Volume 10, Number 4, December 2006

Pages 353-358
Amy Chan, Thomas B. Shea
Supplementation with apple juice attenuates presenilin-1 overexpression during dietary and genetically-induced oxidative stress
Abstract: Gain-of-function mutations in the presenilin-1 (PS-1) promote Alzheimer’s disease (AD) by increasing reactive oxygen species, at least part of which is derived by an accompanying increase in generation of amyloid beta (Aß). Additional studies indicate that impaired Apolipoprotein E function, which also increases oxidative stress and is also associated with AD, potentiates the deleterious activity of PS-1. Folate deficiency is also associated with AD and potentiates the impact of both ApoE deficiency and Aß exposure. More recently, folate deficiency has been shown to increase PS-1 expression. Since dietary supplementation with apple juice provides neuroprotection against ApoE deficiency, Aß exposure and folate deficiency, we examined the impact of apple juice on PS-1 overexpression. Herein, we demonstrate that dietary deficiency in folate and vitamin E increased PS-1 expression in juvenile and adult normal C57B1/6J and ApoE-/- mice and in aged normal mice. Supplementation with apple juice concentrate (AJC) attenuated or prevent these increases. Prior studies demonstrate that impaired DNA methylation resulting from a deficiency in S-adenosylmethionine (SAM, which is rapidly depleted following folate deprivation) leads to PS-1 overexpression, and that direct supplementation with SAM attenuates PS-1 overexpression. We determined that AJC contained levels of SAM comparable to those capable of suppressing PS-1 overexpression, suggesting that the SAM content of AJC represents a potential mechanism for preventing PS-1 overexpression, and further highlighting the possibility that AJC provides neuroprotection by mechanisms in addition to its antioxidant potential.

Commentary
   Pages 359-361
   Debomoy K. Lahiri
   Where the actions of environment (nutrition), gene and protein meet: Beneficial role of fruit and vegetable juices in potentially delaying the onset of Alzheimer’s disease

   Pages 363-364
   Thomas B. Shea, Amy Chan
   Response to Commentary: Food for Thought: Dietary influence on Acetylcholine

Pages 365-369
Fábio Augusto Freiria Barbosa, Roger Willian de Labio, Valdeci de Oliveira S. Rigolin, Thais Minett, Paulo Henrique Ferreira Bertolucci, Marília de Arruda Cardoso Smith, Spencer Luiz Marques Payão
Apolipoprotein A-V gene polymorphism –1131T>C and Alzheimer’s disease
Abstract: Alzheimer disease (AD) is the most common neurodegenerative disorder in the elderly and is also considered a progeroid genetic syndrome. The etiology of AD is complex and the mechanisms underlying its pathophysiology remains to be clarified. It has been suggested that a high serum cholesterol level is a risk factor for Alzheimer’s disease (AD), and that some polymorphisms of genes encoding proteins regulating cholesterol metabolism are associated with AD development. APOA5 is a recently discovered apolipoprotein involved primarily with triglyceride (TG) metabolism disorder. This study investigates the association of AD with the APOA5 gene -1131T>C polymorphisms in samples of 106 patients with Alzheimer’s disease (AD), 76 elderly healthy controls and 93 young healthy controls. DNA samples were isolated from blood cells, amplified by PCR and digested with Tru1l. We observed that the genotype distributions of APOA5 variants were within Hardy-Weinberg equilibrium in all subject samples. Furthermore, chi-square test comparison for genotype distributions and allele frequencies did not reveal any significant difference among the three groups of subjects (P>0.05). These results support the idea that these variants are not involved as a risk factor for developing AD.

Pages 371-378
D. Micheli, C. Bonvicini, A. Rocchi, R. Ceravolo, M. Mancuso, G. Tognoni, M. Gennarelli, G. Siciliano, L. Murri.
No evidence for allelic association of serotonin 2A receptor and transporter gene polymorphisms with depression in Alzheimer disease.
Abstract: Patients with Alzheimer disease (AD) often exhibit psychiatric symptoms associated with cognitive impairment. The serotoninergic system may be involved in the development of depressive symptoms in AD patients, as suggested by the evidence that antidepressant drugs having the serotonin transporter as their target are effectively used to treat depressive AD patients. The aim of this study was to investigate the role of serotonin in depression, searching for association of two serotoninergic polymorphisms (T102C of 5-HT2A and 5-HTTLPR of SLC6A4) with depressive symptoms and considering their possible interactions with Apolipoprotein E and between themselves, in a sample of 208 sporadic AD patients and 116 normal controls from Italy. 5-HTTLPR and T102C are not associated with AD when separately analysed. However, we found out an interaction between the two polymorphisms in L/L and C/C genotype carriers increasing the risk for the disease (p=0.015, OR=8.048; 95% CI: 1.497-43.262). No association of the polymorphisms was detected with depression linked to AD. No interaction between 5-HTTLPR and T102C was detected in depressive AD subjects, even after stratification according to the presence of ApoE4 allele. These results suggest that the serotoninergic system may be not involved in the pathogenesis of depressive symptoms in AD patients, and it may be involved in other aspects of disease pathophysiology like cognitive symptoms and psychosis.

Pages 379-390
Rhian S. Thomas, J. Eryl Liddell, Lynne S. Murphy, David M. Pache, Emma J. Kidd (Communicated by Gerd Multhaup)
An antibody to the ß-secretase cleavage site on amyloid ß-protein precursor inhibits amyloid ß production
Abstract: Proteolytic cleavage of amyloid ß-protein precursor (AßPP) by ß and gamma-secretases results in production of the amyloid ß peptide (Aß) that accumulates in the brains of sufferers of Alzheimer’s disease (AD). We have developed a monoclonal antibody, 2B12, which binds in the vicinity of the ß-secretase cleavage site on AßPP but does not bind within the Aß region. We hypothesised that this antibody, directed against the substrate rather than the enzyme, could inhibit cleavage of AßPP by ß-secretase via steric hindrance and thus reduce downstream production of Aß. The antibody would enter cells by binding to AßPP when it is at the cell surface and then be internalised with the protein. We subsequently demonstrated that, after addition of 2B12 to standard growth media, this antibody was indeed capable of inhibiting Aß40 production in neuroblastoma and astrocytoma cells expressing native AßPP, as measured by an ELISA. This inhibition was both concentration- and time-dependent and was specific to 2B12. We were only able to inhibit approximately 50% of Aß40 production suggesting that not all AßPP is trafficked to the cell surface. We propose that this antibody could be used as a novel, putative therapy for the treatment of AD.

Pages 391-397
D. Allan Butterfield, Anastazija Gnjec, H. Fai Poon, Alessandra Castegna, William M. Pierce, Jon B. Klein, Ralph N. Martins
Redox proteomics identification of oxidatively modified brain proteins in inherited Alzheimer’s disease: an initial assessment
Abstract: Objective: To identify oxidatively modified proteins in brains of persons with inherited Alzheimer’s disease. Methods: Redox proteomics was used to identify oxidatively modified brain proteins in persons with mutations in the genes for presenilin-1 (PS-1). Results: An initial redox proteomics assessment of oxidatively modified proteins from brains of individuals with PS-1 mutations was performed. These PS1 mutations, Q222H and M233T, are completely penetrant causing early-onset familial AD as previously reported in these Australian families. We show that oxidative modifications of ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1), gamma-enolase, actin, and dimethylarginine dimethylaminohydrolase 1 (DMDMAH-1) are present in the brain of familial AD subjects. Conclusions: These initial results suggest that oxidatively modified proteins are important common features in both familial and sporadic AD.

Pages 399-406
Robert G. Riekse, Ge Li, Eric C. Petrie, James B. Leverenz, Darcy Vavrek, Simona Vuletic, John J. Albers, Thomas J. Montine, Virginia M.-Y. Lee, Michael Lee, Peter Seubert, Douglas Galasko, Gerard D. Schellenberg, William R. Hazzard, Elaine R. Peskind (Communicated by Debby Tsuang)
Effect of statins on Alzheimer’s disease biomarkers in cerebrospinal fluid
Abstract: Background: Treatment with HMG-CoA reductase inhibitors (“statins”) has been variably associated with a reduced risk of Alzheimer’s disease (AD) in epidemiologic studies and reduced amyloid-ß (Aß) deposition in animal models of AD. Putative neuroprotective effects of statins may vary in relation to their ability to penetrate into the central nervous system (CNS). Methods: We measured levels of cerebrospinal fluid (CSF) AD biomarkers following 14 weeks of treatment with simvastatin (a CNS permeant statin; n = 10) at 40 mg/day or pravastatin (a CNS impermeant statin; n = 13) at 80 mg/day in hypercholesterolemic subjects without dementia. Results: Simvastatin, but not pravastatin, reduced CSF levels of phospho-tau-181 (p-tau181) in all subjects. There were no differences in CSF levels of total tau, Aß42, Aß40, soluble amyloid ß protein precursor (sAßPP) alpha or ß, or F2-isoprostanes. Conclusions: Statins may modulate the phosphorylation of tau in humans and this effect may depend on the CNS availability of the statin. These results suggest another mechanism by which statins may act to reduce the risk of AD.

Commentary
   Pages 407-408
   Othman Ghribi
   Preservation of the blood brain barrier integrity may underlie neuroprotective effects of statins in Alzheimer’s disease

Pages 409-416
Vicent Villanueva, Ana M. Garcia (Communicated by Francesco Panza)
Validity and reliability of surrogate information for controls in a case-control study on Alzheimer’s disease
Abstract: This study is aimed to investigate proxy respondent’s information usefulness in retrospective studies by comparing information obtained with a questionnaire (with a total of 171 items) from controls and their proxy respondents in a case-control study on Alzheimer’s disease. Kappa indices and intraclass correlation coefficients were calculated to assess reliability, and bias factor and mean differences were calculated to assess validity. Proxy respondent’s personal features (gender, age and relationship with the index subject) were also studied. Kappa indices and intraclass correlation coefficients were in general good or very good (>0.6), specially regarding control’s personal and family data (ranges 0.45-1 for Kappa and 0.86-0.99 for intraclass correlation coefficient) and occupational exposures (range for Kappa 0.48-1). No systematic biases were found (range for bias factor 0.65-4.12 and range for mean differences –1.81-1.30, none of them statistically significant). Proxy respondent’s individual features were not found to systematically affect reliability. The use of surrogate information for controls in etiologic case-control studies of Alzheimer’s disease may be useful without unacceptable loss of information or systematic biases.

Pages 417-422
Weiping Qin, Mark Chachich, Mark Lane, George Roth, Mark Bryant, Rafael de Cabo, Mary Ann Ottinger, Julie Mattison, Donald Ingram, Samuel Gandy, Giulio Maria Pasinetti
Calorie restriction attenuates Alzheimer's disease type brain amyloidosis in squirrel monkeys (Saimiri sciureus)
Abstract: Recent studies from our laboratories and others suggest that calorie restriction (CR) may benefit Alzheimer's disease (AD) by preventing amyloid-ß (Aß) neuropathology in the mouse models of AD. Moreover, we found that promotion of the NAD+-dependent SIRT1 mediated deacetylase activity, a key regulator in CR extension of life span, may be a mechanism by which CR influences AD-type neuropathology. In this study we continued to explore the role of CR in AD-type brain amyloidosis in Squirrel monkeys ( Saimiri sciureus ). Monkeys were maintained on the normal and CR diets throughout the entire lifespan until they died of natural causes. We found that 30% CR resulted in reduced contents of Aß1-40 and Aß1-42 peptides in the temporal cortex of Squirrel monkeys, relative to control (CON) fed monkeys. The decreased contents of cortical Aß peptide inversely correlated with SIRT1 protein concentrations in the same brain region; no detectable change in total full-length AßPP level was found. Most interestingly, we found that 30% CR resulted in a select elevation of alpha- but not ß- or gamma- secretase activity which coincided with decreased ROCK1 protein content in the same brain region, relative to CON group. Collectively, the study suggests that investigation of the role of CR in non-human primates may provide a valuable approach for further clarifying the role of CR in AD.

Pages 423-437
J.A. Joseph, D.R. Fisher, A.N. Carey, A. Neuman, D.F. Bielinski
Dopamine-Induced Stress Signaling in COS-7 Cells Transfected With Selectively Vulnerable Muscarinic Receptor Subtypes is Partially Mediated Via The i3 Loop and Antagonized By Blueberry Extract
Abstract: Muscarinic receptors (MAChRs) are intimately involved in various aspects of both neuronal and vascular functioning, and there is selective oxidative stress sensitivity (OSS) among MAChR subtypes, with M1, M2, and M4 showing > OSS. OSS was assessed by determining the loss of ability of the cell to extrude or sequester Ca2+ following oxotremorine-induced depolarization following exposure to dopamine (DA) subtypes in transfected COS-7 cells. This OSS can be prevented by pretreatment with blueberry (BB) extract. Present studies were carried out to determine BB treatment of the cells transfected with wild type, truncated or chimeric [where the i3 loop of one receptor was switched with the i3 loop of the other; i.e., M1(M3i3) and M3(M1i3)] receptors would alter DA-induced changes in calcium buffering and would confer protection through alterations in pMAPK, pCREB or PKC signaling. These findings also suggest that BB may antagonize OS effects by lowering activation of pCREB and possibly PKCgamma induced by DA. In the truncated and chimeric receptors, results indicated that BB reduced OSS in response to DA in M1-transfected cells. However, BBs were also effective in preventing these Ca2+ buffering deficits in cells transfected with M1 receptors in which the i3 loop had been removed, but only partially enhanced the protective effects of the M3 i3 loop in the M1(M3i3) chimerics. A similar partial effect of BBs was seen in the M3(M1i3) chimerics which showed increased OSS in response to DA. It appears that antioxidants found in BBs might be targeting additional sites on these chimerics to decrease OSS.

Pages 439-443
Isabel Rubio, Carlos Caramelo, Ascención Gil, María Dolores López, Justo García de Yébenes (Communicated by Jesus Avila)
Plasma amyloid-ß, Aß1-42, load is reduced by haemodialysis
Abstract: Patients with chronic renal failure treated with haemodialysis have vascular risk factors that, in the general population, are associated with increased prevalence of Alzheimer´s disease (AD). Patients in haemodialysis, however, present different kinds of dementia but they do not have an increased risk of AD. We have hypothesized that amyloid ß 1-42 is washed out from plasma during the dialysis and that this procedure enhances amyloid ß elimination and reduces the risk of AD. We have measured plasma amyloid ß 1-42 levels in 11 patients with renal failure, before and after haemodialysis. A single procedure reduced the plasma amyloid ß levels in all subjects with a mean decrement of 30% of baseline. Since amyloid ß deposition could be altered by certain metals like Cu and Zn, we have also measured the effects of dialysis on the levels of these ions in plasma. We found no changes in levels of Cu and Zn after dialysis. Haemodialysis, therefore, reduces very effectively plasma amyloid ß without modifying Cu and Zn levels. The potential use of this strategy in patients with AD requires further investigation.

Commentary
   Pages 445-447
   Samanwoy Ghosh-Dastidar, Hojjat Adeli, Nahid Dadmehr
   Voxel-Based Morphometry in Alzheimer’s Patients

   Page 449
   Leslie C. Baxter, Marwan N. Sabbagh
   Response to Commentary: Voxel-Based Morphometry in Alzheimer's Patients

Commentary
   Pages 451-452
   Christopher Exley
   A vexing commentary on the important issue of aluminium and Alzheimer’s disease

Letter
   Pages 453-455
   Nikolaos K. Robakis
   The discovery and mapping to chromosome 21 of the Alzheimer’s amyloid gene: history revised

Pages 457-465
Transcript: Alzheimer Research Forum Live Discussion
Cell Cycle Hypothesis Pedaling into Mainstream Acceptance? Results in Fly, Mouse Models Warrant a Second Look

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