Home Advances for a New Century Advertising
About JAD Alzheimer Award Recommend JAD
Editorial Board Press Releases Feedback
For Authors Subscriptions Search
Contents/Abstracts Related Links Letters to Editor

  JOURNAL OF ALZHEIMER'S DISEASE

an IOS Press publication

CONTENTS/ABSTRACTS

 PDFs of all articles are available from IOS Press. 

F O R   A U T H O R S

VOLUMES 1-18

VOLUME 19

VOLUME 20

VOLUME 21

VOLUME 22

VOLUME 23

VOLUME 24

VOLUME 25

VOLUME 26

VOLUME 27

VOLUME 28

VOLUME 29

VOLUME 30

VOLUME 31

VOLUME 32

VOLUME 33

VOLUME 34

VOLUME 35

VOLUME 36

The Journal of Alzheimer's Disease is published by IOS Press. ©1998-2012 Journal of Alzheimer's Disease

JAD - Volume 32, Number 1

Volume 32, Number 1, September 2012

Pages 1-12
Review
Diego Sepulveda-Falla, Markus Glatzel*, Francisco Lopera* (Handling Associate Editor: Raquel Sánchez-Valle) *These two authors contributed equally.
Phenotypic Profile of Early-Onset Familial Alzheimer’s Disease Caused by Presenilin-1 E280A Mutation
Abstract: Presenilin 1 (PS1) mutations are the most common cause of early-onset familial Alzheimer’s disease (EOFAD). They show a common phenotypic profile characterized by early age of onset, severe dementia and distinct neurodegeneration. The largest population of EOFAD carries the E280A mutation in PS1 and resides in Antioquia, Colombia, currently comprising around 5,000 individuals. Carriers start showing memory impairment in the third decade of life, followed by progressive impairment of language and other cognitive processes. They reach mild cognitive impairment around 45 and dementia around 50 years of age. There is some phenotypic variability among the carriers of this single PS1 mutation. Some patients present with epilepsy, verbal impairment, and cerebellar ataxia. Neuropathologically, PS1 E280A cases show pronounced brain atrophy, severe amyloid-β pathology, distinct hyperphosphorylated tau-related pathology, and cerebellar damage. The earliest event identified by functional magnetic imaging resonance is hyperactivation within the right anterior hippocampus around 33 years of age. This well-studied population with a clear pre-clinical profile and wide phenotypic variability in age of onset and clinical presentation is ideally suited for clinical trials and to study molecular mechanisms of Alzheimer’s disease.

Pages 13-17
Short Communication

Andrea Tedde, Irene Piaceri, Silvia Bagnoli, Ersilia Lucenteforte, Silvia Piacentini, Sandro Sorbi, Benedetta Nacmias (Handling Associate Editor: Silvia Pellegrini)
DAPK1 is associated with FTD and not with Alzheimer’s Disease
Abstract: Apoptosis is correlated with various forms of dementia. Death-associated protein kinase 1 (DAPK1) plays an important role in neuronal apoptosis and could influence the pathology of late-onset Alzheimer’s disease (LOAD) and frontotemporal dementia (FTD). It has been reported that two common polymorphisms (rs4878104 and rs4877365) are associated with LOAD, thus we examined the genotype and allele distributions of the above polymorphisms in 681 Italian subjects, including patients with LOAD and FTD. We showed a positive association between rs4878104 and FTD, suggesting a possible implication of the DAPK1 genetic variant in the susceptibility to FTD.

Pages 19-22
Short Communication
David Wallon*, Anne Rovelet-Lecrux*, Vincent Deramecourt, Jeremie Pariente, Sophie Auriacombe, Isabelle Le Ber, Suzanna Schraen, Florence Pasquier, Dominique Campion, Didier Hannequin *These authors contributed equally to this work.
Definite Behavioral Variant of Frontotemporal Dementia with C9ORF72 Expansions despite Positive Alzheimer’s Disease Cerebrospinal Fluid Biomarkers
Abstract: Hexanucleotide expansion repeats in the C9ORF72 gene are a major cause of familial and, to a lesser extent, sporadic frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and FTLD-ALS. To examine whether C9ORF72 expansions could be involved in early-onset Alzheimer’s disease (EOAD), we genotyped the hexanucleotide repeat region in a large cohort of 114 EOAD patients who all had positive AD cerebrospinal fluid (CSF) biomarkers. We found hexanucleotide expansion repeats of the C9ORF72 gene in 3 out of 114 patients (2.6%). We raise several hypotheses to explain our results and discuss the current status of AD CSF biomarkers in the dementia diagnostic algorithm.

Pages 23-32
Donald R. Royall, Raymond F. Palmer
Estimating the Temporal Evolution of Alzheimer’s Disease Pathology with Autopsy Data
Abstract: The temporal growth of Alzheimer’s disease (AD) neuropathology cannot be easily determined because autopsy data are available only after death. We combined autopsy data from 471 participants in the Honolulu-Asia Aging Study (HAAS) into latent factor measures of neurofibrillary tangle and neuritic plaque counts. These were associated with intercept and slope parameters from a latent growth curve model of 9-year change in cognitive test performance in 3,244 autopsied and non-autopsied HAAS participants. Change in cognition fully mediated the association between baseline cognitive performance and AD lesions counts. The mediation effect of cognitive change on both AD lesion models effectively dates them within the period of cognitive surveillance. Additional analyses could lead to an improved understanding of lesion propagation in AD.

Pages 33-41
Masaaki Waragai*, Madoka Yoshida*, Mutsumi Mizoi, Ryotaro Saiki, Keiko Kashiwagi, Kiyoshi Takagi, Hiroyuki Arai, Jun Tashiro, Makoto Hashimoto, Naomichi Iwai, Kenichi Uemura, Kazuei Igarashi *These authors contributed equally to this work.
Increased Protein-Conjugated Acrolein and Amyloid-ß40/42 Ratio in Plasma of Patients with Mild Cognitive Impairment and Alzheimer’s Disease
Abstract:The objective of this study was to determine whether plasma levels of acrolein, a compound that causes cell damage, and amyloid-ß (Aß) are useful biochemical markers for Alzheimer’s disease (AD). The study included 221 elderly subjects divided into 101 non-demented [33 healthy control and 68 non-demented subjects with white matter hyperintensity (nd-WMH)], 50 mild cognitive impairment (MCI), and 70 AD. Increases in both protein-conjugated acrolein (PC-Acro) and Aß40/42 ratio were observed in MCI and AD patients compared with values in control subjects. When the combined measurements of PC-Acro and Aß40/42 ratio were evaluated using the median value of the relative risk value for dementia, they were in the order AD (0.98) = MCI (0.97) > nd-WMH (0.83) > control (0.35). The results indicate that measurements of PC-Acro and Aß40/42 ratio not only detect AD and MCI patients but also nd-WMH subjects. Furthermore, both PC-Acro and Aß40/42 ratio in plasma for 120 MCI and AD patients were significantly higher than those for 101 control and nd-WMH subjects, indicating that both values become useful biochemical markers for MCI and AD subjects.

Pages 43-56
Neil U. Barua, J. Scott Miners, Alison S. Bienemann, Marcella J. Wyatt, Katharina Welser, Alethea B. Tabor, Helen C. Hailes, Seth Love, Steven S. Gill (Handling Associate Editor: Gary Arendash)
Convection-Enhanced Delivery of Neprilysin: A Novel Amyloid-β-Degrading Therapeutic Strategy
Abstract: Enzymatic degradation contributes to the control of intracerebral amyloid-β (Aβ) peptide levels. Previous studies have demonstrated the therapeutic potential of viral vector-mediated neprilysin (NEP) gene therapy in mouse models of Alzheimer's disease (AD). However, clinical translation of NEP gene therapy is limited by ethical and practical considerations. In this study we have assessed the potential of convection-enhanced delivery (CED) as a means of elevating intracerebral NEP level and activity and degrading endogenous Aβ. We analyzed the interstitial and perivascular distribution of NEP following CED into rat striatum. We measured NEP protein level, clearance, activity, and toxicity by ELISA for NEP and synaptophysin, NEP-specific activity assay, and immunohistochemistry for NEP, NeuN, glial fibrillary acidic protein and Iba1. We subsequently performed CED of NEP in normal aged rats and measured endogenous Aβ by ELISA. CED resulted in widespread distribution of NEP, and a 20-fold elevation of NEP protein level with preservation of enzyme activity and without evidence of toxicity. CED in normal, aged rats resulted in a significant reduction in endogenous Aβ40 (p = 0.04), despite rapid NEP clearance from the brain (half-life ~3 h). CED of NEP has therapeutic potential as a dynamically controllable Aβ40-degrading therapeutic strategy for AD. Further studies are required to determine the longer term effects on Aβ (including Aβ42) and on cognitive function.

Pages 57-76
Rosa M. Solano*, Maria J. Casarejos*, Ana Gómez, Juan Perucho, Justo García de Yébenes, Maria A. Mena *These authors contributed equally to this work.
Parkin Null Cortical Neuronal/Glial Cultures are Resistant to Amyloid-β1-42 Toxicity: A Role for Autophagy?
Abstract: Dementia occurs often in late stages of Parkinson’s disease (PD) but its cause is unknown. Likewise there is little information about the interaction between proteins that produce PD and those implicated in Alzheimer’s disease (AD). Here we have investigated the interactions between parkin protein and the amyloid-β (Aβ)1-42 peptide. We examined the effects of oligomeric Aβ1-42 peptide on the survival, differentiation, and signaling pathways in cortical cultures from wild type (WT) and parkin null (PK-KO) mice. We discovered that PK-KO cells were more resistant than WT to Aβ1-42. This peptide induced neuronal cell death, astrogliosis, microglial proliferation, and increased total and hyperphosphorylated tau and levels of chaperones HSP-70 and CHIP in WT, but not in Aβ-treated PK-KO cultures. Aβ1-42 decreased proteasome activities in WT and PK-KO cultures, but the ubiquitination of proteins only increased in WT cultures. Aβ1-42 induced a short activation of ERK1/2 and AKT signaling pathways, implicated in cell survival, in PK-KO-treated cells, and a shift in the autophagy marker LC3-II/LC3-I ratio. In addition, the percentage of cells immunoreactive to both HSC70 and LAMP-2A increased in PK-KO cultures versus WT and furthermore in PK-KO cultures treated with Aβ1-42. Pre-treatment with inhibitors of glutathione synthesis or autophagy reverted the resistance to Aβ1-42 of the PK-KO cultures. In conclusion, the loss of parkin protein triggers the compensatory mechanisms of cell protection against Aβ1-42. Parkin suppression, therefore, is not a risk factor for dementia of AD type.

Supplementary Data for Solano et al. article (PDF)

Pages 77-94
Xichao Wang, Qun Chen, Da Xing
Focal Adhesion Kinase Activates NF-κB via the ERK1/2 and p38MAPK Pathways in Amyloid-β25-35-Induced Apoptosis in PC12 Cells
Abstract: Increasing evidence supports that amyloid plaques, comprised of amyloid-β (Aβ), are a key feature of Alzheimer’s disease (AD). But the mechanism of Aβ in AD is not yet fully understood. Previous studies have demonstrated that in Aβ-induced apoptosis of nerve cells, differentiated rat pheochromocytoma (PC12) cells, and microglia, nucleus factor kappa B (NF-κB) is activated. Meanwhile, focal adhesion kinase (FAK) is also activated. However, the relationship between NF-κB and FAK remains unclear. Using differentiated PC12 cells, we investigated this relationship in Aβ25-35-induced apoptosis. The results showed that FAK phosphorylation increased at 6-9 hours after Aβ treatment, slightly shorter than the activation of NF-κB (6-12 hours). In this process, both extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (p38MAPK) phosphorylation levels were increased. After FAK expression was inhibited by its siRNA, the activities of ERK1/2, p38MAPK, and NF-κB were all suppressed. When ERK1/2 and p38MAPK expressions were inhibited by their siRNAs respectively, NF-κB activity was also suppressed. But FAK phosphorylation was not affected. When NF-κB expression was inhibited, all of the phosphorylation levels of FAK, ERK1/2, and p38MAPK were not affected. These phenomena indicated that FAK is upstream of ERK1/2, p38MAPK, and NF-κB, and meanwhile both of ERK1/2 and p38MAPK are upstream of NF-κB. Co-immunoprecipitation results demonstrated that it is ERK1/2, but not p38MAPK, which directly interacts with IκB kinase. Taken together, our results suggest that FAK activates NF-κB via ERK1/2 and p38MAPK pathways in Aβ25-35-induced apoptosis of differentiated PC12 cells.

Supplementary Data for Wang et al. article (PDF)

Pages 95-100
Walter Maetzler, Markus Langkamp, Stefanie Lerche, Jana Godau, Kathrin Brockmann, Alexandra Gaenslen, Heiko Huber, Isabel Wurster, Raphael Niebler, Gerhard W. Eschweiler, Daniela Berg (Handling Associate Editor: Gary Arendash)
Lowered Serum Amyloid-β1-42 Autoantibodies in Individuals with Lifetime Depression
Abstract: Reduced levels of naturally occurring autoantibodies against amyloid-β (Aβ) have been described in Alzheimer’s disease (AD). Lifetime depression doubles the risk of AD, thus these autoantibodies may also be reduced in this group. We measured serum IgG autoantibody titers against Aβ1-42, S100b and α-synuclein in 214 individuals with depression and 419 controls. Titers against Aβ1-42 were lower in individuals with lifetime depression (5544.6 ± 389.3) compared to controls (7208.7 ± 482.4; p=0.048). Titers against S100b and α-synuclein were comparable between the cohorts. These data suggest an AD-like impairment of the humoral immune response in a relevant proportion of individuals with depression.

Pages 101-107
Deborah M. Little, Sean Foxely, Orly Lazarov (Handling Associate Editor: Elliott Mufson)
A Preliminary Study Targeting Neuronal Pathways Activated Following Environmental Enrichment by Resting State Functional Magnetic Resonance Imaging
Abstract: We have shown that experience of transgenic mice harboring familial Alzheimer’s disease (FAD)-linked AβPPswe/PS1DE9 in an enriched environment enhances hippocampal neurogenesis and synaptic plasticity and attenuates neuropathology. Nevertheless, the neuronal pathways activated following environmental enrichment underlying this effect are unknown. Using resting-state functional magnetic resonance imaging, we present preliminary evidence to show that transgenic mice, which had been housed in an enriched environment, show increased connectivity between CA1 and cortical areas compared to mice from standard housing. This is the first preliminary demonstration of live-activated neuronal pathways following environmental enrichment in FAD mice. Understanding the activated pathways may unravel the molecular mechanism underlying environmental enrichment-enhanced neuroplasticity in FAD.

Pages 109-125
Yanica Klein-Koerkamp, Marine Beaudoin, Monica Baciu, Pascal Hot (Handling Associate Editor: Beatriz Garcia-Rodriguez)
Emotional Decoding Abilities in Alzheimer’s Disease: A Meta-Analysis
Abstract: Studies on emotional processing in Alzheimer’s disease (AD) have reported abnormalities in emotional decoding. However, it remains unclear whether the impairment depends on a general cognitive decline that characterizes these patients or is an independent deficit. We conducted a comprehensive meta-analysis of existing studies that compared AD patients with age-matched healthy older adults (HOA) on measures of emotional decoding abilities. Our first goal was to quantify the magnitude of the AD patients’ deficit. The second goal was to identify variables that may modulate the deficit, including emotional task design and participants’ characteristics. The random-effects model analysis on 212 effect sizes indicated that AD patients showed significant impairment in emotional decoding abilities. This deficit is consistent regardless of the emotional task, stimuli, type of emotion considered, or disease severity. After we controlled for cognitive status, the emotional performance in AD patients was still poorer than that in HOA. The effect size of emotional performance was significantly lower when the cognitive status was considered than when it was not. Thus, our results suggest that impaired emotion processing in AD patients cannot be solely explained by the cognitive deficit. These findings provide evidence that progressive neuropathological changes characterizing the disease could affect emotional processing, which may suggest that clinicians should be sensitive to the emergence of impairments in emotional decoding. Further research that addresses the limitations of existing studies is needed to draw conclusions about methodological issues and the impact of the AD patient’s depression symptoms on emotional decoding.

Supplementary Data for Klein-Koerkamp et al. article (PDF)

Pages 127-138
Tina L. Beckett*, Robin L. Webb*, Dana M. Niedowicz*, Christopher J. Holler, Sergey Matveev, Irfan Baig, Harry LeVine, III, Jeffrey N. Keller, M. Paul Murphy (Handling Associate Editor: Peter Nelson) *These authors contributed equally to this work.
Postmortem Pittsburgh Compound B (PiB) Binding Increases with Alzheimer’s Disease Progression
Abstract: The development of imaging reagents is of considerable interest in the Alzheimer’s disease (AD) field. Some of these, such as Pittsburgh Compound B (PiB), were designed to bind to the amyloid-β peptide (Aβ), the major component of amyloid deposits in the AD brain. Although these agents were designed for imaging amyloid deposits in vivo, a major avenue of evaluation relies on postmortem cross validation with established indices of AD pathology. In this study, we evaluated changes in the postmortem binding of PiB and its relationship to other aspects of Aβ-related pathology in a series of AD cases and age-matched controls. We also examined cases of preclinical AD (PCAD) and amnestic mild cognitive impairment (MCI), both considered early points in the AD continuum. PiB binding was found to increase with the progression of the disease and paralleled increases in the less soluble forms of Aβ, including SDS-stable Aβ oligomers. Increased PiB binding and its relationship to Aβ was only significant in a brain region vulnerable to the development of AD pathology (the superior and middle temporal gyri) but not in an unaffected region (cerebellum). This implies that the amyloid deposited in disease affected regions may possess fundamental, brain region specific characteristics that may not as yet be fully appreciated. These data support the idea that PiB is a useful diagnostic tool for AD, particularly in the early stage of the disease and also show that PiB could be a useful agent for the discovery of novel disease-related properties of amyloid.

Supplementary Data for Beckett et al. article (PDF)

Pages 139-146
Mark A. Lovell, Melissa A. Bradley, Shuling X.Fister
4-Hydroxyhexenal (HHE) Impairs Glutamate Transport in Astrocyte Cultures
Abstract: Multiple studies show elevations of α,β-unsaturated aldehydic by-products of lipid peroxidation including 4-hydroxynonenal and acrolein in vulnerable brain regions of subjects throughout the progression of Alzheimer’s disease (AD). More recently 4-hydroxyhexenal (HHE), a diffusible α,β-unsaturated aldehyde resulting from peroxidation of ω-3 polyunsaturated fatty acids, was shown to be elevated in the hippocampus/parahippocampal gyrus (HPG) of subjects with preclinical AD (PCAD) and in late stage AD (LAD). HHE treatment of primary rat cortical neuron cultures led to a time- and concentration-dependent decrease in survival and glucose uptake. To determine if HHE also impairs glutamate uptake, primary rat astrocyte cultures were exposed to HHE for 4 hours and glutamate transport measured. Results show subtoxic (2.5 µM) HHE concentrations significantly (p < 0.05) impair glutamate uptake in primary astrocytes. Immunoprecipitation of excitatory amino acid transporter-2 (EAAT-2), the primary glutamate transporter in brain, from normal control, mild cognitive impairment (MCI), PCAD, and LAD HPG followed by quantification of HHE immunolabeling showed a significant increase in HHE positive EAAT-2 in MCI and LAD HPG. Together these data suggest HHE can significantly impair glutamate uptake and may play a role in the pathogenesis of AD.

Pages 147-156
Whitney Wharton, James H. Stein, Claudia Korcarz, Jane Sachs, Sandra R. Olson, Henrik Zetterberg, Maritza Dowling, Shuyun Ye, Carey E. Gleason, Gail Underbakke, Laura E. Jacobson, Sterling C. Johnson, Mark A. Sager, Sanjay Asthana, Cynthia M. Carlsson (Handling Associate Editor: Patrick Kehoe)
The Effects of Ramipril in Individuals at Risk for Alzheimer’s Disease: Results of a Pilot Clinical Trial
Abstract: Research shows that certain antihypertensives taken during midlife confer Alzheimer’s disease (AD) related benefits in later life. We conducted a clinical trial to evaluate the extent to which the angiotensin converting enzyme inhibitor (ACE-I), ramipril, affects AD biomarkers including cerebrospinal fluid (CSF) amyloid-β (Aβ) levels and ACE activity, arterial function, and cognition in participants with a parental history of AD. This four month randomized, double-blind, placebo-controlled, pilot clinical trial evaluated the effects of ramipril, a blood-brain-barrier crossing ACE-I, in cognitively healthy individuals with mild, or Stage I hypertension. Fourteen participants were stratified by gender and apolipoprotein E ε4 (APOE ε4) status and randomized to receive 5 mg of ramipril or matching placebo daily. Participants were assessed at baseline and month 4 on measures of CSF Aβ1-42 and ACE activity, arterial function, and cognition. Participants were middle-aged (mean 54 y) and highly educated (mean 15.4 y), and included 50% men and 50% APOE ε4 carriers. While results did not show a treatment effect on CSF Aβ1-42 (p=0.836), data revealed that ramipril can inhibit CSF ACE activity (p=0.009) and improve blood pressure, however, there were no differences between groups in arterial function or cognition. In this study, ramipril therapy inhibited CSF ACE activity and improved blood pressure, but did not influence CSF Aβ1-42. While larger trials are needed to confirm our CSF Aβ results, it is possible that prior research reporting benefits of ACE-I during midlife may be attributed to alternative mechanisms including improvements in cerebral blood flow or the prevention of angiotensin II-mediated inhibition of acetylcholine.

Pages 157-168
Pawel Gaj, Agnieszka Paziewska, Wojciech Bik, Michalina Dąbrowska, Agnieszka Baranowska-Bik, Maria Styczynska, Małgorzata Chodakowska-Żebrowska, Anna Pfeffer-Baczuk, Maria Barcikowska, Boguslawa Baranowska, Jerzy Ostrowski (Handling Associate Editor: Emilio Di Maria)
Identification of a Late Onset Alzheimer’s Disease Candidate Risk Variant at 9q21.33 in Polish Patients
Abstract: Late onset Alzheimer’s disease (LOAD) accounts for about 95% of all Alzheimer’s disease cases. While the APOE ε4 variant seems to have unparalleled influence on increased LOAD risk, it does not explain all of the heritability of LOAD. In this study, we present the application of a cost-effective, pooled DNA genome-wide association study (GWAS) to uncover genetic risk variants associated with LOAD in Polish women diagnosed with either mild cognitive impairment (MCI) or well-defined LOAD. A group of 141 patients (94 LOAD and 47 MCI), as well as 141 controls, were assayed using Affymetrix Genome-Wide Human SNP 6.0 arrays. Allele frequency distributions were compared using χ2-tests, and significantly associated SNPs at p < 0.0001 with a proxy SNP were selected. GWAS marker selection was conducted using PLINK, and selected SNPs were validated on DNA samples from the same cohort using KASPar Assays. In addition, to determine the genotype of APOE variants (rs429358, rs7412), a multiplex tetra-primer amplification refractory mutation system was applied. The GWAS revealed nine SNPs associated with MCI and/or LOAD. Of these, the association of seven SNPs was confirmed by genotyping of individual patients. Furthermore, the APOE ε4 appeared to be a risk variant for LOAD, while the APOE ε3 showed a protective effect. Multivariate analysis showed association between rs7856774 and LOAD, independently from the effect of APOE variation. Pooled DNA GWAS enabled the identification of a novel LOAD candidate risk variant, rs7856774 (9q21.33), tagging a possible genomic enhancer affecting proximal transcribed elements including DAPK1 gene.

Supplementary Data for Gaj et al. article (PDF)

Pages 168-181
Pascale Fehlbaum-Beurdeley, Olivier Sol, Laurent Désiré, Jacques Touchon, Thierry Dantoine, Martine Vercelletto, Audrey Gabelle, Anne-Charlotte Jarrige, Raphaël Haddad, Jean Christophe Lemarié, Weiyin Zhou, Harald Hampel, Richard Einstein, Bruno Vellas on behalf of the EHTAD/002 study group (Handling Associate Editor: Silvia Pellegrini)
Validation of AclarusDx™, a Blood-Based Transcriptomic Signature for the Diagnosis of Alzheimer’s Disease
Abstract: Biomarkers have gained an increased importance in the past years in helping physicians to diagnose Alzheimer’s disease (AD). This study was designed to identify a blood-based, transcriptomic signature that can differentiate AD patients from control subjects. The performance of the signature was then evaluated for robustness in an independent blinded sample population. RNA was extracted from 177 blood samples (90 AD patients and 87 controls) and gene expression profiles were generated using the human Genome-Wide Splice Array™. These profiles were used to establish a signature to differentiate AD patients from controls. Subsequently, prediction results were optimized by establishing grey zone boundaries that discount prediction scores near the disease status threshold. Signature validation was then performed on a blinded independent cohort of 209 individuals (111 AD and 98 controls). The AclarusDx™ signature consists of 170 probesets which map to 136 annotated genes, a significant number of which are associated with inflammatory, gene expression, and cell death pathways. Additional signature genes are known to interact with pathways involved in amyloid and tau metabolism. The validation sample set, after removal of 45 individuals with prediction profile scores within the grey zone, consisted of 164 subjects. The AclarusDx™ performance on this validation cohort had a sensitivity of 81.3% (95% CI: [73.3%; 89.3%]); and a specificity of 67.1% (95% CI: [56.3%; 77.9%]). AclarusDx™ is a non-invasive blood-based transcriptomic test that, in combination with standard assessments, can provide physicians with objective information to support the diagnosis of AD.

Pages 183-196
Myriam Kervern, Arnaud Angeli, Olivier Nicole, Frédéric Léveillé, Bénédicte Parent, Vincent Villette, Alain Buisson, Patrick Dutar (Handling Associate Editor: Luis Aguayo)
Selective Impairment of Some Forms of Synaptic Plasticity by Oligomeric Amyloid-β Peptide in the Mouse Hippocampus: Implication of Extrasynaptic NMDA Receptors
Abstract: Alzheimer’s disease is characterized by the loss of memory and synaptic damages. Evidence is accumulating for a causal role of soluble oligomeric species of amyloid-β peptide (Aβo) in the impairment of synaptic plasticity and cognition but the precise mechanisms underlying these effects are still not clear. Synaptic plasticity such as long-term potentiation is thought to underlie learning and memory. While the effect of Aβ on long-term potentiation is well documented, a more general understanding of Aβ action on various aspects of plasticity involving synaptic and extrasynaptic receptors and the nature of the mechanisms involved in its effects are lacking. Using a combination of electrophysiological and biochemical techniques in mouse hippocampal slices, we show here that Aβo drastically affects synaptic plasticities induced by high stimulation frequencies through the involvement of extrasynaptic glutamate receptors. Experiments on hippocampal slices as well as on cultured cortical neurons show that Aβo potentiates extrasynaptic NMDA receptors-mediated responses. Pharmacological characterization indicates that GluN2B-containing NMDARs are involved in these responses. When synaptic and extrasynaptic glutamate receptor-mediated effects are dissociated using cortical neurons in culture, it appears that Aβo has differential effects on these two receptors types. We conclude that the pool of extrasynaptic GluN2B-containing NMDARs is a major target of Aβo in the hippocampus. During high frequency stimulation, Aβo dramatically impairs long-term neuronal responses.

Supplementary Data for Kervern et al. article (PDF)

Pages 197-215
Janelle N. Fawver*, Karen T. Duong*, Olivia Wise-Scira*, Hayley E. Schall, Orkid Coskuner, Xiongwei Zhu, Luis V. Colom, Ian V.J. Murray (Handling Associate Editor: Debomoy Lahiri) *These authors contributed equally to the manuscript.
Probing and Trapping a Sensitive Conformation: Amyloid-β Fibrils, Oligomers, and Dimers
Abstract: Alzheimer’s disease (AD) is a devastating neurodegenerative disease with pathological misfolding of amyloid-β protein (Aβ). The recent interest in Aβ misfolding intermediates necessitates development of novel detection methods and ability to trap these intermediates. We speculated that two regions of Aβ may allow for detection of specific Aβ species: the N-terminal and 22-35, both likely important in oligomer interaction and formation. We determined via epitomics, proteomic assays, and electron microscopy that the Aβ42 species (wild type, ∆E22, and MetOx) predominantly formed fibrils, oligomers, or dimmers, respectively. The 2H4 antibody to the N-terminal of Aβ, in the presence of 2% SDS, primarily detected fibrils, and an antibody to the 22-35 region detected low molecular weight Aβ species. Simulated molecular modeling provided insight into these SDS-induced structural changes. We next determined if these methods could be used to screen anti-Aβ drugs as well as identify compounds that trap Aβ in various conformations. Immunoblot assays determined that taurine, homotaurine (tramiprosate), myoinositol, methylene blue, and curcumin did not prevent Aβ aggregation. However, calmidazolium chloride trapped Aβ at oligomers, and berberine reduced oligomer formation. Finally, pretreatment of AD brain tissues with SDS enhanced 2H4 antibody immunostaining of fibrillar Aβ. Thus we identified and characterized Aβs that adopt specific predominant conformations (modified Aβ or via interactions with compounds), developed a novel assay for aggregated Aβ, and applied it to drug screening and immunohistochemistry. In summary, our novel approach facilitates drug screening, increases the probability of success of antibody therapeutics, and improves antibody-based detection and identification of different confirmations of Aβ.

Pages 217-232
Andrew B. Wolf, B. Blair Braden, Heather Bimonte-Nelson, Yael Kusne, Nicole Young, Elizabeth Engler-Chiurazzi, Alexandra N. Garcia, Douglas G. Walker, Guna S.D. Moses, Hung Tran, Frank LaFerla, LihFen Lue, Nancy Emerson Lombardo, Jon Valla (Handling Associate Editor: Thomas Shea)
Broad-Based Nutritional Supplementation in 3xTg Mice Corrects Mitochondrial Function and Indicates Sex-Specificity in Response to Alzheimer’s Disease Intervention
Abstract: Nutrition has been highlighted as a potential factor in Alzheimer’s disease (AD) risk and decline and has been investigated as a therapeutic target. Broad-based combination diet therapies have the potential to simultaneously effect numerous protective and corrective processes, both directly (e.g., neuroprotection) and indirectly (e.g., improved vascular health). Here we administered either normal mouse chow with a broad-based nutritional supplement or mouse chow alone to aged male and female 3xTg mice and wildtype (WT) controls. After approximately 4 months of feeding, mice were given a battery of cognitive tasks and then injected with a radiolabeled glucose analog. Brains were assessed for differences in regional glucose uptake and mitochondrial cytochrome oxidase activity, AD pathology, and inflammatory markers. Supplementation induced behavioral changes in the 3xTg, but not WT, mice, and the mode of these changes was influenced by sex. Subsequent analyses indicated that differential response to supplementation by male and female 3xTg mice highlighted brain regional strategies for the preservation of function. Several regions involved have been shown to mediate responses to steroid hormones, indicating a mechanism for sex-based vulnerability. Thus, these findings may have broad implications for the human response to future therapeutics.

Pages 233-240
Jaume del Valle, Sergi Bayod, Antoni Camins, Carlos Beas-Zárate, Dulce A. Velázquez-Zamora, Ignacio González-Burgos, Merce Pallàs
Dendritic Spine Abnormalities in Hippocampal CA1 Pyramidal Neurons Underlying Memory Deficits in the SAMP8 Mouse Model of Alzheimer’s Disease
Abstract: SAMP8 is a strain of mice with accelerated senescence. These mice have recently been the focus of attention as they show several alterations that have also been described in Alzheimer’s disease (AD) patients. The number of dendritic spines, spine plasticity, and morphology are basic to memory formation. In AD, the density of dendritic spines is severely decreased. We studied memory alterations using the object recognition test. We measured levels of synaptophysin as a marker of neurotransmission and used Golgi staining to quantify and characterize the number and morphology of dendritic spines in SAMP8 mice and in SAMR1 as control animals. While there were no memory differences at 3 months of age, the memory of both 6- and 9-month-old SAMP8 mice was impaired in comparison with age-matched SAMR1 mice or young SAMP8 mice. In addition, synaptophysin levels were not altered in young SAMP8 animals, but SAMP8 aged 6 and 9 months had less synaptophysin than SAMR1 controls and also less than 3-month-old SAMP8 mice. Moreover, while spine density remained stable with age in SAMR1 mice, the number of spines started to decrease in SAMP8 animals at 6 months, only to get worse at 9 months. Our results show that from 6 months onwards SAMP8 mice show impaired memory. This age coincides with that at which the levels of synaptophysin and spine density decrease. Thus, we conclude that together with other studies that describe several alterations at similar ages, SAMP8 mice are a very suitable model for studying AD.

RETURN TO INDEX

top