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

Authors: Cummings, Jeffrey L. | Ringman, John | Metz, Karen

Article Type: Research Article

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 outcomes research; and active education, dissemination, and recruitment activities. The UCLAEaston 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 memory 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 3 investigators and serves as an incubator for new scientists, agents, models, technologies and concepts that will significantly influence the future of AD treatment and AD research. Show more

DOI: 10.3233/JAD-2010-1286

Citation: Journal of Alzheimer's Disease, vol. 19, no. 2, pp. 375-388, 2010

Authors: Rudrabhatla, Parvathi | Pant, Harish C.

Article Type: Review Article

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. Show more

Keywords: Alzheimer's disease, amyotrophic lateral sclerosis, neurodegeneration, neuronal cytoskeletal proteins, Pin1

DOI: 10.3233/JAD-2010-1243

Citation: Journal of Alzheimer's Disease, vol. 19, no. 2, pp. 389-403, 2010

Authors: von Bernhardi, Rommy

Article Type: Review Article

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. Show more

Keywords: Alzheimer's disease, amyloid-β, amyloid clearance, cognitive impairment, glial cells, immunization, microglia, neuroinflammation, senile plaques

DOI: 10.3233/JAD-2010-1248

Citation: Journal of Alzheimer's Disease, vol. 19, no. 2, pp. 405-421, 2010

Authors: Villemagne, Victor L. | Pike, Kerryn | Pejoska, Svetlana | Boyd, Alison | Power, Margaret | Jones, Gareth | Masters, Colin L. | Rowe, Christopher C.

Article Type: Short Communication

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 11 C-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 11 C-PiB-PET studies. Brain PiB regional distribution was compared to those from cohorts of healthy controls and AD patients. While no significant cortical 11 C-PiB retention was present, a high degree of cerebellar 11 C-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 11 C-PiB retention. Show more

Keywords: Amyloid, brain imaging, Familial British Dementia, PiB, positron emission tomography, Worster-Drought syndrome

DOI: 10.3233/JAD-2010-1241

Citation: Journal of Alzheimer's Disease, vol. 19, no. 2, pp. 423-428, 2010

Authors: Summers, William K. | Martin, Roy L. | Cunningham, Michael | DeBoynton, Velda L. | Marsh, Gary M.

Article Type: Research Article

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. Show more

Keywords: Antioxidant, cognitive enhancement, homocysteine, memory, synergistic pharmacology, working memory

DOI: 10.3233/JAD-2010-1229

Citation: Journal of Alzheimer's Disease, vol. 19, no. 2, pp. 429-439, 2010

Authors: Morley, John E. | Farr, Susan A. | Banks, William A. | Johnson, Steven N. | Yamada, Kelvin A. | Xu, Lin

Article Type: Research Article

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. Show more

Keywords: Acetylcholine, amyloid-β, learning, long term potentiation, memory

DOI: 10.3233/JAD-2010-1230

Citation: Journal of Alzheimer's Disease, vol. 19, no. 2, pp. 441-449, 2010

Authors: Hansen, Elizabeth | Krautwald, Martina | Maczurek, Annette E. | Stuchbury, Grant | Fromm, Phillip | Steele, Megan | Schulz, Oliver | Benavente Garcia, Obdulio | Castillo, Julian | Körner, Heinrich | Münch, Gerald

Article Type: Research Article

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. Show more

Keywords: Co-culture, inflammation, microglia, neurons, neurotoxicity

DOI: 10.3233/JAD-2010-1233

Citation: Journal of Alzheimer's Disease, vol. 19, no. 2, pp. 451-464, 2010

Authors: Cataldo, Janine K. | Prochaska, Judith J. | Glantz, Stanton A.

Article Type: Research Article

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. Show more

Keywords: Alzheimer's disease, cigarette, cognition, cognitive impairment, smoking, tobacco

DOI: 10.3233/JAD-2010-1240

Citation: Journal of Alzheimer's Disease, vol. 19, no. 2, pp. 465-480, 2010

Authors: Politis, Antonis | Olgiati, Paolo | Malitas, Petros | Albani, Diego | Signorini, Alessandra | Polito, Letizia | De Mauro, Stefania | Zisaki, Aikaterini | Piperi, Christina | Stamouli, Evangelia | Mailis, Antonis | Batelli, Sara | Forloni, Gianluigi | De Ronchi, Diana | Kalofoutis, Anastasios | Liappas, Ioannis | Serretti, Alessandro

Article Type: Research Article

Abstract: Alzheimer's disease (AD) has been associated with up-regulation of pro-inflammatory cytokines (e.g., specific gene variants for TNF-α; IL-6; IFN-γ) and low plasma levels of cyanocobalamin (vitamin B12). Our goal was to relate B12 levels to AD symptoms and to expression of pro-inflammatory cytokines. Clinical manifestations were investigated for a case series of fifty-five outpatients using the MMSE, Neuropsychiatric Inventory (NPI) and Cornell Scale for Depression in Dementia (CDDS). 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 (PBMC culture supernatant). 47 patients were genotyped for APOE. Ten …patients (18%) had their B12 levels below <250 pg/ml. They did not statistically differ from those 45 who had normal levels in most demographic and clinical features; their MMSE scores were lower (14.7 vs 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 vs 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 AD. Show more

Keywords: Alzheimer's disease, APOE gene, cytokine, inflammatory response, vitamin B12

DOI: 10.3233/JAD-2010-1252

Citation: Journal of Alzheimer's Disease, vol. 19, no. 2, pp. 481-488, 2010

Authors: Martín, Virginia | Fabelo, Noemí | Santpere, Gabriel | Puig, Berta | Marín, Raquel | Ferrer, Isidre | Díaz, Mario

Article Type: Research Article

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. Show more

Keywords: Alzheimer's disease, docosahexaenoic acid, human brain cortex, lipid rafts, membrane phospholipids, polyunsaturated fatty acids

DOI: 10.3233/JAD-2010-1242

Citation: Journal of Alzheimer's Disease, vol. 19, no. 2, pp. 489-502, 2010