17, Number 4, August 2009
Amyloid-β, Tau, and Dementia
Abstract: Alzheimer’s disease (AD) is clinically characterized as a progressive dementia starting with memory dysfunction and characterized pathologically as neurodegeneration accompanied by deposition of amyloid-β, neurofibrillary tangles, and neuronal loss. AD research has endeavored to explain the clinical symptoms of AD through pathological changes and to develop various therapies for AD. Fulfillment of these goals, however, remains on the horizon. In this article, I review the relationship between neuropathological changes that occur in the brain and clinical progression of AD, and propose a hypothesis that brain aging, characterized by neurofibrillary tangles in entorhinal cortex, is pre-requisite for development of AD.
Russell H. Swerdlow (Communicated by Xiongwei Zhu)
The Neurodegenerative Mitochondriopathies
Abstract: Mitochondria are physically or functionally altered in many neurodegenerative diseases. This is the case for very rare neurodegenerative disorders as well as extremely common age-related ones such as Alzheimer’s disease and Parkinson’s disease. In some disorders very specific patterns of altered mitochondrial function or systemic mitochondrial dysfunction are demonstrable. Some disorders arise from mitochondrial DNA mutation, some from nuclear gene mutation, and for some the etiology is not definitively known. This review classifies neurodegenerative diseases using mitochondrial dysfunction as a unifying feature, and in doing so defines a group of disorders called the neurodegenerative mitochondriopathies. It discusses what mitochondrial abnormalities have been identified in various neurodegenerative diseases, what is currently known about the mitochondria-neurodegeneration nexus, and speculates on the significance of mitochondrial function in some disorders not classically thought of as mitochondriopathies.
Janardan P. Pandey
Immunoglobulin GM Genes as Functional Risk and Protective Factors for the Development of Alzheimer’s Disease
Abstract: There is growing body of evidence for the involvement of herpes simplex virus type 1 (HSV1) in the etiology of Alzheimer’s disease (AD). HSV1 has evolved strategies for decreasing the efficacy of the host immune response and interfering with viral clearance. Based on their putative role as the modulators of these immune avoidance strategies, I hypothesize that immunoglobulin (Ig) GM genes—genetic markers of IgG heavy chains located on chromosome 14—are functional risk and protective factors for AD. Results from genome-wide association and linkage studies in support of this hypothesis, testable predictions, and possible therapeutic implications are discussed.
Bruno P. Imbimbo
Why Did Tarenflurbil Fail in Alzheimer’s Disease?
Abstract: There has been a lot of disappointment surrounding the recent failure of the largest ever study in patients with Alzheimer’s disease (AD) with tarenflurbil, a compound believed to modulate the activity of γ-secretase, the pivotal enzyme that generates the amyloid-β (Aβ) peptide from the amyloid-β protein precursor. What are the reasons for this setback after the previous apparently encouraging results in a Phase II study? A straightforward explanation of this failure is that the γ-secretase is not the right target for therapy or that, in general, blocking Aβ does not produce clinical benefits in AD. If one still accepts a physiopathological role of Aβ in AD, tarenflurbil could not be the right compound because of its weak pharmacological activity as an Aβ1-42 lowering agent and its poor brain penetration. In addition, based on previous negative results with several anti-inflammatory drugs in AD, it is hypothesized that the residual anti-inflammatory activity of tarenflurbil may have a detrimental effect on disease progression.
Flavio Nobili, Fabrizio De Carli, Giovanni B. Frisoni, Florence Portet, Frans Verhey, Guido Rodriguez, Anna Caroli, Jacques Touchon, Silvia Morbelli, Ugo P. Guerra, Barbara Dessi, Andrea Brugnolo and Pieter Jelle Visser (Communicated by Patrizia Mecocci)
SPECT Predictors of Cognitive Decline and Alzheimer’s Disease in Mild Cognitive Impairment
Abstract: Baseline brain single photon emission computed tomography (SPECT) was evaluated in eighty subjects with mild cognitive impairment (MCI) who were followed for a mean of about two years, when twelve patients developed Alzheimer’s disease (AD), nineteen showed memory decline (D), and forty-three had normal cognition assessment (stable: S) (six drop-out). Volumetric Regions of Interest (VROI) analysis was performed in six associative cortical areas in each hemisphere. ANOVA for repeated measures showed significant effects for both the group (S, D, and AD; p<0.004) and VROI (p<0.0001) factors, with significant group*region interaction (p<0.01). At post-hoc comparison, hippocampal VROIs values were lower in AD than in D and S, while parietal VROIs values were lower in D and AD than in S. These four VROI significantly correlated with verbal delayed recall score at follow-up visit.Receiver operating characteristic (ROC) curves for the mean hippocampal VROI value showed 0.81 sensitivity with 0.86 specificity in separation of S+D from AD (p<0.0001), and 0.69 sensitivity with 0.75 specificity in separation of S from D+AD (p<0.0002). ROC curves for the mean parietal VROI value showed 0.62 sensitivity with 0.70 specificity in separation of S from D+AD (p<0.0002). Baseline SPECT can support outcome prediction in subjects with MCI.
Ana María Simón, Rakel López de Maturana, Ana Ricobaraza, Luis Escribano, Lucio Schiapparelli, Mar Cuadrado-Tejedor, Alberto Pérez-Mediavilla, Jesús Avila, Joaquín Del Río and Diana Frechilla
Early Changes in Hippocampal Eph Receptors Precede the Onset of Memory Decline in Mouse Models of Alzheimer’s Disease
Abstract: Synapse loss occurs early in Alzheimer’s disease (AD) and is considered the best pathological correlate of cognitive decline. Ephrins and Eph receptors are involved in regulation of excitatory neurotransmission and play a role in cytoskeleton remodeling. We asked whether alterations in Eph receptors could underlie cognitive impairment in an AD mouse model overexpressing human amyloid-β protein precursor (hAβPP) with familial mutations (hAβPPswe-ind mice). We found that EphA4 and EphB2 receptors were reduced in the hippocampus before the development of impaired object recognition and spatial memory. Similar results were obtained in another line of transgenic AβPP mice, Tg2576. A reduction in Eph receptor levels was also found in postmortem hippocampal tissue from patients with incipient AD. At the time of onset of memory decline in hAβPPswe-ind mice, no change in surface expression of AMPA or NMDA receptor subunits was apparent, but we found changes in Eph-receptor downstream signaling, in particular a decrease in membrane-associated phosho-cofilin levels that may cause cytoskeletal changes and disrupted synaptic activity. Consistent with this finding, Eph receptor activation in cell culture increased phosho-cofilin levels. The results suggest that alterations in Eph receptors may play a role in synaptic dysfunction in the hippocampus leading to cognitive impairment in a model of AD.
Israel Ampuero, Javier Alegre-Abarrategui, Izaskun Rodal, Antonio España, Raquel Ros, José Luis Lopez Sendón, Eva García Galloway, Ángeles Cervelló, Ana Belén Caminero, Antxon Zabala, Elena Erro, Fernando Jarauta, Lorenzo Morlán, Eva López-Valdés, Yolanda Aladro, Manuel Seijo, Guillermo García Rivas, David G. Muñoz and Justo García de Yébenes
On the Diagnosis of CADASIL
Abstract: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a genetic arteriopathy related to Notch3 mutations, is difficult to diagnosis. The goal of this study was to determine the value of clinical, immunohistochemical, and molecular techniques for the diagnosis of CADASIL. Clinical features and the immunohistochemical and molecular findings in 200 subjects with suspected CADASIL in whom 93 biopsies and 190 molecular studies are reported. Eighteen pathogenic mutations of the Notch3 gene, six of them previously unreported, were detected in 67 patients. The clinical features did not permit differentiation between CADASIL and CADASIL-like syndromes. The sensitivity and specificity of the skin biopsies was 97.7% and 56.5%, respectively, but increased to 100% and 81.5%, respectively, in cases with proven family history. In conclusion, a clinical diagnosis of CADASIL is difficult to determine and confirmatory techniques should be used judiciously.
Lourdes Vega, Ángel A. Arroyo, Arantxa Tabernero and José M. Medina
Albumin-Blunted Deleterious Effect of Amyloid-β by Preventing the Internalization of the Peptide into Neurons
Abstract: Amyloid-β (Aβ) is the main component of senile plaques, one of the hallmarks of Alzheimer’s disease. Our results showed that Aβ25-35 decreased neuronal viability while it increased generation of reactive oxygen species (ROS). Under these circumstances, albumin (BSA) prevented ROS production and neuronal death in a dose- and time-dependent manner. In addition, BSA partially prevented the decrease in the expression of GAP-43, MAP-2, and tubulin, and the phosphorylation of tau protein caused by Aβ, suggesting that BSA protects against the loss of plasticity caused by the peptide. Our findings suggest that BSA exerts its protective effect by binding to Aβ in an equimolecular way, which prevents heterodimer (Aβ-BSA) entry into neurons. In fact, BSA prevented Aβ internalization, as shown by confocal immunocytochemistry, suggesting that BSA causes its protective effect by sequestrating Aβ, which cannot reach its intracellular targets. This is consistent with the idea that Aβ must enter neurons to exert its deleterious effects.
Donald H. Taylor, Jr., Truls Østbye, Kenneth M. Langa, David Weir, Brenda L. Plassman
The Accuracy of Medicare Claims as an Epidemiological Tool: The Case of Dementia Revisited
Abstract: Our study estimates the sensitivity and specificity of Medicare claims to identify clinically-diagnosed dementia, and documents how errors in dementia assessment affect dementia cost estimates. We compared Medicare claims from 1993-2005 to clinical dementia assessments carried out in 2001–2003 for the Aging Demographics and Memory Study (ADAMS) cohort (n= 758) of the Health and Retirement Study. The sensitivity and specificity of Medicare claims was 0.85 and 0.89 for dementia (0.64 and 0.95 for AD). Persons with dementia cost the Medicare program (in 2003) $7,135 more than controls (P<0.001) when using claims to identify dementia, compared to $5,684 more when using ADAMS (P<0.001). Using Medicare claims to identify dementia results in a 110% increase in costs for those with dementia as compared to a 70% increase when using ADAMS to identify disease, net of other variables. Persons with false positive Medicare claims notations of dementia were the most expensive group of subjects ($11,294 versus $4,065, for true negatives P<0.001). Medicare claims undercount the true prevalence of dementia, but there are both false positive and negative assessments of disease. The use of Medicare claims to identify dementia results in an overstatement of the increase in Medicare costs that are due to dementia.
Suzanne M. de la Monte and Ming Tong (Communicated by Paula Moreira)
Mechanisms of Nitrosamine-Mediated Neurodegeneration: Potential Relevance to Sporadic Alzheimer’s Disease
Abstract: Streptozotocin (STZ) is a nitrosamine-related compound that causes Alzheimer’s disease (AD)-type neurodegeneration with cognitive impairment, brain insulin resistance, and brain insulin deficiency. Nitrosamines and STZ mediate their adverse effects by causing DNA damage, oxidative stress, lipid peroxidation, pro-inflammatory cytokine activation, and cell death, all of which occur in AD. We tested the hypothesis that exposure to N-nitrosodiethylamine (NDEA), which is widely present in processed/preserved foods, causes AD-type molecular and biochemical abnormalities in central nervous system (CNS) neurons. NDEA treatment of cultured post-mitotic rat CNS neurons (48 h) produced dose-dependent impairments in ATP production and mitochondrial function, and increased levels of 8-hydroxy-2’-deoxyguanosine, 4-hydroxy-2-nonenal, phospho-tau, amyloid-β protein precursor-amyloid-β (AβPP-Aβ), and ubiquitin immunoreactivity. These effects were associated with decreased expression of insulin, insulin-like growth factor (IGF)-I, and IGF-II receptors, and choline acetyltransferase. Nitrosamine exposure causes neurodegeneration with a number of molecular and biochemical features of AD including impairments in energy metabolism, insulin/IGF signaling mechanisms, and acetylcholine homeostasis, together with increased levels of oxidative stress, DNA damage, and AβPP-Ab immunoreactivity. These results suggest that environmental exposures and food contaminants may play critical roles in the pathogenesis of sporadic AD.
Ming Tong, Alexander Neusner, Lisa Longato, Margot Lawton, Jack R. Wands and Suzanne M. de la Monte (Communicated by Paula Moreira)
Nitrosamine Exposure Causes Insulin Resistance Diseases: Relevance to Type 2 Diabetes Mellitus, Non-Alcoholic Steatohepatitis, and Alzheimer’s Disease
Abstract: The current epidemics of type 2 diabetes mellitus (T2DM), non-alcoholic steatohepatitis (NASH), and Alzheimer’s disease (AD) all represent insulin-resistance diseases. Previous studies showed that streptozotocin, a nitrosamine-related compound, causes insulin resistance diseases including, T2DM, NASH, and AD-type neurodegeneration. We hypothesize that chronic human exposure to nitrosamine compounds, which are widely present in processed foods, contributes to the pathogenesis of T2DM, NASH, and AD. Long Evans rat pups were treated with N-nitrosodiethylamine (NDEA) by i.p. (x3) or i.c. (x1) injection, and 2-4 weeks later, they were evaluated for cognitive-motor dysfunction, insulin resistance, and neurodegeneration using behavioral, biochemical, and molecular approaches. NDEA treatment caused T2DM, NASH, deficits in motor function and spatial learning, and neurodegeneration characterized by insulin resistance and deficiency, lipid peroxidation, cell loss, increased levels of amyloid-β protein precursor-amyloid-β, phospho-tau, and ubiquitin immunoreactivities, and upregulated expression of pro-inflammatory cytokine and pro-ceramide genes, which together promote insulin resistance. In conclusion, environmental and food contaminant exposures to nitrosamines play critical roles in the pathogenesis of major insulin resistance diseases including T2DM, NASH, and AD. Improved detection and prevention of human exposures to nitrosamines will lead to earlier treatments and eventual quelling of these costly and devastating epidemics.
Enika Nagababu*, Peter V. Usatyuk*, Divya Enika, Viswanathan Natarajan, Joseph M. Rifkind *Equal contribution (Communicated by Jack de la Torre)
Vascular Endothelial Barrier Dysfunction Mediated by Amyloid-β Proteins
Abstract: Neuronal inflammation is very common in Alzheimer’s disease (AD). This inflammation can be caused by infiltration of neutrophils across the blood brain barrier. Endothelial permeability changes are required for the infiltration of high molecular weight components to the brain. Deposition of toxic amyloid-β (Aβ) fibrils in the cerebral vasculature, as well as in brain neurons, has been implicated in the development of AD. This study investigates the effect of Aβ fibrils on the permeability of the endothelium and the mechanism for the observed permeability changes. Aβ1-40 and Aβ1-42 fibrils, but not monomers, were found to increase permeability of bovine pulmonary arterial endothelial cells in a dose- and time-dependent manner as detected by transendothelial electrical resistance. This increase in permeability is only partially (25%) inhibited by catalase and is not associated with an increase in cytosolic Ca+2 or tyrosine phosphorylation. These results indicate that hydrogen peroxide is not the primary mediator for the permeability changes. Treatment of cells with both amyloid fibrils resulted in stress fiber formation, disruption and aggregation of actin filaments, and cellular gap formation. The results of this study reveal that Aβ increases the permeability of endothelium by inducing change in the cytoskeleton network.
Robert Perneczky, Stefan Wagenpfeil, Kathryn L. Lunetta, L. Adrienne Cupples, Robert C. Green, Charles DeCarli, Lindsay A. Farrer, Alexander Kurz, for the MIRAGE Study Group (Communicated by Kurt Jellinger)
Education Attenuates the Effect of Medial Temporal Lobe Atrophy on Cognitive Function in Alzheimer’s Disease: The MIRAGE Study
Abstract: Functional imaging and neuropathological studies suggest that individuals with higher education have better cognitive performance at the same level of brain pathology than less educated subjects. No in vivo studies are available that directly test how education modifies the effect of structural pathology on cognition in Alzheimer’s disease (AD). The present study therefore aimed to measure this effect using data from a large multi-center study. 270 patients with AD underwent cognitive testing using the Mini Mental State Examination (MMSE), apolipoprotein E (APOE) genotyping, and cerebral magnetic resonance imaging. A linear regression analysis was used to examine the relation of medial temporal lobe atrophy (MTA), as a proxy of AD pathology, to MMSE score, adjusting for age, gender, APOE, cerebrovascular disease, ethnicity, education, and disease duration. An interaction term for MTA and education was introduced to test the hypothesis that education modifies the effect of MTA on cognition. There was a significant inverse association between MTA and cognition. Most interestingly, the interaction term between education and MTA was significant suggesting that education modifies the relation of MTA to cognition. At any level of pathology, cognition remained higher for better educated individuals.
Felix Meyne, Sara Friederike Gloeckner, Barbara Ciesielczyk, Uta Heinemann, Anna Krasnianski, Bettina Meissner, Inga Zerr
Total Prion Protein Levels in the Cerebrospinal Fluid are Reduced in Patients with Various Neurological Disorders
Abstract: We performed a study on levels of the total prion protein (PrP) in humans affected by different neurological diseases and assessed the influence of several factors such as age, gender, and disease severity on the cerebrospinal fluid PrP levels. PrP-ELISA technique was used to analyze cerebrospinal fluid (CSF) samples. 293 CSF samples of patients with Creutzfeldt-Jakob-disease (CJD), Alzheimer’s disease, dementia with Lewy-bodies, Parkinson’s disease, multiple sclerosis, cerebral ischemia, generalized epileptic seizures, and meningitis and encephalitis in comparison to controls were analyzed. We found a significant reduction of CSF PrP levels in patients suffering from all neurodegenerative disorders analyzed. This group exhibited mean PrP values of 164 ng/ml while non-neurodegenerative disorder patients and healthy controls showed PrP levels of 208 ng/ml and 226 ng/ml, respectively. CSF levels correlated with disease severity in CJD, Alzheimer’s disease, and dementia with Lewy-bodies. The finding of decreased PrP levels in the CSF of patients not only with CJD but also in other neurodegenerative disorders is intriguing. Age-, gender-, and genetic-specific factors might be involved in the PrPc regulation.
Sebastien Haneuse, Eric Larson, Rod Walker, Thomas Montine, Joshua Sonnen (Communicated by Sara Debanne)
Neuropathology-Based Risk Scoring for Dementia Diagnosis in the Elderly
Abstract: Current neuropathologic consensus criteria for diagnosis of dementia yield a classification of processes that likely contributed to dementia in that individual. While dementia diagnosis currently relies on clinical criteria, practicing neuropathologists and researchers might benefit from a simple, accurate risk scoring protocol for the neuropathologic diagnosis of dementia. Using 232 consecutive autopsies from the population-based Adult Changes in Thought study, we developed two logistic regression-based risk scoring systems; one solely using neuropathologic measures and a second additionally including demographic information. Inverse-probability weighting was used to adjust for inherent selection bias in autopsy-based studies of dementing illnesses. Both systems displayed high levels of predictive accuracy; bias-adjusted area-under-the-curve statistics were 0.78 (95% CI 0.71, 0.85) and 0.87 (95% CI 0.83, 0.92), indicating improved performance with the inclusion of demographic characteristics, specifically age and birth cohort information. Application of the combined neuropathlogy/demographic model yielded bias-adjusted sensitivity and specificity of 81% each. In contrast, application of NIA-Reagan criteria yielded sensitivity and specificity of 53% and 84%. Our proposed scoring systems provide neuropathologists with tools to make a diagnosis, and interpret their diagnosis in the light of known sensitivity and specificity estimates. Evaluation in independent samples will be important to verify our findings.
Kristina F. Zdanys, Timothy G. Kleiman, Huiping Zhang, Fatih Ozbay, Martha G. MacAvoy, Joel Gelernter, Christopher H. van Dyck (Communicated by Maire Percy)
BDNF Variants, Premorbid Educational Attainment, and Disease Characteristics in Alzheimer’s Disease: An Exploratory Study
Abstract: Brain-derived neurotrophic factor (BDNF) is a neurotrophin that promotes neuronal survival, growth, and differentiation. The role of BDNF in learning and memory suggests that it may also modulate the clinical course of Alzheimer’s disease (AD). This study aimed to determine whether BDNF genetic variants are related to premorbid educational attainment, progression of cognitive and functional decline, and associated neuropsychiatric symptoms in AD patients. A sample of AD subjects (N=341) was genotyped for the BDNF polymorphisms: Val66Met, C270T, and G-712A. Subjects received tests of cognition and daily function at baseline and at multiple subsequent time points. They were also characterized for the frequency and severity of neuropsychiatric symptoms. There was a significant effect of Val66Met genotype on educational attainment (F=7.49, df=2, 329, P=.00066), with Met/Met homozygotes having significantly lower education than both the Val/Met and Val/Val groups. No association was observed between any BDNF polymorphism and measures of cognitive or functional decline. The T-allele of the C270T polymorphism was associated with a higher prevalence of neuropsychiatric symptoms and specifically with the presence of hallucinations. The effect of the Val66Met polymorphism on premorbid educational attainment is intriguing and should be verified in a larger sample.
Francesco Panza, Alessia D’Introno, Anna M. Colacicco, Cristiano Capurso, Angelo Del Parigi, Richard J. Caselli, Vincenza Frisardi, Pierluigi Scapicchio, Roberta Chiloiro, Emanuele Scafato, Claudia Gandin, Gianluigi Vendemiale, Antonio Capurso, Vincenzo Solfrizzi; for the Italian Longitudinal Study on Aging Working Group
Temporal Relationship between Depressive Symptoms and Cognitive Impairment: The Italian Longitudinal Study on Aging
Abstract: The temporal relationship between depression and cognitive decline has not been extensively investigated in prospective population-based studies, and most of these have only looked in one direction. We estimated the bidirectional temporal relationship between depressive symptoms and cognitive function in older subjects, excluding subjects with a clinical diagnosis of dementia or mild cognitive impairment (MCI). In a total of 2,963 individuals from the Italian Longitudinal Study on Aging, depressive symptoms, global cognitive function, and episodic memory were measured. Dementia, Alzheimer’s disease, vascular dementia, and MCI were classified using current clinical criteria. Depressive symptoms at baseline were associated with an accelerated global cognitive function decline and an accelerated rate of episodic memory delayed recall decline in a 3.5-year follow-up. Finally, an accelerated increase with time of depressive symptoms during the same follow-up period was not associated with global cognitive function and episodic memory (immediate and delayed recall). In older subjects non-cognitively impaired, depressive symptoms at baseline predicted change over time of global cognitive decline and episodic memory delayed recall. Global cognitive function and episodic memory at baseline were not associated with the course of depressive symptoms during the follow-up.
Martin Cente, Peter Filipcik, Stanislava Mandakova, Norbert Zilka, Gabriela Krajciova, Michal Novak
Expression of a Truncated Human Tau Protein Induces Aqueous-Phase Free Radicals in a Rat Model of Tauopathy: Implications for Targeted Antioxidative Therapy
Abstract: Oxidative stress has been implicated in the pathogenesis of many neurodegenerative diseases including Alzheimer’s disease (AD). We investigated the effect of a truncated form of the human tau protein in the neurons of transgenic rats. Using electron paramagnetic resonance we observed significantly increased accumulation of ascorbyl free radicals in brains of transgenic animals (up to 1.5-fold increase; P<0.01). Examination of an in vitro model of cultured rat corticohippocampal neurons revealed that even relatively low level expression of human truncated tau protein (equal to 50% of endogenous tau) induced oxidative stress that resulted in increased depolarization of mitochondria (~1.2-fold above control, P<0.01) and increases in reactive oxygen species (~1.3-fold above control, P<0.001). We show that mitochondrial damage-associated oxidative stress is an early event in neurodegeneration. Furthermore, using two common antioxidants (vitamin C and E), we were able significantly eliminate tau-induced elevation of reactive oxygen species. Interestingly, vitamin C was found to be selective in the scavenging activity, suggesting that expression of truncated tau protein preferentially leads to increases in aqueous phase oxidants and free radicals such as hydrogen peroxide and hydroxyl and superoxide radicals. Our results suggest that antioxidant strategies designed to treat AD should focus on elimination of aqueous phase oxidants and free radicals.
M. Cristina Polidori, Domenico Praticó, Francesca Mangialasche, Elena Mariani, Olivier Aust, Timur Anlasik, Ni Mang, Ludger Pientka, Wilhelm Stahl, Helmut Sies, Patrizia Mecocci, Gereon Nelles
High Fruit and Vegetable Intake is Positively Correlated with Antioxidant Status and Cognitive Performance in Healthy Subjects
Abstract: A higher daily intake of fruits and vegetables in healthy elderly is associated with an improved antioxidant status in comparison to subjects consuming diets poor in fruits and vegetables, but the impact on cognitive performance is unclear. Healthy community dwellers (45 to 102 years old, n=193) underwent cognitive testing and blood withdrawal for the measurement of antioxidant micronutrients and biomarkers of oxidative stress as well as administration of a food frequency questionnaire to assess the daily intake of fruits and vegetables (high intake HI, low intake LI). Ninety-four subjects of the HI group had significantly higher cognitive test scores, higher levels of carotenoids, α- and γ-tocopherol as well as lower levels of F2α isoprostanes than the 99 subjects of the LI group. Cognitive scores were directly correlated with blood levels of α-tocopherol and lycopene and negatively correlated with F2α isoprostanes and protein carbonyls. The results were independent of age, gender, body mass index, education, total cholesterol, LDL- and HDL-cholesterol, triglycerides, and albumin. Healthy subjects of any age with a high daily intake of fruits and vegetables have higher antioxidant levels, lower levels of biomarkers of oxidative stress, and better cognitive performance than healthy subjects of any age consuming low amounts of fruits and vegetables. Modification of nutritional habits aimed at increasing intake of fruits and vegetables should be encouraged to lower prevalence of cognitive impairment in later life.
Xin-Wen Zhou, Bengt Winblad, Zhizhong Guan, Jin-Jing Pei
Interactions Between Glycogen Synthase Kinase 3β, Protein Kinase B, and Protein Phosphatase 2A in Tau Phosphorylation in Mouse N2a Neuroblastoma Cells
Abstract: In this study, we investigated how tau phosphorylation is regulated by protein kinase glycogen synthase kinase 3β (GSK3β), protein kinase B (PKB), and protein phosphatase 2A (PP2A) in mouse N2a neuroblastoma cells. Results showed that GSK3β overexpression significantly increased PKB phosphorylation at the S473 site but not the T308 site. Neither GSK3β nor PKB overexpression could reduce the PP2AC phosphorylation at the Y307 site. In contrast, either PKB or GSK3β knockdown could increase PP2A phosphorylation at the Y307 site. PP2AC knockdown increased GSK3β phosphorylation at the S9 site but not at the Y216 site, and PKB phosphorylation at the T308 site but not at the S473 site. Tau phosphorylation at the S396 site was increased by GSK3β or PKB overexpression. Tau phosphorylation at the S214 site was only induced by PKB overexpression in the study. While GSK3β knockdown decreased tau phosphorylation at the S396 site, PKB knockdown increased tau phosphorylation at both the S396 and S214 sites. PP2AC knockdown decreased tau phosphorylation at the S396 and S214 sites. These findings suggested that tau phosphorylation at the S396 and S214 sites is differentially regulated by GSK3β, PKB, and PP2A in N2a cells. The end phosphorylation state of tau is possibly caused by the synergic action of the three enzymes.
Meeting Report from the Alzheimer Research Forum
Keystone Symposium, Neurodegenerative Diseases: New Molecular Mechanisms, 17-22 February 2009
Book Review: The Caregiver: A Life with Alzheimer's, by Aaron Alterra, IRL Press/Cornell Paperbacks, Ithaca, NY, 2008, 213 pp. Reviewed by Diana Morris.