Journal of Alzheimer's Disease - Volume 32, issue 1

Authors: Sepulveda-Falla, Diego | Glatzel, Markus | Lopera, Francisco

Article Type: Review Article

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. Show more

Keywords: Alzheimer's disease, early onset, phenotype, presenilin-1

DOI: 10.3233/JAD-2012-120907

Citation: Journal of Alzheimer's Disease, vol. 32, no. 1, pp. 1-12, 2012

Authors: Tedde, Andrea | Piaceri, Irene | Bagnoli, Silvia | Lucenteforte, Ersilia | Piacentini, Silvia | Sorbi, Sandro | Nacmias, Benedetta

Article Type: Short Communication

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.

Keywords: Alzheimer's disease, DAPK1, frontotemporal dementia, SNP

DOI: 10.3233/JAD-2012-120556

Citation: Journal of Alzheimer's Disease, vol. 32, no. 1, pp. 13-17, 2012

Authors: Wallon, David | Rovelet-Lecrux, Anne | Deramecourt, Vincent | Pariente, Jeremie | Auriacombe, Sophie | Le Ber, Isabelle | Schraen, Suzanna | Pasquier, Florence | Campion, Dominique | Hannequin, Didier

Article Type: Short Communication

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. Show more

Keywords: Alzheimer's disease, C9ORF72, cerebrospinal fluid biomarkers, dementia/diagnosis, frontotemporal lobar degeneration

DOI: 10.3233/JAD-2012-120877

Citation: Journal of Alzheimer's Disease, vol. 32, no. 1, pp. 19-22, 2012

Authors: Royall, Donald R. | Palmer, Raymond F.

Article Type: Research Article

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 (LGC) model of 9-year change in cognitive test performance in 3244 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. Show more

Keywords: Alzheimer's disease, longitudinal, neuropathology, old age

DOI: 10.3233/JAD-2012-120430

Citation: Journal of Alzheimer's Disease, vol. 32, no. 1, pp. 23-32, 2012

Authors: Waragai, Masaaki | Yoshida, Madoka | Mizoi, Mutsumi | Saiki, Ryotaro | Kashiwagi, Keiko | Takagi, Kiyoshi | Arai, Hiroyuki | Tashiro, Jun | Hashimoto, Makoto | Iwai, Naomichi | Uemura, Kenichi | Igarashi, Kazuei

Article Type: Research Article

Abstract: The objective of this study was to determine whether plasma levels of acrolein, a compound that causes cell damage, and amyloid-β (Aβ) 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 Aβ40/42 ratio were observed in MCI and AD patients compared with values in control subjects. When the combined measurements of PC-Acro and Aβ40/42 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 Aβ40/42 ratio not only detect MCI and AD patients but also nd-WMH subjects. Furthermore, both PC-Acro and Aβ40/42 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. Show more

Keywords: Alzheimer's disease, amyloid-β, magnetic resonance imaging, plasma biomarker, protein-conjugated acrolein, white matter hyperintensity

DOI: 10.3233/JAD-2012-120253

Citation: Journal of Alzheimer's Disease, vol. 32, no. 1, pp. 33-41, 2012

Authors: Barua, Neil U. | Miners, J. Scott | Bienemann, Alison S. | Wyatt, Marcella J. | Welser, Katharina | Tabor, Alethea B. | Hailes, Helen C. | Love, Seth | Gill, Steven S.

Article Type: Research Article

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. Show more

Keywords: Alzheimer's disease, amyloid-β, convection-enhanced delivery, neprilysin, therapy

DOI: 10.3233/JAD-2012-120658

Citation: Journal of Alzheimer's Disease, vol. 32, no. 1, pp. 43-56, 2012

Authors: Solano, Rosa M. | Casarejos, Maria J. | Gómez, Ana | Perucho, Juan | de Yébenes, Justo García | Mena, Maria A.

Article Type: Research Article

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. Show more

Keywords: Alzheimer's disease, apoptosis, autophagy-lysosomal pathway, chaperones, cortical neuron/glial cultures, glutathione, Park 2 gene, ubiquitin proteasome system

DOI: 10.3233/JAD-2012-120406

Citation: Journal of Alzheimer's Disease, vol. 32, no. 1, pp. 57-76, 2012

Authors: Wang, Xichao | Chen, Qun | Xing, Da

Article Type: Research Article

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. Show more

Keywords: Amyloid-β, ERK1/2, focal adhesion kinase, NF-κB, p38MAPK, PC12

DOI: 10.3233/JAD-2012-120526

Citation: Journal of Alzheimer's Disease, vol. 32, no. 1, pp. 77-94, 2012

Authors: Maetzler, Walter | Langkamp, Markus | Lerche, Stefanie | Godau, Jana | Brockmann, Kathrin | Gaenslen, Alexandra | Huber, Heiko | Wurster, Isabel | Niebler, Raphael | Eschweiler, Gerhard W. | Berg, Daniela

Article Type: Research Article

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. Show more

Keywords: Alzheimer's disease, autoimmune disease, depression, risk factor

DOI: 10.3233/JAD-2012-120625

Citation: Journal of Alzheimer's Disease, vol. 32, no. 1, pp. 95-100, 2012

Authors: Little, Deborah M. | Foxely, Sean | Lazarov, Orly

Article Type: Research Article

Abstract: We have shown that experience of transgenic mice harboring familial Alzheimer's disease (FAD)-linked AβPPswe/PS1ΔE9 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. Show more

Keywords: Alzheimer's disease, brain plasticity, environmental enrichment, resting state functional MRI

DOI: 10.3233/JAD-2012-111508

Citation: Journal of Alzheimer's Disease, vol. 32, no. 1, pp. 101-107, 2012

Authors: Klein-Koerkamp, Yanica | Beaudoin, Marine | Baciu, Monica | Hot, Pascal

Article Type: Research Article

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. Show more

Keywords: Alzheimer's disease, emotion, meta-analysis

DOI: 10.3233/JAD-2012-120553

Citation: Journal of Alzheimer's Disease, vol. 32, no. 1, pp. 109-125, 2012

Authors: Beckett, Tina L. | Webb, Robin L. | Niedowicz, Dana M. | Holler, Christopher J. | Matveev, Sergey | Baig, Irfan | LeVine III, Harry | Keller, Jeffrey N. | Murphy, M. Paul

Article Type: Research Article

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. Show more

Keywords: Alzheimer's disease, amyloid-β peptide, amyloid-β protein precursor, frontotemporal dementia, mild cognitive impairment, preclinical Alzheimer's disease

DOI: 10.3233/JAD-2012-120655

Citation: Journal of Alzheimer's Disease, vol. 32, no. 1, pp. 127-138, 2012

Authors: Lovell, Mark A. | Bradley, Melissa A. | Fister, Shuling X.

Article Type: Research Article

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. Show more

Keywords: Excitatory amino acid transporter-2, glutamate transport, 4-hydroxyhexenal, lipid peroxidation

DOI: 10.3233/JAD-2012-120409

Citation: Journal of Alzheimer's Disease, vol. 32, no. 1, pp. 139-146, 2012

Authors: Wharton, Whitney | Stein, James H. | Korcarz, Claudia | Sachs, Jane | Olson, Sandra R. | Zetterberg, Henrik | Dowling, Maritza | Ye, Shuyun | Gleason, Carey E. | Underbakke, Gail | Jacobson, Laura E. | Johnson, Sterling C. | Sager, Mark A. | Asthana, Sanjay | Carlsson, Cynthia M.

Article Type: Research Article

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. Show more

Keywords: Alzheimer's disease, angiotensin converting enzyme, antihypertensive, arterial function, blood pressure, clinical trial, cognition, hypertension, prevention, vascular risk

DOI: 10.3233/JAD-2012-120763

Citation: Journal of Alzheimer's Disease, vol. 32, no. 1, pp. 147-156, 2012

Authors: Gaj, Pawel | Paziewska, Agnieszka | Bik, Wojciech | Dąbrowska, Michalina | Baranowska-Bik, Agnieszka | Styczynska, Maria | Chodakowska-Żebrowska, Małgorzata | Pfeffer-Baczuk, Anna | Barcikowska, Maria | Baranowska, Boguslawa | Ostrowski, Jerzy

Article Type: Research Article

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. Show more

Keywords: APOE, DAPK1, genetic polymorphisms, genome wide association study, late onset Alzheimer's disease

DOI: 10.3233/JAD-2012-120520

Citation: Journal of Alzheimer's Disease, vol. 32, no. 1, pp. 157-168, 2012

Authors: Fehlbaum-Beurdeley, Pascale | Sol, Olivier | Désiré, Laurent | Touchon, Jacques | Dantoine, Thierry | Vercelletto, Martine | Gabelle, Audrey | Jarrige, Anne-Charlotte | Haddad, Raphaël | Lemarié, Jean Christophe | Zhou, Weiyin | Hampel, Harald | Einstein, Richard | Vellas, Bruno | on behalf of the EHTAD/002 study group

Article Type: Research Article

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. Show more

Keywords: Alzheimer's disease, biomarker, blood, gene expression, molecular signature, transcriptome

DOI: 10.3233/JAD-2012-120637

Citation: Journal of Alzheimer's Disease, vol. 32, no. 1, pp. 169-181, 2012

Authors: Kervern, Myriam | Angeli, Arnaud | Nicole, Olivier | Léveillé, Frédéric | Parent, Bénédicte | Villette, Vincent | Buisson, Alain | Dutar, Patrick

Article Type: Research Article

Abstract: Alzheimer's disease is characterized by the loss of memory and synaptic damage. 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. Show more

Keywords: Alzheimer's disease, amyloid-β peptide, calcium imaging, cultured neurons, hippocampal slices, GluN2B subtypes, long-term depression, long-term potentiation, NMDA receptor

DOI: 10.3233/JAD-2012-120394

Citation: Journal of Alzheimer's Disease, vol. 32, no. 1, pp. 183-196, 2012

Authors: Fawver, Janelle N. | Duong, Karen T. | Wise-Scira, Olivia | Petrofes Chapa, Rachel | Schall, Hayley E. | Coskuner, Orkid | Zhu, Xiongwei | Colom, Luis V. | Murray, Ian V.J.

Article Type: Research Article

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, ΔE22, and MetOx) predominantly formed fibrils, oligomers, or dimers, 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 conformations of Aβ. Show more

Keywords: Alzheimer's disease, amyloid, antibodies, berberine, curcumin, homotaurine, methylene blue, molecular modeling, protein folding, taurine

DOI: 10.3233/JAD-2012-120880

Citation: Journal of Alzheimer's Disease, vol. 32, no. 1, pp. 197-215, 2012

Authors: Wolf, Andrew B. | Braden, B. Blair | Bimonte-Nelson, Heather | Kusne, Yael | Young, Nicole | Engler-Chiurazzi, Elizabeth | Garcia, Alexandra N. | Walker, Douglas G. | Moses, Guna S.D. | Tran, Hung | LaFerla, Frank | Lue, LihFen | Emerson Lombardo, Nancy | Valla, Jon

Article Type: Research Article

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. Show more

Keywords: Biomarkers, cytochrome-c oxidase (Complex IV), diet therapy, memory, sex, transgenic mice

DOI: 10.3233/JAD-2012-120478

Citation: Journal of Alzheimer's Disease, vol. 32, no. 1, pp. 217-232, 2012

Authors: del Valle, Jaume | Bayod, Sergi | Camins, Antoni | Beas-Zárate, Carlos | Velázquez-Zamora, Dulce A. | González-Burgos, Ignacio | Pallàs, Merce

Article Type: Research Article

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. Show more

Keywords: Alzheimer's disease, dendrites, learning, memory, object recognition test, SAMP8, senescence, synaptophysin

DOI: 10.3233/JAD-2012-120718

Citation: Journal of Alzheimer's Disease, vol. 32, no. 1, pp. 233-240, 2012

Article Type: Other

DOI: 10.3233/JAD-2012-120719

Citation: Journal of Alzheimer's Disease, vol. 32, no. 1, pp. 241-242, 2012