JAD - Volume 19, Number 4

Volume 19, Number 4, March 2010

Pages 1101-1122
Review Article
Kirk R. Daffner
Promoting Successful Cognitive Aging: A Comprehensive Review
Abstract: Promoting successful cognitive aging is a topic of major importance to individuals and the field of public health. This review presents a coherent framework not only for evaluating factors, protective activities, and enhancing agents that have already been proposed, but also ones that will be put forward in the future. The promotion of successful cognitive aging involves the dual goals of preventing loss of information processing capacity and cognitive reserve, and enhancing brain capacity and cognitive reserve. Four major lines of evidence are available for evaluating whether a proposed factor promotes successful cognitive aging: 1) epidemiologic/cohort studies; 2) animal/basic science studies; 3) human “proof-of-concept” studies; and 4) human intervention studies. Each line of evidence has advantages and limitations that will be discussed. Through illustrative examples, we trace the ways in which each method informs us about the potential value of several proposed factors. Currently, lines of converging evidence allow the strongest case to be made for physical and cognitively stimulating activities. Although epidemiological data seem to favor the use of statins to lower the risk of dementia, more definitive recommendations await further randomized controlled studies. There is presently no clear evidence that antioxidants or Ginkgo biloba promote successful cognitive aging. The impact of resveratrol, fish oil, and a long list of other proposed agents needs to be determined. Clinicians remain well-positioned to identify and aggressively treat vascular risk factors, diabetes, sleep disorders, and other conditions that may reduce brain capacity, and to encourage activities that can build cognitive reserve.

Paiges 1123-1139
Review Article
Balenahalli N. Ramesh, T.S. Sathyanarayana Rao, Annamalai Prakasam, Kumar Sambamurti, K.S. Jagannatha Rao
Neuronutrition and Alzheimer’s Disease Abstract: Alzheimer’s disease (AD) is a complex neurological disorder resulting from both genetic and environmental factors with the latter being particularly important for the sporadic form of the disease. As such, diets rich in saturated fatty acids and alcohol, and deficient in antioxidants and vitamins appear to promote the onset of the disease, while diets rich in unsaturated fatty acids, vitamins, antioxidants, and wine likely suppress its onset. In addition, evidence suggests that diets rich in polyphenols and some spices suppress the onset of AD by scavenging free radicals and preventing oxidative damage. Metal ions are known to catalyze the production of free radicals and induce mental retardation or dementia, and several studies have also identified metals such as Pb, Fe, Al, Cu, and Zn in AD pathogenesis. While specific metal chelators have been tested for therapy, they have not been very successful, probably due to their late administration, i.e., after brain damage has been triggered. Since several dietary polyphenols are known to chelate metals, their routine use may also be protective against the onset of AD. In this review, we summarize beneficial dietary techniques in the fight against AD.

Pages 1141-1142
Letter
Liang Shen and Hong-Fang Ji
Insights into the Disappointing Clinical Trials of Antioxidants in Neurodegenerative Diseases

Pages 1143-1148
Short Communication
Cristoforo Comi, Miryam Carecchio, Annalisa Chiocchetti, Stefania Nicola, Daniela Galimberti, Chiara Fenoglio, Giuseppe Cappellano, Francesco Monaco, Elio Scarpini, Umberto Dianzani
Osteopontin is Increased in the Cerebrospinal Fluid of Patients with Alzheimer’s Disease and Its Levels Correlate with Cognitive Decline
Abstract: Inflammation is believed to play a role in Alzheimer’s disease (AD). Osteopontin (OPN) is a molecule involved in macrophage recruitment and activation and implicated in neurodegeneration. In order to elucidate the role of OPN in AD, we evaluated its levels in serum and cerebrospinal fluid (CSF) of 67 AD patients, 46 frontotemporal dementia (FTD) patients, and 69 controls. We found that OPN levels: i) are significantly increased in the CSF of AD patients; ii) correlate with MMSE score; and iii) are higher in the early disease phases (<2 years). These findings support a role of OPN in AD pathogenesis.

Pages 1149-1153
Short Communication
Brian T. VanFossen, G. Stennis Watson, Laura D. Baker, Kristoffer W. Rhoads, Brenna A. Cholerton, Mark A. Reger, Stephen R. Plymate, Gerald Schellenberg, Suzanne Craft
Statin Users Without an APOE-ε4 Allele have Increased Insulin Resistance
Abstract: The present study examined the relationships among statin use, APOE genotype, and insulin resistance as measured by the homeostasis model assessment of insulin resistance (HOMA-IR) in healthy older adults. APOE ε4- (i.e., not having an ε4 allele) statin users had higher HOMA-IR values compared with ε4+/statin users (p = 0.0169), and with non-users who were ε4- (p = 0.0003) or ε4+ (p = 0.0006). These results suggest that statin use may modulate insulin levels for individuals without an APOE ε4 allele.

Pages 1155-1167
Steven J. Greco*, Kathryn J. Bryan*, Sraboni Sarkar, Xiongwei Zhu, Mark A. Smith, J. Wesson Ashford, Jane M. Johnston, Nikolaos Tezapsidis, Gemma Casadesus (Handling Editor: Jesus Avila) *Contributed equally
Chronic Leptin Supplementation Ameliorates Pathology and Improves Cognitive Performance in a Transgenic Mouse Model of Alzheimer’s Disease
Abstract: We have previously reported anti-amyloidogenic effects of leptin using in vitro and in vivo models and, more recently, demonstrated the ability of leptin to reduce tau phosphorylation in neuronal cells. The present study examined the efficacy of leptin in ameliorating the Alzheimer’s disease (AD)-like pathology in 6-month old CRND8 transgenic mice (TgCRND8) following 8 weeks of treatment. Leptin-treated transgenic mice showed significantly reduced levels of amyloid-β (Aβ)1-40 in both brain extracts (52% reduction, p=0.047) and serum (55% reduction, p=0.049), as detected by ELISA, and significant reduction in amyloid burden (47% reduction, p=0.041) in the hippocampus, as detected by immunocytochemistry. The decrease in the levels of Aβ in the brain correlated with a decrease in the levels of C99 C-terminal fragments of the amyloid-β protein precursor, consistent with a role for β-secretase in mediating the effect of leptin. In addition, leptin-treated TgCRND8 mice had significantly lower levels of phosphorylated tau, as detected by AT8 and anti-tau-Ser396 antibodies. Importantly, after 4 or 8 weeks of treatment, there was no significant increase in the levels of C-reactive protein, tumor necrosis factor-α, and cortisol in the plasma of leptin-treated TgCRND8 animals compared to saline-treated controls, indicating no inflammatory reaction. These biochemical and pathological changes were correlated with behavioral improvements, as early as after 4 weeks of treatment, as recorded by a novel object recognition test and particularly the contextual and cued fear conditioning test after 8 weeks of treatment. Leptin-treated TgCRND8 animals significantly outperformed saline-treated littermates in these behavioral tests. These findings solidly demonstrate the potential for leptin as a disease modifying therapeutic in transgenic animals of AD, driving optimism for its safety and efficacy in humans.

Pages 1169-1175
Karolien Bettens, Nathalie Brouwers, Helen Van Miegroet, Ana Gil, Sebastiaan Engelborghs, Peter P. De Deyn, Rik Vandenberghe, Christine Van Broeckhoven, Kristel Sleegers (Handling Associate Editor: Eliecer Coto)
Follow-Up Study of Susceptibility Loci for Alzheimer’s Disease and Onset Age Identified by Genome-Wide Association
Abstract: Replication of genetic association findings in independent studies represents an important validation tool in the search for susceptibility genes for complex diseases such as Alzheimer’s disease (AD). In a well-characterized memory-clinic based study comprising 1078 unrelated AD patients and 652 control individuals, we set out to replicate previously reported genome-wide association of four novel risk SNPs with AD and onset age, with first stage p-values ranging from 0.001 to 0.000004. We obtained evidence for association between rs179943, an intronic SNP in ATXN1 at 6p22.3, and affection status (OR = 0.63 (95% CI = 0.44-0.90; nominal p = 0.01)). Overall, our data provided independent support for association of at least one chromosomal locus with AD and warranted a more in-depth investigation of these regions for possible underlying functional variants.

Pages 1177-1183
Joanna Suszynska, Joanna Tisonczyk, Hyoung-gon Lee, Mark A. Smith, Hieronim Jakubowski (Handling Editor: Jesus Avila; Handling Associate Editor: Sudha Seshadri)
Reduced Homocysteine-Thiolactonase Activity in Alzheimer’s Disease
Abstract: Elevated plasma homocysteine (Hcy) is a risk factor for Alzheimer’s disease (AD). Bleomycin hydrolase (BLH), a thiol-dependent enzyme that has Hcy-thiolactonase (HTase) and aminopeptidease (APase) activities, has also been implicated in Alzheimer’s disease (AD). In order to examine its role in AD, BLH activities were measured in postmortem brain tissue from twelve AD patients and twelve control patients who died from non-neurological causes. We found that HTase and APase activities in human brain extracts were strongly correlated and sensitive to the thiol reagent iodoacetamide, indicating that they are associated with BLH. Both activities were significantly decreased in brain tissue extracts from AD patients relative to controls (7.6±4.2 vs. 13.5±5.5 units, p=0.003 for HTase, and 3.82±1.27 vs. 5.33±1.68 units, p=0.010 for APase). HTase and APase activities were positively correlated with N-linked protein Hcy, but not with tHcy, in AD and control brains. Levels of brain total Hcy and N-linked protein Hcy did not differ between AD cases and controls. These results suggest that diminished functional BLH activity could contribute to the pathology of AD.

Pages 1185-1197
Ianessa A. Humbert, Donald G. McLaren, Kris Kosmatka, Michele Fitzgerald, Sterling Johnson, Eva Porcaro, Stephanie Kays, Eno-Obong Umoh, JoAnne Robbins
Early Deficits in Cortical Control of Swallowing in Alzheimer’s Disease
Abstract: The goal of this study was to determine whether functional changes in cortical control of swallowing are evident in early Alzheimer’s disease (AD), before dysphagia (swallowing impairment) is evident. Cortical function was compared between an early AD group and a group of age-matched controls during swallowing. Swallowing oropharyngeal biomechanics examined from videofluoroscopic recordings were also obtained to more comprehensively characterize changes in swallowing associated with early AD. Our neuroimaging results show that the AD group had significantly lower Blood-Oxygen-Level-Dependent (BOLD) response in many cortical areas that are traditionally involved in normal swallowing (i.e., pre and postcentral gyri, Rolandic and frontal opercula). There were no regions where the AD group showed more brain activity than the healthy controls during swallowing, and only 13% of all active voxels were unique to the AD group, even at this early stage. This suggests that the AD group is not recruiting new regions, nor are they compensating within regions that are active during swallowing. In videofluoroscopic measures, the AD group had significantly reduced hyo-laryngeal elevation than the controls. Although, swallowing impairment is usually noted in the late stages of AD, changes in cortical control of swallowing may begin long before dysphagia becomes apparent.

Pages 1199-1203
Rüdiger Zimmermann, Georg Beck, Sabine Knispel, Juan Manuel Maler, Markus Weih, Jens Wiltfang, Johannes Kornhuber, Piotr Lewczuk (Handling Associate Editor: Henrik Zetterberg)
Intrathecal IgG Synthesis in Patients with Alterations in the Neurochemical Dementia Diagnostics
Abstract: Neurochemical Dementia Diagnostics (NDD), i.e., analysis of the cerebrospinal fluid (CSF) concentrations of amyloid-β peptides and tau/phospho-tau proteins plays important role in the diagnosis of neurodegeneration and dementias. Several studies show alterations of these biomarkers in Alzheimer's disease (AD), however, only a few reports address alterations of other CSF biomarkers (albumin and immunoglobulins' quotients, cell count, lactate concentration, etc.) in the pathophysiology and diagnostic procedures of dementias. Therefore, we analyzed these biomarkers in patients diagnosed for dementia syndromes and carefully characterized with the state-of-the-art NDD analysis: Aβ1-42, Aβx-42, Aβx-42/x-40 ratio, tau, and ptau181. We found intrathecal IgG synthesis in 5 out of 112 patients showing alterations of the NDD biomarkers, and in four out of these five subjects, we could not find any satisfying reason for the intrathecal humoral response. In 25.9% of the patients with altered NDD biomarkers, we found an increased albumin quotient indicating a dysfunction of the blood-CSF barrier; however a similar figure of 25.2% was found in the group of patients without alterations in the NDD. Our findings suggest that at least some patients with increased CSF concentrations of tau/ptau proteins and decreased concentrations of Aβ42 peptides show simultaneously CSF alterations found otherwise in neuroinflammatory processes. This, in turn, suggests that extended diagnosis should be performed in patients with "isolated" alterations of NDD biomarkers or intrathecal immunoglobulin synthesis.

Pages 1205-1219
Yazhou Li, Kara B. Duffy, Mary Ann Ottinger, Balmiki Ray, Jason A. Bailey, Harold W. Holloway, David Tweedie, TracyAnn Perry, Mark P. Mattson, Dimitrios Kapogiannis, Kumar Sambamurti, Debomoy K. Lahiri, Nigel H. Greig
GLP-1 Receptor Stimulation Reduces Amyloid-β Peptide Accumulation and Cytotoxicity in Cellular and Animal Models of Alzheimer’s Disease
Abstract: Type 2 (T2) diabetes mellitus (DM) has been associated with an increased incidence of neurodegenerative disorders, including Alzheimer’s disease (AD). Several pathological features are shared between diabetes and AD, including dysfunctional insulin signaling and a dysregulation of glucose metabolism. It has therefore been suggested that not only may the two conditions share specific molecular mechanisms but also that agents with proven efficacy in one may be useful against the other. Hence, the present study characterized the effects of a clinically approved long-acting analogue, exendin-4 (Ex-4), of the endogenous insulin releasing incretin, glucagon-like peptide-1 (GLP-1), on stress-induced toxicity in neuronal cultures and on amyloid-β protein (Aβ) and tau levels in triple transgenic AD (3xTg-AD) mice with and without streptozocin (STZ)-induced diabetes. Ex-4 ameliorated the toxicity of Aβ and oxidative challenge in primary neuronal cultures and human SH-SY5Y cells in a concentration-dependent manner. When 11 to 12.5 month old female 3xTg AD mice were challenged with STZ or saline, and thereafter treated with a continuous subcutaneous infusion of Ex-4 or vehicle, Ex-4 ameliorated the diabetic effects of STZ in 3xTg-AD mice, elevating plasma insulin and lowering both plasma glucose and hemoglobin A1c (HbA1c) levels. Furthermore, brain levels of Aβ protein precursor and Aβ, which were elevated in STZ 3xTg-AD mice, were significantly reduced in Ex-4 treated mice. Brain tau levels were unaffected following STZ challenge, but showed a trend toward elevation that was absent following Ex-4 treatment. Together, these results suggest a potential value of Ex-4 in AD, particularly when associated with T2DM or glucose intolerance.

Pages 1221-1229
Wei Qian, Jianhua Shi, Xiaomin Yin, Khalid Iqbal, Inge Grundke-Iqbal, Cheng-Xin Gong, Fei Liu (Handling Associate Editor: Xuemin Xu)
PP2A Regulates Tau Phosphorylation Directly and also Indirectly via Activating GSK-3β
Abstract: Abnormal hyperphosphorylation of tau appears to be crucial in neurofibrillary degeneration in Alzheimer’s disease (AD). Previous studies suggest that a down-regulation of protein phosphatase 2A (PP2A), the major tau phosphatase in human brain, contributes to tau hyperphosphorylation in AD. However, the effects of PP2A down-regulation on site-specific tau hyperphosphorylation have not been well understood. In the present study, we showed that PP2A dephosphorylated tau at several phosphorylation sites with different efficiencies. Among the sites studies, Thr205, Thr212, Ser214, and Ser262 were the most favorable sites, and Ser199 and Ser404 were the least favorable sites for PP2A in vitro. Inhibition of PP2A with okadaic acid in metabolically active rat brain slices caused inhibition of glycogen synthase kinase-3β (GSK-3β) via an increase in its phosphorylation at Ser9. GSK-3β phosphorylated tau at many sites, with Ser199, Thr205, and Ser396 being the most favorable sites in cells. The overall alterations in tau phosphorylation induced by PP2A inhibition were the result of combined effects of both reduced tau dephosphorylation due to PP2A inhibition directly and reduced phosphorylation by GSK-3β due to its inhibition. Because the impacts of tau phosphorylation on its biological activity and on neurofibrillary degeneration are site-specific, this study provides a new insight into the role of PP2A down-regulation in neurofibrillary degeneration in AD.

Pages 1231-1241
Soon-Tae Lee, Kon Chu, Keun-Hwa Jung, Daejong Jeon, Jae-Joon Ban, Jin-Hee Kim, Sang Kun Lee, Manho Kim, Jae-Kyu Roh
Dysfunctional Characteristics of Circulating Angiogenic Cells in Alzheimer’s Disease
Abstract: Vascular senescence contributes to the progression of Alzheimer’s disease (AD), and circulating angiogenic cells (CACs) participate in the maintenance of the endothelium. As a step toward developing endothelial regeneration therapies for AD, we investigated the functional characteristics of CACs in AD patients. We enrolled AD patients and non-demented risk factor control subjects after matching for age, gender, and Framingham risk score. CACs were cultured from peripheral blood samples taken from each subjects and used for various ex vivo assays. CACs from AD patients showed reduced chemotaxis, increased senescence, reduced paracrine angiogenic activity, and altered gene expression patterns compared to CACs from risk factor controls. Addition of a high concentration of amyloid-β (Aβ)1-42 (200, 2000 ng/mL) to the CAC culture reduced CAC counts and endothelial nitric oxide synthase/Akt phosphorylation and induced apoptosis. However, a lower concentration of Aβ1-42 (2, 20 ng/mL) failed to reduce the CAC counts. CACs from AD patients were more susceptible to the cytotoxic effect of Aβ1-42 than CACs from risk factor controls. In summary, AD patients were found to have intrinsic dysfunctions of CACs, which provides an extended concept of vascular endothelial pathogenesis in AD.

Pages 1241-1243
Commentary on Lee et al.
Martin J. Sadowski
Circulating Angiogenic Cells and Alzheimer's Disease: Contribution of the Bone Marrow to Pathogenesis of the Disease

Pages 1245-1257
Juan Perucho, Isabel Rubio, Maria J. Casarejos, Ana Gomez, Jose A. Rodriguez-Navarro, Rosa M. Solano, Justo Garcia de Yébenes, Maria A. Mena
Anesthesia with Isoflurane Increases Behavioral Abnormalities and Amyloid Pathology in Mice Models of Alzheimer’s Disease
Abstract: There is a great interest in the environmental and genetic factors which modify the risk of Alzheimer’s disease since the manipulation of these factors could help to change the prevalence and natural course of this disease. Among the first group, anesthesia and surgery have been considered as risk enhancers, based mostly on “in vitro” experiments and epidemiological studies. We have investigated the effects of repetitive anesthesia, twice a week, for 3 months, from 7 to 10 months of age, with isoflurane on survival, behavior, apoptosis in hippocampal cells, amyloid-β (Aβ) peptide and tau patterns, chaperones and autophagy in WT and AβPPswe mice. We have found that AβPPswe mice treated with isoflurane have increased mortality, less responsiveness after anesthesia, long lasting reduced exploratory behavior, increased number of TUNEL+ apoptotic cells, and increased ratio of pro-apoptotic proteins in hippocampus, reduced astroglial and increased microglial responses, increased Aβ aggregates and high molecular weight peptides, abnormal chaperone responses and reduced autophagy. These effects were not present in WT mice, suggesting that the deleterious impact of isoflurane on behavior, survival, neuronal cell death, and processing of proteins involved in neurodegeneration is restricted to subjects with special susceptibility but does not affect normal subjects.

Supplementary Data for Perucho et al. article (PDF)

Pages 1259-1260
Commentary on Perucho et al.
Maryellen F. Eckenhoff, Roderic G. Eckenhoff
A Smoking Gun but Still No Victim

Page 1261
Response letter from Perucho et al.

Pages 1263-1272
Pedro Paulo de Magalhães Oliveira Jr., Ricardo Nitrini, Geraldo Busatto, Carlos Buchpiguel, João Ricardo Sato, Edson Amaro Jr.
Use of SVM Methods with Surface-Based Cortical and Volumetric Subcortical Measurements to Detect Alzheimer’s Disease
Abstract: Here, we examine morphological changes in cortical thickness of patients with Alzheimer’s disease (AD) using image analysis algorithms for brain structure segmentation and study automatic classification of AD patients using cortical and volumetric data. Cortical thickness of AD patients (n=14) was measured using MRI cortical surface-based analysis and compared with healthy subjects (n=20). Data was analyzed using an automated algorithm for tissue segmentation and classification. A Support Vector Machine (SVM) was applied over the volumetric measurements of subcortical and cortical structures to separate AD patients from controls. The group analysis showed cortical thickness reduction in the superior temporal lobe, parahippocampal gyrus, and enthorhinal cortex in both hemispheres. We also found cortical thinning in the isthmus of cingulate gyrus and middle temporal gyrus at the right hemisphere, as well as a reduction of the cortical mantle in areas previously shown to be associated with AD. We also confirmed that automatic classification algorithms (SVM) could be helpful to distinguish AD patients from healthy controls. Moreover, the same areas implicated in the pathogenesis of AD were the main parameters driving the classification algorithm. While the patient sample used in this study was relatively small, we expect that using a database of regional volumes derived from MRI scans of a large number of subjects will increase the SVM power of AD patient identification.

Pages 1273-1282
Andrea Cherubini, Patrice Péran, Ilaria Spoletini, Margherita Di Paola, Fulvia Di Iulio, Gisela Elizabeth Hagberg, Giuseppe Sancesario, Walter Gianni, Paola Bossù, Carlo Caltagirone, Umberto Sabatini, Gianfranco Spalletta
Combined Volumetry and DTI in Subcortical Structures of Mild Cognitive Impairment and Alzheimer’s Disease Patients
Abstract: The aim of this work was to investigate the hypothesis that multimodal MRI is able to detect the progressive disruption of volume and microstructure of subcortical structures in patients with amnestic mild cognitive impairment (a-MCI) and mild Alzheimer’s disease (AD) in comparison with healthy controls (CTRL). We combined volumetric and diffusion tensor imaging (DTI) techniques in a cross-sectional study including 30 a-MCI, 30 AD patients, and 30 age-matched CTRL. We employed a fully automated model-based segmentation algorithm on 3 Tesla MRI anatomical images and accurate coregistration of DTI to anatomical images to extract regional values of DTI parameters. The hippocampi significantly and progressively decreased in volume from CTRL through MCI to AD. Both the thalami showed a progressive and significant decrease in volume from CTRL to AD. Mean diffusivity (MD) values increased progressively across the three groups in the bilateral hippocampus, amygdala, and in the right caudate. No differences in fractional anisotropy (FA) values were found. Two distinct but overlapping patterns of progression of structural (i.e., atrophy) and microstructural (i.e., MD increase) damage were observed. Particularly, the pattern of atrophy was mirrored by the increasing value of the averaged MD, which provided a further indicator of subtle tissue disruption in the hippocampal structure in mild AD patients. Combining different MRI modalities can allow identifying sensitive indicators of the subtle pathogenic mechanisms that occur in subcortical areas of AD patients.

Pages 1283-1294
Xiao-Yu Xin, Jian-Qing Ding, Sheng-Di Chen
Apolipoprotein E Promoter Polymorphisms and Risk of Alzheimer’s Disease: Evidence From Meta-Analysis
Abstract: Apolipoprotein E (APOE) promoter polymorphisms have long been linked to Alzheimer disease (AD) susceptibility, although the established data remains controversial. Using meta-analysis, our study aimed to clarify the nature of the genetic risks contributed by the three polymorphisms for developing AD. Medline, Embase, and Alzgene search identified 40 studies with 9,662 cases and 9.696 controls. Both -491A/T polymorphism (AA vs AT + TT: OR = 1.49, 95% CI = 1.29–1.72) and -219T/G polymorphism (TT vs TG + GG: OR = 1.30, 95% CI = 1.10–1.55) showed a significant association with AD susceptibility; however, significant association was not identified in the analysis for -427T/C polymorphism (TT vs TC + CC: OR = 1.03, 95% CI = 0.82–1.30). Among the APOE ε4 carriers, the -491A homozygotes were at higher risk to develop AD compared with the -491T carriers (OR = 1.42, 95% CI = 1.15–1.76). For subjects carrying the -491AA genotype, the presence of the APOE ε4 alleleincreased the risk of AD 4.37-fold (95% CI = 3.43–5.56). Subgroup analysis restricted to the late-onset or the Caucasian individuals revealed a similar association as that identified without restriction regarding -491A/T polymorphism. Our results confirm a significant but modest association between APOE promoter -491A/T and -219T/G polymorphisms and AD susceptibility.

Pages 1295-1301
Tanja Maria Michel, Wieland Gsell, Ludwig Käsbauer, Thomas Tatschner, Abigail Jane Sheldrick, Irene Neuner, Frank Schneider, Edna Grünblatt, Peter Riederer
Increased Activity of Mitochondrial Aldehyde Dehydrogenase (ALDH) in the Putamen of Individuals with Alzheimer’s Disease: A Human Postmortem Study
Abstract: For decades, it has been acknowledged that oxidative stress due to free radical species contributes to the pathophysiology of aging and neurodegenerative diseases. Aldehyde dehydrogenases (ALDH) not only transform aldehydes to acids but also act as antioxidant enzymes. However, little is known about the implications of the enzymatic family of ALDH in the context of neurodegenerative processes such as Alzheimer’s disease (AD). We therefore examined the enzymatic activity of the mitochondrial ALDH-isoform in different regions of the postmortem brain tissue isolated from patients with AD and controls. We found that the mitochondrial ALDH activity was significantly increased only in the putamen of patients suffering from AD compared to controls. This is of particular interest since mediators of oxidative stress, such as iron, are increased in the putamen of patients with AD. This study adds to the body of evidence that suggests that oxidative stress as well as aldehyde toxicity play a role in AD.

Pages 1303-1315
Jaume del Valle, Joaquim Duran-Vilaregut, Gemma Manich, Gemma Casadesús, Mark A. Smith, Antoni Camins, Mercè Pallàs, Carme Pelegrí*, Jordi Vilaplana* (Handling Editor: Jesus Avila) *Contributed equally to this study
Early Amyloid Accumulation in the Hippocampus of SAMP8 Mice
Abstract: Late-onset Alzheimer’s disease (AD) is the most common form of AD appearing after 65 years of age. To date, however, there are no non-genetically manipulated rodent models that develop a similar sporadic onset of AD with age-related amyloid-β (Aβ) deposition. Although the senescence accelerated mouse prone 8 (SAMP8) mice have been proposed as a model of AD, the presence of Aβ deposits remains controversial. In this study, we describe the time course of Aβ deposition in SAMP8 mice and in the control strains SAMR1 and ICR-CD1 mice. From as early as 6 months onward, SAMP8 mice show early Aβ deposition in the hippocampus that increase in number and extent with age. These deposits are constituted by clustered granules that comprise Aβ42, Aβ40, and other Aβ protein precursor fragments. By marked contrast, control mice show only low numbers of Aβ clusters that do not develop until 15 months of age. The demonstration that SAMP8 mice present amyloid deposits in their hippocampus makes this animal model a useful tool to understand the mechanisms involved in the formation of Aβ deposition in AD.

Supplementary Video for del Valle et al. article (.mpg)

Pages 1317-1322
Claudia Cantoni, Chiara Fenoglio, Francesca Cortini, Eliana Venturelli, Chiara Villa, Francesca Clerici, Alessandra Marcone, Luisa Benussi, Roberta Ghidoni, Salvatore Gallone, Diego Scalabrini, Massimo Franceschi, Stefano Cappa, Giuliano Binetti, Claudio Mariani, Innocenzo Rainero, Maria Teresa Giordana, Nereo Bresolin, Elio Scarpini, Daniela Galimberti (Handling Associate Editor: Gabriella Marcon)
FUS/TLS GeneticVariability in Sporadic Frontotemporal Lobar Degeneration
Abstract: Two hundred and fifty one Italian patients with sporadic frontotemporal lobar degeneration (FTLD) and 259 age-matched controls were tested for association with the tagging single nucleotide polymorphisms (SNPs) rs741810 and rs1052352 in the fused in sarcoma/translated in liposarcoma gene (FUS/TLS). Only patients negative for GRN mutations were included. Considering each SNP alone, no differences in either allelic or genotypic frequencies between patients and controls were found (P>0.05), even stratifying according to gender or the presence of concomitant motor neuron disease. Haplotype analysis failed to detect haplotypes associated with FTLD. According to these results, FUS/TLS is not a susceptibility factor for the development of sporadic FTLD.

Pages 1323-1329
Massimo Innocenti, Emanuele Salvietti, Martina Guidotti, Angela Casini, Silvano Bellandi, Maria Luisa Foresti, Chiara Gabbiani, Andrea Pozzi, Paolo Zatta, Luigi Messori
Trace Copper(II) or Zinc(II) Ions Drastically Modify the Aggregation Behavior of Amyloid-β1-42: An AFM Study
Abstract: Formation of amyloid-β (Aβ)1-42 amyloid fibrils, a characteristic feature of Alzheimer’s disease (AD), was monitored in situ through atomic force microscopy (AFM). Well-structured amyloid fibrils slowly formed in solution within 24 hours for which high quality AFM pictures could be obtained. Remarkably, addition of either copper(II) or zinc(II) ions to the incubation medium, even at extremely low molar ratios, dramatically changed the Aβ1-42 aggregation profile and prevented fibril formation. Aggregates of different morphology appeared in accordance with previous observations: small globular aggregates upon addition of zinc; ill-structured micro-aggregates in the case of copper. The implications of these AFM results are discussed in the frame of current AD metallobiology.

Pages 1331-1336
Gene L. Bowman, Jackilen Shannon, Balz Frei, Jeffrey A. Kaye, Joseph F. Quinn
Uric Acid as a Central Nervous System Antioxidant
Abstract: Oxidative damage is a consistent finding in a number of central nervous system (CNS) disorders. Several lines of evidence suggest that plasma uric acid (UA), a potent hydrophilic antioxidant, may modulate outcomes in neurologic disease, but little attention has been paid to CNS levels of UA. Our objective was to test the hypotheses that cerebrospinal fluid (CSF) UA is determined by plasma UA, modified by blood-brain barrier (BBB) integrity, and associated with rate of cognitive decline in Alzheimer’s disease (AD). Also, since UA and ascorbic acid may act as antioxidants for one another, we also explored a potential interaction between them in the brain. Thirty-two patients with mild to moderate AD participated in a longitudinal biomarker study for one year involving standardized clinical assessments. CSF and blood were collected at baseline for UA, ascorbic acid, and albumin. Cognitive measures were collected at baseline and again one year later. CSF UA was independent of age, gender, and AD severity. CSF and plasma UA were positively correlated (r = 0.669, p = 0.001) and BBB impairment was associated with higher CSF levels of UA (p = 0.028). Neither plasma nor CSF UA reached significant association with rates of cognitive decline over 1 year. CSF UA and CSF ascorbic acid were positively correlated (r = 0.388, p = 0.001). The hypothesis that CSF UA is determined by plasma UA and BBB integrity is supported, as is the hypothesis that UA and ascorbic acid are associated in CSF but not plasma. Adequately powered prospective studies would help assess any role for UA in primary and secondary prevention of AD.

Pages 1337-1338
Commentary on Bowman et al.
Sergei Spitsin, Hilary Koprowski
Role of uric acid in Alzheimer�s disease

Pages 1339-1357
Jana Doehner, Amrita Madhusudan, Uwe Konietzko, Jean-Marc Fritschy, Irene Knuesel
Co-Localization of Reelin and Proteolytic AβPP Fragments in Hippocampal Plaques in Aged Wild-Type Mice
Abstract: Reelin is a large extracellular glycoprotein required for proper neuronal positioning during development. In the adult brain, Reelin plays a crucial modulatory role in the induction of synaptic plasticity and successful formation of long-term memory. Recently, alterations in Reelin-mediated signaling have been suggested to contribute to neuronal dysfunction associated with Alzheimer’s disease (AD). We previously reported that aging in several species is characterized by a decline in Reelin-expressing interneurons and concomitant accumulation in amyloid-like plaques in the hippocampal formation, significantly correlating with cognitive impairments. In transgenic AD mice, we detected Reelin in oligomeric amyloid-β aggregates and in tight association with fibrillary plaques. Here, we used immunohistochemistry at the light and electron microscopy level to characterize further the morphology, temporal and spatial progression, as well as the potential of Reelin-positive plaques to sequester murine amyloid-β peptides in wild-type mice across aging. We developed a new immunohistochemical protocol involving a stringent protease pretreatment which markedly enhanced Reelin-immunoreactivity and allowed specific detection of variable shapes of murine anti-amyloid-β protein precursor-immunoreactivity in plaques in the hippocampus, likely representing N-terminal fragments and amyloid-β species. Ultrastructural investigations confirmed the presence of Reelin in extracellular space, somata of interneurons in young and aged wild-type mice. In aged mice, Reelin- and amyloid-β-immunoreactivity was detected in extracellular, spherical deposits, likely representing small intermediates or fragments of amyloid fibrils. Our results suggest that Reelin itself aggregates into abnormal oligomeric or protofibrillary deposits during aging, potentially creating a precursor condition for fibrillary amyloid-β plaque formation.

Supplementary Data for Doehner et al. article (PDF)

Pages 1359-1370
Jian-Ping Guo, Sheng Yu and Patrick L. McGeer
Simple In Vitro Assays to Identify Amyloid-β Aggregation Blockers for Alzheimer’s Disease Therapy
Abstract: Compounds that will inhibit buildup of amyloid-β (Aβ) deposits in Alzheimer’s disease (AD) brain are potential therapeutic agents. Here we report the development of two simple in vitro screening assays to identify such agents. We use these assays to evaluate the relative potency of some possible candidates. One assay is based on binding of fluorescence-tagged Aβ1-42 to synthetic Aβ1-42 plated in wells of fluorescent black-wall microplates. Fluorescence-tagged Aβ1-42 solutions with and without blockers are then added to the plates, and the amount of bound fluorescence is measured. Another is a tissue type assay, where sections of unfixed AD or AD model transgenic mouse brains are mounted on glass slides. The same solutions assayed in the microplate test are then added to tissue sections. Binding of fluorescence-tagged Aβ1-42 to the Aβ deposits in AD or transgenic brain tissue is detected with a fluorescence microscope. Good agreement is obtained between the two methods. Most of the tested agents have too low an affinity for Aβ1-42 to be effective clinically. Agents that may have marginal affinity according to these tests include 1,2,3,4,6-penta-O-galloyl-b-D-glucopyranose (PGG), S-diclofenac, epigallocatechin gallate (EGCG), resveratrol, and extracts of spirulina, ginger, rhubarb, cinnamon, blueberries, and turmeric. Compounds which failed to show binding include scyllo-inositol, myo-inositol, rhamnose, ginkgolide A, emodin, rhein, caryophellene, curcumin, valproic acid, tramiprosate, and garlic extract.

Pages 1371-1376
Insub Kim*, Junhee Lee*, Hyun Joo Hong, Eun Sun Jung, Yun Hyi Ku, In Kyong Jeong, Young Min Cho, Insuk So, Kyong Soo Park, Inhee Mook-Jung *equal contribution as the first author
A Relationship Between Alzheimer’s Disease and Type 2 Diabetes Mellitus Through the Measurement of Serum Amyloid-β Autoantibody
Abstract: Increasing evidence suggests that type 2 diabetes mellitus (T2DM) is strongly correlated with Alzheimer’s disease (AD). To examine the relationship between T2DM and AD, autoantibodies against Aβ were measured in the serum of T2DM patients and age-matched controls. Levels of Aβ autoantibody were measured by ELISA in serum samples of T2DM patients (n=92) and age-matched control group (n=106). Statistical analysis was performed. Aβ autoantibody levels were increased in T2DM compared with age-matched controls by 45.4±8.1 % (p<0.001). Females had higher Aβ autoantibody levels than males in both T2DM and control subjects. Aβ autoantibody levels in the DM group were positively correlated with the levels of cholesterol (p=0.011), low density lipoprotein cholesterol (p=0.020), and triglycerides (p=0.039). Level of Aβ autoantibody is dramatically elevated in patient sera of T2DM. It might be used as a possible biomarker for T2DM.

Pages 1377-1386
Mythili Yenjerla, Nichole E LaPointe, Manu Lopus, Corey Cox, Mary Ann Jordan, Stuart C Feinstein and Leslie Wilson
The Neuroprotective Peptide NAP Does Not Directly Affect Polymerization or Dynamics of Reconstituted Neural Microtubules
Abstract: NAP (Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln) is a neuroprotective peptide that shows cognitive protection in patients with amnestic mild cognitive impairment, a precursor to Alzheimer’s disease. NAP exhibits potent neuroprotective properties in several in vivo and cellular models of neural injury. While it has been found in many studies to affect microtubule assembly and/or stability in neuronal and glial cells at fM concentrations, it has remained unclear whether it acts directly or indirectly on tubulin or microtubules. We analyzed the effects of NAP (1 fM-1 μM) on the assembly of reconstituted bovine brain microtubules in vitro and found that it did not significantly (p < 0.05) alter polymerization of either purified tubulin or of a mixture of tubulin and unfractionated microtubule-associated proteins. NAP also had no significant effect (p < 0.05) on the growing and shortening dynamics of steady-state microtubules at their plus ends, nor did it alter the polymerization or dynamics of microtubules assembled in the presence of 3-repeat or 4-repeat tau. Thus, the neuroprotective activity of NAP does not appear to involve a direct action on the polymerization or dynamics of purified tubulin or microtubules.

Pages 1387-1400
Danielle G. Smith, Giuseppe D. Ciccotosto, Deborah J. Tew, Keyla Perez, Cyril C. Curtain, John F. Boas, Colin L. Masters, Roberto Cappai, Kevin J. Barnham (Handling Associate Editor: Brett Garner)
Histidine 14 Modulates Membrane Binding and Neurotoxicity of the Alzheimer’s Disease Amyloid-β Peptide
Abstract: Amyloid-β peptide (Aβ) toxicity is thought to be responsible for the neurodegeneration associated with Alzheimer’s disease. While the mechanism(s) that modulate this toxicity are still widely debated, it has previously been demonstrated that modifications to the three histidine residues (6, 13, and14) of Aβ are able to modulate the toxicity. Therefore to further elucidate the potential role of the histidine (H) residues in Aβ toxicity, we synthesized Aβ peptides with single alanine substitutions for each of the three histidine residues and ascertained how these substitutions affect peptide aggregation, metal binding, redox chemistry, and cell membrane interactions, factors which have previously been shown to modulate Aβ toxicity. Aβ42H13A and Aβ42H6A modified peptides were able to induce significant cell toxicity in primary cortical cell cultures at levels similar to the wild-type peptide. However, Aβ42H14A did not induce any measurable toxicity in the same cultures. This lack of toxicity correlated with the inability of the Aβ42H14A to bind to cell membranes. The interaction of Aβ with cell membranes has previously been shown to be dependent on electrostatic interactions between Aβ and the negatively charged head group of phosphatidylserine. Our data suggests that it is the imidazole sidechain of histidine 14 that modulates this interaction and strategies inhibiting this interaction may have therapeutic potential for Alzheimer’s disease.

Pages 1401-1408
Esther L.G.E. Koedam, Vivian Lauffer, Annelies E. van der Vlies, Wiesje M. van der Flier, Philip Scheltens, Yolande A.L. Pijnenburg
Early- versus Late-Onset Alzheimer’s Disease: More than Age Alone
Abstract: Alzheimer’s disease (AD) is the most common cause of dementia at older age. Although less prevalent before the age of 65 years, it is still the most frequent cause of early-onset dementia followed by frontotemporal dementia. The typical presentation of AD is memory dysfunction, however, presentations with prominent cognitive impairment in other domains besides memory, like prominent apraxia, language problems, or executive dysfunction, may occur and are relatively more common in early-onset AD. In this retrospective descriptive study, we determined the prevalence of non-memory presentations in a large sample of early-onset AD patients compared to late-onset AD. The clinical files of 270 patients with AD starting before the age of 65 years and 90 patients with late-onset AD (≥ 65 years) were reviewed to assess clinical characteristics. Patients were classified as memory presentation and non-memory presentation according to their clinical presentation. The mean age of the early-onset group was 56 ± 5 years and 74 ± 6 years for the late-onset group. A third of the early-onset AD group presented with non-memory symptoms compared to only 6% in the late-onset group (p<0.001). Within the group with non-memory presentations, apraxia/visuospatial dysfunction was the most prevalent presenting symptom (12%). Patients with early-onset AD often present with a non-memory phenotype, of which apraxia/visuospatial dysfunction is the most common presenting symptom. Atypical presentations of AD should be considered in the clinical differential diagnosis of early-onset dementia.

Pages 1409-1415
Meeting Report from the Alzheimer Research Forum
The Society for Neuroscience 2009 Meeting Report, Part 2

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