the peroxisomal population in the Tg2576 mouse model of Alzheimer's disease (AD), at the age of three months when no apparent signs of behavioral, neuroanatomical, cytological, or biochemical alterations have been so far described. The expression and localization of peroxisomal (PMP70, CAT, AOX, and THL) and peroxisome-related proteins (PEX5p, GPX1, SOD1, and SOD2) were studied in the neocortex and hippocampus of transgenic and wild-type animals. Oxidative stress markers (TBARS, acrolein, …and 8-OHG) were also evaluated. Our results demonstrate that significant alterations are already detectable at this early stage of the disease and also involve peroxisomes. Their number and protein composition change concomitantly with early oxidative stress. Interestingly, the neocortex shows a compensatory response, consisting in an increase of reactive oxygen species scavenging enzymes, while the hippocampus appears more prone to the oxidative insult. This different behavior could be related to metabolic differences in the two brain areas, also involving peroxisome abundance and/or enzymatic content. Show more

Keywords: Acyl-CoA β-oxidation, Alzheimer's disease, antioxidant enzymes, catalase, hippocampus, neocortex, oxidative stress, reactive oxygen species, peroxisomes, Tg2576

DOI: 10.3233/JAD-2009-1199

Citation: Journal of Alzheimer's Disease, vol. 18, no. 4, pp. 935-952, 2009

Authors: Di Maria, Emilio | Bonvicini, Cristian | Bonomini, Cristina | Alberici, Antonella | Zanetti, Orazio | Gennarelli, Massimo

Article Type: Research Article

Abstract: The occurrence of neuropsychiatric symptoms in patients with Alzheimer's disease hampers the clinical management and exacerbates the burden for caregivers. To what extent psychotic symptoms are genetically determined and which are the genes involved has to be established. We tested the hypothesis that the occurrence of delusions and hallucinations in AD is associated with variations in the G72/DAOA gene, which is supposed to play a key role in the glutamate pathway regulated through the NMDA receptors. A panel of single nucleotide polymorphisms were genotyped in a cohort of 185 Alzheimer's disease patients. The analysis demonstrated a nominally significant association (p< …0.05) with one single nucleotide polymorphism (rs2153674). In addition, multivariate regression showed that the rs2153674 genotype accounts for up to 15% of the variance in delusions severity, as assessed by using the Neuropsychiatric Inventory. If the results from the present study will be replicated, the glutamate hypothesis could be invoked to explain the occurrence of psychosis in neurodegenerative disorders. Show more

Keywords: Association study, Alzheimer's disease, behavioral and psychological symptoms in dementia (BPSD), d-serine amino acid oxidase activator (DAOA), G72/G30, neuropsychiatric symptoms (NPS), psychotic symptoms

DOI: 10.3233/JAD-2009-1194

Citation: Journal of Alzheimer's Disease, vol. 18, no. 4, pp. 953-960, 2009

Authors: Boutajangout, Allal | Goni, Fernando | Knudsen, Elin | Schreiber, Fernanda | Asuni, Ayodeji | Quartermain, David | Frangione, Blas | Chabalgoity, Alejandro | Wisniewski, Thomas | Sigurdsson, Einar M.

Article Type: Research Article

Abstract: Immunotherapy holds great promise for Alzheimer's disease (AD) and other conformational disorders but certain adverse reactions need to be overcome. Prior to the side effects in the first Elan/Wyeth AD vaccine trial, we proposed using amyloid-β (Aβ) derivatives as a safer approach. The route of administration may also affect vaccine safety. To assess the feasibility of oral immunization that promotes mucosal immunity, Tg2576 AD model mice were treated prophylactically three times over 6 weeks starting at 3–5 months of age with a Salmonella vaccine expressing K6Aβ1-30 . At 22–24 months of age, cortical Aβ plaque burden and total Aβ40 /42 …levels were reduced by 48–75% in the immunized mice compared to controls, which received unmodified Salmonella. Plaque clearance was not associated with increased microglial activation, which may be explained by the long treatment period. Furthermore, cerebral microhemorrhages were not increased in the treated mice in contrast to several passive Aβ antibody studies. These results further support our findings with this immunogen delivered subcutaneously and demonstrate its efficacy when given orally, which may provide added benefits for human use. Show more

Keywords: Amyloid-β, immunization, microhemorrhages, oral, salmonella, transgenic mice, vaccine

DOI: 10.3233/JAD-2009-1204

Citation: Journal of Alzheimer's Disease, vol. 18, no. 4, pp. 961-972, 2009

Authors: Strobel, Gabrielle

Article Type: Research Article

DOI: 10.3233/JAD-2009-1250

Citation: Journal of Alzheimer's Disease, vol. 18, no. 4, pp. 973-990, 2009

Authors: Andreadis, Athena

Article Type: Book Review

DOI: 10.3233/JAD-2009-1232

Citation: Journal of Alzheimer's Disease, vol. 18, no. 4, pp. 991-992, 2009

Article Type: Correction

DOI: 10.3233/JAD-2009-1279

Citation: Journal of Alzheimer's Disease, vol. 18, no. 4, pp. 993-993, 2009

Article Type: Other

DOI: 10.3233/JAD-2009-1249

Citation: Journal of Alzheimer's Disease, vol. 18, no. 4, pp. 995-998, 2009

Article Type: Announcement

DOI: 10.3233/JAD-2009-1251

Citation: Journal of Alzheimer's Disease, vol. 18, no. 4, pp. 999-1000, 2009