Volume 19, Number 2, January 2010

Pages 375-388
Jeffrey L. Cummings, John Ringman and Karen Metz
Mary S. Easton Center of Alzheimer's Disease Research at UCLA: Advancing the Therapeutic Imperative
Abstract: The Mary S. Easton Center for Alzheimer’s Disease Research (UCLA-Easton Alzheimer’s Center) is committed to the “therapeutic imperative” and is devoted to finding new treatments for Alzheimer’s disease (AD) and to developing technologies (biomarkers) to advance that goal. The UCLA-Easton Alzheimer’s Center has a continuum of research and research-related activities including basic/foundational studies of peptide interactions; translational studies in transgenic animals and other animal models of AD; clinical research to define the phenotype of AD, characterize familial AD, develop biomarkers, and advance clinical trials; health services and outcome research; and active education, dissemination, and recruitment activities. The UCLA-Easton Alzheimer’s Center is supported by the National Institutes on Aging, the State of California, and generous donors who share our commitment to developing new therapies for AD. The naming donor (Jim Easton) provided substantial funds to endow the center and to support projects in AD drug discovery and biomarker development. The Sidell-Kagan Foundation supports the Katherine and Benjamin Kagan Alzheimer’s Treatment Development Program, and the Deane F. Johnson Alzheimer’s Research Foundation supports the Deane F. Johnson Center for Neurotherapeutics at UCLA. The John Douglas French Alzheimer’s Research Foundation provides grants to junior investigators in critical periods of their academic development. The UCLA-Easton Alzheimer’s Center partners with community organizations including the Alzheimer’s Association California Southland Chapter and the Leeza Gibbons Foundation. Collaboration with pharmaceutical companies, biotechnology companies, and device companies is critical to developing new therapeutics for AD and these collaborations are embraced in the mission of the UCLA-Easton Alzheimer’s Center. The Center supports excellent senior investigators and serves as an incubator for new scientists, agents, models, technologies and concepts that will significantly influence the future of AD and AD research.

Pages 389-403
Review Article
Parvathi Rudrabhatla and Harish C. Pant
Phosphorylation-Specific Peptidyl-Prolyl Isomerization of Neuronal Cytoskeletal Proteins by Pin1: Implications for Therapeutics in Neurodegeneration
Abstract: Pin1 [Protein Interacting with NIMA (never in mitosis A)] is a peptidyl prolyl cis-trans isomerase that isomerizes phospho-Serine/Threonine-Proline [p(S/T)-P] motifs of its target proteins. Pin1 functions in concert with proline directed kinases such as cyclin-dependent protein kinases, extracellular signal-regulated kinases, and c-Jun N- terminal kinase, and protein phosphatases such as protein phosphatase 2A (PP2A) and PP2B, in the regulation of a wide range of cellular processes including cell division, DNA damage response, and gene transcription, and in susceptibility to cancer and neurodegenerative diseases. This review focuses on the roles of Pin1 in neurodegenerative disorders including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and Frontotemporal dementia associated with parkinsonism linked to chromosome 17. Pin1 interacts with neuronal cytoskeletal proteins such as tau, amyloid-β protein precursor, α-synuclein, and neurofilaments, often in association with phosphorylation events that influence their functions in the neuronal cytoskeleton. Overexpression of Pin1 reduces WT tau stability but increases P301L mutant tau stability. Pin1 associates with neurofilament H (NF-H) and modulates excitotoxic and oxidative stress induced perikaryal phosphorylation of NF-H. Pin1 mediates the neural specific apoptosis machinery. The specific inhibitors of Pin1 may have potential therapeutic implications in neurodegeneration.

Pages 405-421
Review Article
Rommy von Bernhardi
Immunotherapy in Alzheimer’s Disease: Where Do We Stand? Where Should We Go?
Abstract: Alzheimer’s disease (AD) is a highly prevalent neurodegenerative disease. In addition to its enormous personal and socioeconomic costs, the situation is worsened by the lack of an effective prevention and treatment. Anti-amyloid-β (Aβ) immunization strategies showed excellent results when tested on AD transgenic models. However, clinical studies with active and passive immunotherapy have been disappointing in several aspects, especially lately, when reports analyzing long term result of immunization protocols failed to show improvement in cognitive function and disease progression. Furthermore, some of the active immunotherapy protocols appear to be associated with severe side effects, including brain inflammation and amyloid angiopathy mediated hemorrhage. However, even through detailed information on the mechanism for Aβ clearance is still missing, results are valuable for the understanding of the disease. The focus of this review is to discuss the current experience with the various types of immunotherapy tested in animal models and AD patients, and the information they provide regarding disease mechanisms. In light of those results, alternatives or conditions that could improve immunotherapy utility are analyzed. Regardless of the setbacks, immunotherapy as a combination therapy, including humoral and cell-based approaches, still holds a promise for the treatment of AD.

Pages 423-428
Short Communication
Victor L Villemagne, Kerryn Pike, Svetlana Pejoska, Alison Boyd, Margaret Power, Gareth Jones, Colin L Masters, Christopher C Rowe
11C-PiB PET ABri Imaging in Worster-Drought Syndrome (Familial British Dementia): A Case Report
Abstract: Brain amyloid imaging is becoming an essential tool for the pre-mortem evaluation of Alzheimer’s disease (AD). This study explores the pattern of 11C-PiB retention in a subject with Worster-Drought syndrome (WDS). A 55 year-old male carrier of the WDS gene mutation with mild signs of ataxia and subtle cognitive impairment underwent MRI and 11C-PiB-PET studies. Brain PiB regional distribution was compared to those from cohorts of healthy controls and AD patients. While no significant cortical 11C-PiB retention was present, a high degree of cerebellar 11C-PiB retention was observed in a genetically confirmed carrier of the WDS gene. We speculate that the sparsity of ABri plaques in the neocortex together with its high deposition in the cerebellum, might explain the observed pattern of 11C-PiB retention.

Pages 429-439
William K. Summers, Roy L. Martin, Michael Cunningham, Velda L. DeBoynton, Gary M. Marsh
Complex Antioxidant Blend Improves Memory in Community-Dwelling Seniors
Abstract: One hundred thirteen community dwelling subjects between the ages of 50 and 75 without dementia were recruited. A blind administrator randomly assigned 54 subjects to placebo and 59 to active treatment groups. The active treatment consisted of four months treatment with a complex antioxidant blend. Placebo treatment was an identical gel and bottle administered for four months. Forty-eight active subjects and 38 placebo subjects completed the study. Memory testing with a 50 part paired association test and a 20-word immediate recall test were significantly improved, p=0.015 and p=0.005 respectively. A secondary study of serum homocysteine was completed in 25 active treatment subjects and 17 placebo subjects. Significant reduction in serum homocysteine levels was seen in the active treatment subjects (p=0.005). A complex antioxidant blend taken over four months improves performance on two difficult memory tests in community dwelling elderly subjects. Furthermore, the antioxidant significantly reduced the serum homocysteine level in treatment group.

Pages 441-449
John E. Morley, Susan A. Farr, William A. Banks, Steven N. Johnson, Kelvin A. Yamada, Lin Xu
A Physiological Role for Amyloid-β Protein: Enhancement of Learning and Memory
Abstract: Amyloid-β protein (Aβ) is well recognized as having a significant role in the pathogenesis of Alzheimer’s disease (AD). The reason for the presence of Aβ and its physiological role in non-disease states is not clear. In these studies, low doses of Aβ enhanced memory retention in two memory tasks and enhanced acetylecholine production in the hippocampus in vivo. We then tested whether endogenous Aβ has a role in learning and memory in young, cognitively intact mice by blocking endogenous Aβ in healthy 2-month-old CD-1 mice. Blocking Aβ with antibody to Aβ or DFFVG (which blocks Aβ binding) or decreasing Aβ expression with antisense directed at the Aβ precursor, AβPP, all resulted in impaired learning in T-maze foot-shock avoidance. Finally, Aβ1-42 facilitated induction and maintenance of long term potentiation in hippocampal slices, whereas antibodies to Aβ inhibited hippocampal LTP. In conclusion, these results indicate that in normal healthy young animals the presence of Aβ is important for learning and memory.

Pages 451-464
Elizabeth Hansen, Martina Krautwald, Annette E. Maczurek, Grant Stuchbury, Phillip Fromm, Megan Steele, Oliver Schulz, Obdulio Benavente Garcia, Julian Castillo, Heinrich Körner, Gerald Münch (Communicated by Ralph Martins)
A Versatile High Throughput Screening System for the Simultaneous Identification of Anti-Inflammatory and Neuroprotective Compounds
Abstract: In many chronic neurodegenerative diseases including Frontotemporal Dementia and Alzheimer’s disease (AD), microglial activation is suggested to be involved in pathogenesis or disease progression. Activated microglia secrete a variety of cytokines, including interleukin-1β, interleukin-6, and tumor necrosis factor as well as reactive oxygen and nitrogen species (ROS/RNS). ROS and RNS contribute to alterations in neuronal glucose uptake, inhibition of mitochondrial enzymes, a decrease in mitochondrial membrane potential, impaired axonal transport, and synaptic signaling. In addition, ROS act as signaling molecules in pro-inflammatory redox-active signal transduction pathways. To establish a high throughput screening system for anti-inflammatory and neuroprotective compounds, we have constructed an “Enhanced Green Fluorescent protein” (EGFP) expressing neuronal cell line and set up a murine microglia/neuron co-culture system with these EGFP expressing neuronal cells. We show that microglia activation leads to neuronal cell death, which can be conveniently measured by loss of neuronal EGFP fluorescence. Moreover, we used this system to test selected polyphenolic compounds for their ability to downregulate inflammatory markers and to protect neurons against microglial insult. We suggest that this system might allow accelerated drug discovery for the treatment of inflammation-mediated neurodegenerative diseases.

Pages 465-480
Janine K. Cataldo, Judith J. Prochaska, Stanton A. Glantz
Cigarette Smoking is a Risk Factor for Alzheimer’s Disease: An Analysis Controlling for Tobacco Industry Affiliation
Abstract: To examine the relationship between smoking and Alzheimer’s disease (AD) after controlling for study design, quality, secular trend, and tobacco industry affiliation of the authors, electronic databases were searched; 43 individual studies met the inclusion criteria. For evidence of tobacco industry affiliation, http://legacy.library.ucsf.edu was searched. One fourth (11/43) of individual studies had tobacco-affiliated authors. Using random effects meta-analysis, 18 case control studies without tobacco industry affiliation yielded a non-significant pooled odds ratio of 0.91 (95% CI, 0.75-1.10), while 8 case control studies with tobacco industry affiliation yielded a significant pooled odds ratio of 0.86 (95% CI, 0.75-0.98) suggesting that smoking protects against AD. In contrast, 14 cohort studies without tobacco-industry affiliation yielded a significantly increased relative risk of AD of 1.45 (95% CI, 1.16-1.80) associated with smoking and the three cohort studies with tobacco industry affiliation yielded a non-significant pooled relative risk of 0.60 (95% CI 0.27-1.32). A multiple regression analysis showed that case-control studies tended to yield lower average risk estimates than cohort studies (by -0.27±0.15, P=0.075), lower risk estimates for studies done by authors affiliated with the tobacco industry (by -0.37±0.13, P=0.008), no effect of the quality of the journal in which the study was published (measured by impact factor, P=0.828), and increasing secular trend in risk estimates (0.031/year ±0.013, P=0.02). The average risk of AD for cohort studies without tobacco industry affiliation of average quality published in 2007 was estimated to be 1.72±0.19 (P<0.0005). The available data indicate that smoking is a significant risk factor for AD.

Pages 481-488
Antonis Politis, Paolo Olgiati, Petros Malitas, Diego Albani, Alessandra Signorini, Letizia Polito, Stefania De Mauro, Aikaterini Zisaki, Christina Piperi, Evangelia Stamouli, Antonis Mailis, Sara Batelli, Gianluigi Forloni, Diana De Ronchi, Anastasios Kalofoutis, Ioannis Liappas, Alessandro Serretti
Vitamin B12 Levels in Alzheimer’s Disease: Association with Clinical Features and Cytokine Production
Abstract: Alzheimer’s disease has been associated with upregulation of pro-inflammatory cytokines (e.g., specific gene variants for TNF-α, IL-6, IFN-γ) and low plasma levels of cobalamin (vitamin B12). Our goal was to relate B12 levels to symptoms of Alzheimer’s disease and to expression of pro-inflammatory cytokines. Clinical manifestations were investigated for a case series of fifty-five outpatients using the Mini-Mental Status Examination (MMSE), Neuropsychiatric Inventory, and Cornel Scale for Depression in Dementia. Plasma B12 levels were measured by radioligand binding assay. Basal and PMA-stimulated levels of IFN-γ, TNF-α, and IL-6 were measured by ELISPOT (peripheral blood mononuclear cell culture supernatant). Forty-seven patients were genotyped for APOE. While ten patients (18%) had B12 levels below <250 pg/ml, they did not statistically differ from those 45 who had normal levels in most demographic and clinical features. However, their MMSE scores were lower (14.7 versus 19.6, p=0.03) but not after adjustment for disease duration. A greater basal production of IL-6 was reported in patients who had low B12 levels compared to normal B12 subjects (1333 pg/ml versus 976, p<0.01). This association was confirmed after controlling for age of onset and APOE genotype. In conclusion, low B12 level is associated with greater production of IL-6 in peripheral blood mononuclear cells. Further research is warranted to elucidate whether this neuroinflammatory effect of cobalamin is implicated in the pathophysiology of Alzheimer’s disease.

Pages 489-502
Virginia Martín, Noemí Fabelo, Gabriel Santpere, Berta Puig, Raquel Marín, Isidre Ferrer, Mario Díaz
Lipid Alterations in Lipid Rafts from Alzheimer’s Disease Human Brain Cortex
Abstract: Lipid rafts are membrane microdomains intimately associated with cell signaling. These biochemical microstructures are characterized by their high contents of sphingolipids, cholesterol and saturated fatty acids and a reduced content of polyunsaturated fatty acids (PUFA). Here, we have purified lipid rafts of human frontal brain cortex from normal and Alzheimer’s disease (AD) and characterized their biochemical lipid composition. The results revealed that lipid rafts from AD brains exhibit aberrant lipid profiles compared to healthy brains. In particular, lipid rafts from AD brains displayed abnormally low levels of n-3 long chain polyunsaturated fatty acids (LCPUFA, mainly 22:6n-3, docosahexaenoic acid) and monoenes (mainly 18:1n-9, oleic acid), as well as reduced unsaturation and peroxidability indexes. Also, multiple relationships between phospholipids and fatty acids were altered in AD lipid rafts. Importantly, no changes were observed in the mole percentage of lipid classes and fatty acids in rafts from normal brains throughout the lifespan (24-85 years). These indications point to the existence of homeostatic mechanisms preserving lipid raft status in normal frontal cortex. The disruption of such mechanisms in AD brains leads to a considerable increase in lipid raft order and viscosity, which may explain the alterations in lipid raft signaling observed in AD.

Pages 503-515
Sergio Della Sala, Gianna Cocchini, Robert H. Logie, Michael Allerhand, Sarah E. MacPherson (Communicated by Valeria Drago)
Dual Task During Encoding, Maintenance, and Retrieval in Alzheimer’s Disease
Abstract: Previous dual task studies have demonstrated minimal costs when healthy individuals simultaneously perform two tasks at their own individual ability levels. Conversely, Alzheimer’s disease (AD) patients show dual task decrements, but it is unclear whether the problem arises at the encoding, maintenance, and/or retrieval phases of memory. Two experiments combined digit recall and visuo-motor tracking to investigate dual task effects during encoding, maintenance, and/or retrieval for AD patients compared with healthy adults. The demands of each single task were titrated for the ability of each participant. In Experiment 1, the dual task requirement was present throughout both encoding and retrieval of digit recall and the differential dual task effects on a secondary tracking task were examined post-hoc. In Experiment 2, the impact of dual task during encoding only, during maintenance only, and during retrieval only was examined systematically. The findings suggest that the specific AD deficit reflects impairment of a cognitive function that supports the simultaneous performance of two tasks in the healthy brain, particularly during the encoding and retrieval phases of the memory task.

Pages 517-527
Eric D. Vidoni*, Robyn A. Honea* and Jeffrey M. Burns *joint first authors
Neural Correlates of Impaired Functional Independence in Early Alzheimer’s Disease
Abstract: Cognitive and physical decline are important predictors of functional independence in Alzheimer’s disease (AD). However, little is known about AD-related neural change leading to decreased independence. We hypothesized that regional gray matter atrophy, including the medial frontal cortex, would be related to cognition, physical function, and functional independence. Individuals without dementia (n=56) and subjects with early-stage AD (n=58) underwent MRI and a comprehensive cognitive and physical function evaluation. The relationship of cognitive and physical function measures and independence performing complex daily activities was explored using correlation and mediation analysis. These results suggest that cognition had both a strong direct effect and mediated the influence of physical function on independence for those with AD. We followed this with a voxel-based morphometric global conjunction analysis of imaging data within each group to identify neural substrates common to our function measures. Imaging evidence supported our mediation analysis results. Imaging evidence revealed that in AD, regional gray matter atrophy measures in medial frontal and temporo-parietal areas were related to decreased cognition, physical function, and independence. Loss of independence in early AD is closely related to impaired cognition associated with performing complex behaviors. People with early AD may have decreased gray matter volume in the medial frontal and temporal-parietal cortices that is associated with loss of independence in activities of daily living. These results are the first to identify regionally specific brain volume changes that may be related to functional dependence seen in early AD.

Pages 529-544
Jia Cui, Qiuyue Chen, Xiaojing Yue, Xuejun Jiang, George F. Gao, Long-Chuan Yu, Yan Zhang
Galanin Protects Against Intracellular Amyloid Toxicity in Human Primary Neurons
Abstract: Galanin and galanin receptors are upregulated in the brain regions associated with Alzheimer’s disease (AD). However, the consequence of this overexpression is still unknown, particularly in human neurons. Here, we investigate the possible protective effects of galanin against intracellular amyloid-β (Aβ)1-42 toxicity, as well as other insults including staurosporine, etoposide, hydrogen peroxide, and serum depletion in cultured human primary neurons. The results show that galanin is protective against intracellular Aβ cytotoxicity and all of the above insults at sub-nanomolar physiological concentrations. The galanin protection may be mediated by galanin receptor 2 and down-regulation of Bax level. The data from the present study provide a potential drug target for therapy or prevention of neurodegenerative diseases, including AD.

Pages 545-550
Antonia MW Coppus, Heleen M Evenhuis, Gert-Jan Verberne, Frank E Visser, Pim Eikelenboom, Willem A van Gool, A Cecile JW Janssens, Cornelia M van Duijn
Early Age at Menopause is Associated with Increased risk of Dementia and Mortality in Women with Down Syndrome
Abstract: In a prospective longitudinal cohort study of dementia and mortality in persons with Down syndrome aged 45 years and older, 85 postmenopausal women were followed for a mean follow-up time of 4.3 years (range 0.0 to 7.4 years). The effect of age at menopause on age at diagnosis of dementia and survival was estimated using correlation analysis and Cox Proportional Hazard Model. We found a significant correlation between age at menopause and age at diagnosis of dementia (ρ=0.52; p<0.001), and between age at menopause and age at death (ρ=0.49; p=0.01). Early age at menopause is associated with a 1.8 fold increased risk of dementia: Hazard Ratio (HR): 1.82 (95%Confidence Interval (CI): 1.31-2.52) and with risk of death: HR: 2.05 (95%CI: 1.33-3.16). Our study suggests that age at menopause in women with Down syndrome is a determinant of age at onset of dementia and mortality.

Pages 551-557
Florinda Listì, Calogero Caruso, Domenico Lio, Giuseppina Colonna-Romano, Martina Chiappelli, Federico Licastro, Giuseppina Candore
Role of Cyclooxygenase-2 and 5-Lipoxygenase Polymorphisms in Alzheimer’s Disease in a Population from Northern Italy: Implication for Pharmacogenomics
Abstract: Alzheimer’s disease (AD) is a neurodegenerative disorder clinically characterized by cognitive deficit with progressive worsening of memory. Recent data indicate that neurons, as well as other brain cells, can express enzymes such as cyclooxygenases (COXs) and 5-lipoxygenase (5-LO) which are considered important in inflammatory cells. Moreover, it has been demonstrated that COX-2 and 5-LO enzymes play a considerable role in the pathophysiology of AD. In order to assess the possible role of COX-2 and 5-LO single nucleotide polymorphisms (SNPs) in AD, we examined their distribution in 341 AD patients and 190 controls from Northern Italy. A significant difference was observed in the distribution of the -765G COX-2 and -1708A 5-LO alleles between AD cases and controls (p=0.03 for -765G/C COX-2 SNP; and p=0.007 for -1708G/A 5-LO SNP). Hence, COX-2 -765G and 5-LO -1708A alleles were overrepresented in AD patients and underrepresented in controls. Our data suggest that these alleles of COX-2 and 5-LO could be risk factors for AD. These results seem of some importance for a pharmacogenomic approach.

Pages 559-572
Antonio Ciaramella, Federica Bizzoni, Francesca Salani, Diego Vanni, Gianfranco Spalletta, Nunzia Sanarico, Silvia Vendetti, Carlo Caltagirone, Paola Bossù (Communicated by Daniela Galimberti)
Increased Pro-Inflammatory Response by Dendritic Cells from Patients with Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) is characterized by abnormal accumulation of amyloid-β peptide (Aβ) into extracellular fibrillar deposits, paralleled by chronic neuroinflammatory processes. Although Aβ seems to be causative in AD brain damage, the role of the immune system and its mechanisms still remain to be clarified. We have recently shown that normal monocyte-derived dendritic cells (MDDCs), when differentiated in the presence of Aβ1-42, acquire an inflammatory phenotype and a reduced antigen presenting ability. Here we studied MDDCs derived from AD patients in comparison with MDDCs obtained from healthy control subjects (HC). MDDCs from AD patients, at variance with HC-derived cells, were characterized by an augmented cell recovery, a consistent increase in the expression of the pro-inflammatory ICAM-1 molecule, a decrease in the expression of the co-stimulatory CD40 molecule, and an impaired ability to induce T cell proliferation. Furthermore, MDDCs from AD produced higher amounts of IL-6 than HC-derived cells, confirming the more pronounced pro-inflammatory features of these cells in AD patients. Consistent results have been also obtained with monocytes, the MDDC precursors. In fact, while unstimulated monocytes do not appear to be different in AD and HC, after stimulation with lipopolysaccharides, AD monocytes overexpressed ICAM-1 with respect to controls, suggesting that common pathways of monocyte activation and MDDC differentiation are altered in AD. Overall, these findings show that AD-linked dysregulated immune mechanisms exist, which lead to dendritic cell-mediated over-activation of inflammation and impaired antigen presentation, thus supporting the view that immune cell activation could play an important role in AD pathogenesis.

Pages 573-589
Leonel E. Rojo, Jans Alzate-Morales, Iván N. Saavedra, Peter Davies, Ricardo B. Maccioni
Selective Interaction of Lansoprazole and Astemizole with Tau Polymers: Potential New Clinical Use in Diagnosis of Alzheimer’s Disease
Abstract: We describe the interactions of two benzimidazole derivatives, astemizole (AST) and lansoprazole (LNS), with anomalous aggregates of tau protein (neurofibrillary tangles). Interestingly, these compounds, with important medical applications in the treatment of allergies and gastrointestinal disorders respectively, specifically bind to aggregated variants of tau protein and to paired helical filaments isolated from brains of Alzheimer’s disease (AD) patients. These ligands appear to be a powerful tool to tag brain-isolated tau-aggregates and heparin-induced polymers of recombinant tau. The interactions of AST and LNS with tau aggregates were assessed by classical radioligand assays, surface plasmon resonance, and bioinformatic approaches. The affinity of AST and LNS for tau aggregates was comparatively higher than that for amyloid-β polymers according to our data. This is relevant since senile plaques are also abundant but are not pathognomonic in AD patients. Immunochemical studies on paired helical filaments from brains of AD patients and surface plasmon resonance studies confirm these findings. The capacity of these drugs to penetrate the blood-brain barrier was evaluated: i) in vitro by parallel artificial membrane permeability assay followed by experimental Log P determinations; and ii) in vivo by pharmacokinetic studies comparing distribution profiles in blood and brain of mice using HPLC/UV. Importantly, our studies indicate that the brain/blood concentration ratios for these compounds were suitable for their use as PET radiotracers. Since neurofibrillary tangles are positively correlated with cognitive impairment, we concluded that LNS and AST have a great potential in PET neuroimaing for in vivo early detection of AD and in reducing the formation of neurofibrillary tangles.

Pages 591-600
Konstantinos Stellos, Victoria Panagiota, Saskia Sachsenmaier, Theresia Trunk, Guido Straten, Thomas Leyhe, Peter Seizer, Tobias Geisler, Meinrad Gawaz, Christoph Laske (Communicated by Milan Fiala)
Increased Circulating CD34+/CD133+ Progenitor Cells in Alzheimer’s Disease Patients with Moderate to Severe Dementia: Evidence for Vascular Repair and Tissue Regeneration?
Abstract: Cerebrovascular dysfunction is a common finding in patients with Alzheimer’s disease (AD) and may contribute to cognitive decline. Abundant evidence suggests that vascular and neuronal repair mechanisms are mediated by circulating progenitor cells in vivo. Whether CD34+ and, specifically, CD34+/CD133+ progenitor cells are involved in the pathophysiology of AD is poorly understood so far. In the present study, peripheral blood concentrations of circulating CD34+/CD133+ and CD34+ progenitor cells were measured in 45 AD patients and in 30 healthy elderly controls by flow cytometry. The severity of dementia was assessed by Mini-Mental Status Examination and Clinical Dementia Rating scale. AD patients were stratified into two groups showing mild (n=17) and moderate to severe (n=28) dementia. In the present study, AD patients with moderate to severe dementia, but not those with mild dementia, showed significantly increased circulating CD34+/CD133+ and CD34+ progenitor cells compared to healthy elderly controls independent of cardiovascular risk factors and medication. In addition, the number of circulating CD34+/CD133+ progenitor cells in AD patients was significantly inversely correlated with cognitive function, age, and plasma levels of SDF-1, the most potent chemokine for progenitor cells. Our findings suggest a stage-dependent upregulation of circulating CD34+/CD133+ and CD34+ progenitor cells in AD patients, which could take part in tissue healing processes of the brain in AD.

Pages 601-615
Alicia Coduras, Isabel Rabasa, Ana Frank, Felix Bermejo-Pareja, Secundino López-Pousa, Jesús-María López-Arrieta, Juan Del Llano, Teresa León, Javier Rejas
Prospective One-Year Cost-of-Illness Study in a Cohort of Patients with Dementia of Alzheimer’s Disease Type in Spain: The ECO Study
Abstract: In this study, we analyzed the economic impact of one-year healthcare and non-healthcare resources utilization by patients with dementia of Alzheimer’s disease (AD) under usual medical practice in Spain. A one-year, prospective, naturalistic, multicenter cohort study was designed to recruit patients with mild, moderate to severe, and severe AD according to Clinical Dementia Rating scale: the ECO study. Healthcare resources (medical visits, drugs and concomitant treatments, complementary and diagnostic tests, institutionalization and use of home-nursing facilities) and non-healthcare resources (inventory materials, consumables, professional and non-professional caregivers’ time for care and supervision) were recorded and valued at 2006 prices. A total of 560 patients with possible/probable AD by DSM-IV-NINCDS-ADRDA criteria were included in the study: 68% women, 77±6 years old, 29% treatment naïve. Monthly average cost per patient was €1,425.73, and increased 10.08% at the end of the study (baseline monthly cost; €1,316.22). Non-healthcare costs (€1059.00, 74.30% of total cost) decreased €4.30/month (0.40%) at the end of the year, while healthcare costs, which presented a total average of €366.66, grew by €136.94 in the period (54.06%), mainly due to cost of drugs, nursing home utilization, and institutionalization. The 87.26% of the overall cost (€1,244.22) was not financed by National Health Service (NHS), and the majority of this cost corresponded to caregiver-associated cost. The caregiver’s total burden represented 70.86% of the overall cost-of-illness. In conclusion, monthly overall mean cost of dementia of AD type was high in Spain (€1,412.73). Almost 88% of the cost-of-illness is funded by the patient’s own family, adding a financial burden to the suffering of these families.

Pages 617-619
Commentary on Coduras et al.
   Anders Wimo
   The Art of Cost of Illness

Pages 621-630
Xin Cheng*, Libang Yang*, Ping He, Rena Li, Yong Shen (Communicated by Cheng-xin Gong) *Contributed equally to this study
Differential Activation of Tumor Necrosis Factor Receptors Distinguishes between Brains from Alzheimer’s Disease and Non-Demented Patients
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 125I-TNF-α binding technique, we found that, in AD brains, 125I-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.

Pages 631-646
Graham Cocks, Jonathan I. Wilde, Simon J Graham, Vicky Bousgouni, David Virley, Simon Lovestone, Jill Richardson
The Thiazolidinedione Pioglitazone Increases Cholesterol Biosynthetic Gene Expression in Primary Cortical Neurons by a PPARg-Independent Mechanism
Abstract: In a recent clinical study, the thiazolidinedione (TZD) pioglitazone (ActosTM) 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-g (PPARg), 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 PPARg 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.

Pages 647-664
WonHee Kim, Sangmook Lee, Cheolwha Jung, Ambar Ahmed, Gloria Lee, Garth F. Hall (Communicated by Thomas Shea)
Interneuronal Transfer of Human Tau Between Lamprey Central Neurons in situ
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.

Pages 665-672
Santiago Hernandez, McKee J. McClendon, Xiao-Hua Andrew Zhou, Michael Sachs, Alan J. Lerner
Pharmacological Treatment of Alzheimer’s Disease: Effect of Race and Demographic Variables
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.

Pages 673-679
Marie van Dijk, Jan van Bezu, Ankie Poutsma, Robert Veerhuis, Annemieke J. Rozemuller, Wiep Scheper, Marinus A. Blankenstein, Cees B. Oudejans
The Pre-Eclampsia Gene STOX1 Controls a Conserved Pathway in Placenta and Brain Upregulated in Late-Onset Alzheimer’s Disease
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.

Supplementary Data for van Dijk et al. article (PDF)

Pages 681-690
Laura E. Dosanjh, Marishka K. Brown, Gautam Rao, Christopher D. Link, Yuan Luo
Behavioral Phenotyping of a Transgenic C. Elegans Expressing Neuronal Amyloid-β
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 experiment-dependent learning and egg laying. These newly identified learning-deficit behavioral phenotypes in the neuronal expression of Aβ C. elegans suggest that the model may be used to elucidate underlying pathological events related to development of AD and for pharmaceutical intervention.

Pages 691-704
Konstanze Plaschke, Juergen Kopitz, Markus Siegelin, Reinhard Schliebs, Melita Salkovic-Petrisic, Peter Riederer, Siegfried Hoyer
Insulin-Resistant Brain State After Intracerebroventricular Streptozotocin Injection Deteriorates Alzheimer-like Changes in Tg2576 AβPP-Overexpressing Mice
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.

Pages 705-719
Karelle Leroy, Kunie Ando, Céline Héraud, Zehra Yilmaz, Michèle Authelet, Jean-Marie Boeynaems, Luc Buée, Robert De Decker, Jean-Pierre Brion
Lithium Treatment Arrests the Development of Neurofibrillary Tangles in Mutant Tau Transgenic Mice with Advanced Neurofibrillary Pathology
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 re-assessed 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.

Supplementary Data for Leroy et al. article (PDF)

Pages 721-733
Matthew A. Tremblay, Christopher M. Acker, Peter Davies (Communicated by Robert Bowser)
Tau Phosphorylated at Tyrosine 394 is Found in Alzheimer’s Disease Tangles and Can Be a Product of the Abl-Related Kinase, Arg
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.

Pages 735-746
Yang-Yang Yin, Hao Liu, Xiao-Bin Cong, Zhao Liu, Qun Wang, Jian-Zhi Wang, Ling-Qiang Zhu
Acetyl-L-Carnitine Attenuates Okadaic Acid Induced Tau Hyperphosphorylation and Spatial Memory Impairment inRats
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 provided the first in vivo evidence that ALCAR could attenuate AD-like PP2A inhibition, tau hyperphosphorylation, and spatial memory deficit of the rats. It suggests that ALCAR may be potential in AD treatment.

Pages 747-758
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