Journal of Alzheimer's Disease - Volume 28, issue 2

Authors: Haas, Christopher

Article Type: Review Article

Abstract: Therapeutic options for Alzheimer's disease are currently limited to symptomatic treatment that only provides modest and temporary maintenance of cognitive and memory functions, without altering disease progression. Although a variety of therapeutics targeting amyloid production or plaque degradation as well as tau hyperphosphorylation and aggregation have been proposed, examined in pre-clinical models and introduced into clinical trials, many have failed to provide significant therapeutic benefit. Concerns over the adequacy of currently used pre-clinical models, in addition to questions pertaining to the timing of therapeutic administration, vis-à-vis synaptic and neuronal loss have been raised, and are further complicated by the genetic …diversity of individual patients. This review will provide a brief overview of Alzheimer's disease pathophysiology and the currently approved therapeutics, while the main section will focus on therapeutics currently evaluated in pre-clinical models and clinical trials. Show more

Keywords: Alzheimer's disease, amyloid-β, drug therapy, humans, investigational drugs, pathophysiology, tau

DOI: 10.3233/JAD-2011-110986

Citation: Journal of Alzheimer's Disease, vol. 28, no. 2, pp. 241-281, 2012

Authors: Skulachev, Vladimir P.

Article Type: Article Commentary

Abstract: Much experimental evidence suggests that age-related brain pathologies are most often mediated by reactive oxygen species primarily originating from mitochondria (mROS). Two papers with such evidence have been recently published in the Journal of Alzheimer's Disease (Stefanova et al., J Alzheimers Dis 21, 476–491, 2010; Lloret et al., J Alzheimers Dis, doi: 10.3233/JAD-2011-110890). In the first paper, it was shown that appearance of a typical behavioral trait of aging in rats (that old animals do not enter an open arm in a maze) was completely reversed by ten weeks treatment of the old rats with the mitochondria-targeted antioxidant SkQ1. In …the second article, the authors identified molecular mechanisms by which amyloid-β-induced mROS can mediate hyperphosphorylation of the tau protein, a key event in Alzheimer's disease. Conventional antioxidants prevented such hyperphosphorylation. In this article, I will summarize the present state of the art in this field. I conclude that mitochondria-targeted rechargeable antioxidants are promising as tools to treat brain pathologies developing in elderly humans. Show more

Keywords: Alzheimer's disease, behavior, hippocampus, mitochondria-targeted antioxidant, plastoquinone, stroke

DOI: 10.3233/JAD-2011-111391

Citation: Journal of Alzheimer's Disease, vol. 28, no. 2, pp. 283-289, 2012

Authors: Insua, Daniel | Corredoira, Angélica | González-Martínez, Ángela | Suárez, María-Luisa | Santamarina, Germán | Sarasa, Manuel | Pesini, Pedro

Article Type: Short Communication

Abstract: The canine cognitive dysfunction syndrome (CDS) has been identified as a natural model for Alzheimer's disease (AD). We have used unbiased stereology to estimate the total number of basal forebrain cholinergic neurons expressing the nerve growth factor p75NTR receptor in young, aged cognitively-unimpaired (CU) and aged cognitively-impaired (CI) dogs. Aged-CI dogs showed a ∼20% decrement (p = 0.009) in p75NTR neurons compared to both the young and the aged-CU animals. These results suggest that the basal forebrain cholinergic system is affected in dogs with CDS and provide additional support for the use this canine syndrome as a model …for AD research. Show more

Keywords: Aging, Alzheimer's disease, basal forebrain cholinergic neurons (BFCN), p75NTR, unbiased stereology

DOI: 10.3233/JAD-2011-110905

Citation: Journal of Alzheimer's Disease, vol. 28, no. 2, pp. 291-296, 2012

Authors: Ramos, Maria C. | Sierra, Saleta | Ramirez, Carlos | Velasco, Javier | Burgos, Javier S.

Article Type: Short Communication

Abstract: This work describes a novel mechanism of neuroprotection by simvastatin: the modulation of seladin-1, an enzyme involved in Alzheimer's disease. Genomic and proteomic studies in human neuronal cells showed seladin-1 production to be increased in a dose- and time-dependent manner by simvastatin. This was confirmed in mice by immunohistochemical and qRT-PCR studies.

Keywords: Alzheimer's disease, brain, cholesterol, neuroprotection, seladin-1, simvastatin

DOI: 10.3233/JAD-2011-111118

Citation: Journal of Alzheimer's Disease, vol. 28, no. 2, pp. 297-301, 2012

Authors: Antonell, Anna | Gelpi, Ellen | Sánchez-Valle, Raquel | Martínez, Ramiro | Molinuevo, José L. | Lladó, Albert

Article Type: Short Communication

Abstract: AβPP locus duplications have been recently identified in early-onset Alzheimer's disease. We describe a patient who initiated memory problems and behavioral disturbances at 57 years, with a progressive cognitive decline, who died at the age of 68 years with dementia. Neuropathological examination revealed a temporobasal hemorrhage, extensive Alzheimer-type pathology, and severe cerebral amyloid angiopathy. We observed a chromosomal 21 region duplication spanning 0.59 Mb, which comprised JAM2, ATP5J, GABPA, and AβPP genes. We propose a replication based mutational mechanism (single Fork-Stalling and Template-Switching) or a recombination based one (non-homologous end-joining repair) for the AβPP locus duplication in this case.

Keywords: Alzheimer's disease, amyloid-β protein precursor (AβPP), cerebral amyloid angiopathy (CAA), chromosomal duplication, chromosome breakpoint

DOI: 10.3233/JAD-2011-110911

Citation: Journal of Alzheimer's Disease, vol. 28, no. 2, pp. 303-308, 2012

Authors: Maruszak, Aleksandra | Pepłońska, Beata | Safranow, Krzysztof | Chodakowska-Żebrowska, Małgorzata | Barcikowska, Maria | Żekanowski, Cezary

Article Type: Research Article

Abstract: Recently, it has been reported that TOMM40 variable-length poly-T sequence polymorphism (rs10524523) in combination with APOE alleles (E2, E3, E4) significantly influences late-onset Alzheimer's disease (LOAD) age of onset. In a group of 414 LOAD patients, 173 centenarians and 305 neurologically healthy individuals, we investigated the impact of TOMM40 poly-T tracts on LOAD incidence, age of onset, and longevity. TOMM40 allelic variants were classified into four categories: short (S; 14–16T), long a (La; 20–22T), long b (Lb; 26–30T), and very long (VL; 31–39T). Our results demonstrate that La and Lb share similar characteristics in affecting LOAD risk, thus for some …analyses they were combined into L category. We observed significantly lower frequency of VL allele (p < 0.0001) and significantly higher frequency of L alleles in the LOAD patients compared to the control individuals (p < 0.0001). S/S, S/VL, and VL/VL genotypes and VL-E2, S-E3, VL-E3 haplotypes are significantly associated with lower LOAD risk. VL-E3 haplotype carriers significantly more frequently developed LOAD when they were ≥79 years old. Additionally, S/L genotype is associated with a significantly increased LOAD risk (p < 0.0001). We conclude that in the carriers of TOMM40-APOE haplotypes comprising E4 allele, the TOMM40 rs10524523 allele does not play substantial role in establishing LOAD risk. Nevertheless, TOMM40 L allele increases the risk when E4 is absent. Finally, L allele, as well as genotypes (S/L, V/L) and haplotypes (L-E3, L-E4) comprising L significantly reduce the likelihood of living up to 100 years. Show more

Keywords: Alzheimer's disease, APOE, association study, haplotype, late-onset Alzheimer's disease, longevity, TOMM40

DOI: 10.3233/JAD-2011-110743

Citation: Journal of Alzheimer's Disease, vol. 28, no. 2, pp. 309-322, 2012

Authors: Boutoleau-Bretonnière, Claire | Lebouvier, Thibaud | Delaroche, Odile | Lamy, Estelle | Evrard, Christelle | Charriau, Tiphaine | Bretonnière, Cédric | Damier, Philippe | Derkinderen, Pascal | Vercelletto, Martine

Article Type: Research Article

Abstract: The objective of this study was to examine the diagnostic accuracy of imaging and CSF biomarkers in clinically ambiguous dementia (CAD). 69 patients were prospectively followed. The endpoint was clinical diagnosis at follow-up of 24 months based upon existing criteria. Medial temporal lobe atrophy score on MRI, distinctive patterns on 99 mTc-HMPAO-SPECT, and CSF levels of amyloid-β peptide, total tau protein, and P-tau181P were used together with neuropsychological testing to assess Se (sensitivity) and Sp (specificity) of separate and combined markers. 60 patients reached the endpoint. A definite diagnosis was achieved in 48 patients. CSF biomarkers had a Sp …of 71% and a Se of 100% for Alzheimer's disease (AD) diagnosis. Sp increased to 88% and 93% when MRI and MRI + SPECT were combined, at the expense of Se. CSF biomarkers levels also provided clues to frontotemporal (FTD) or vascular dementias (VaD) diagnosis when situated in an intermediate range between normal and pathological values. MRI and SPECT contributed mostly to the diagnosis of VaD (Se 88%, Sp 75%) and FTD (Se 73%, Sp 78%), respectively. Initial neuropsychological testing had a poor diagnostic accuracy, except for a neuropsychiatric inventory score >40 for the diagnosis of FTD (Se 73%, Sp 84%). Independent of the clinical diagnosis, medial temporal lobe atrophy and total-tau were best correlated with cognitive decline at 2 years. In conclusion, CSF biomarkers efficiently predict evolution toward an AD phenotype in CAD. Imaging biomarkers mostly contribute to the differential diagnosis between non-AD dementias. Initial neuropsychological testing was poorly contributive in CAD diagnosis. Show more

Keywords: Alzheimer's disease, biomarkers, dementia, emission-computed, frontotemporal dementia, magnetic resonance imaging, neuropsychological tests, single-photon, tomography, vascular dementia

DOI: 10.3233/JAD-2011-110761

Citation: Journal of Alzheimer's Disease, vol. 28, no. 2, pp. 323-336, 2012

Authors: Baig, Shabnam | Palmer, Laura E. | Owen, Michael J. | Williams, Julie | Kehoe, Patrick G. | Love, Seth

Article Type: Research Article

Abstract: Clusterin, a multifunctional lipoprotein is expressed in a number of tissues but expression is particularly high in the brain, where it binds to amyloid-β (Aβ), possibly facilitating Aβ transport into the bloodstream. Its concentration in peripheral blood was identified as a potential biomarker for Alzheimer's disease (AD) and predicted retention of 11 C–Pittsburgh Compound B in the temporal lobe. Single-nucleotide polymorphisms in the clusterin gene, CLU, are associated with the risk of developing AD. We measured clusterin mRNA levels in control and AD brains and investigated the relationship of the clusterin protein to soluble, insoluble, and plaque-associated Aβ. Clusterin mRNA …levels were unchanged when normalized to GAPDH but modestly increased in the frontal and temporal cortex in AD in relation to NSE and MAP-2. Levels of NSE and MAP-2 mRNA were reduced in the AD frontal cortex. Clusterin protein concentration was unchanged and did not correlate with the amount of Aβ present. In the frontal cortex, clusterin concentration was higher in APOE ε4-negative brains but no effect of APOE was detected in the temporal cortex or thalamus. Overall clusterin mRNA and protein levels are unaltered in the neocortex in AD and clusterin concentration does not reflect Aβ content. The increase in clusterin noted in peripheral blood in AD may reflect increased passage of this chaperone protein across the blood-brain barrier but further work is needed to determine how CLU variants influence the development of AD. Show more

Keywords: Alzheimer's disease, amyloid-β, apolipoprotein E, clusterin

DOI: 10.3233/JAD-2011-110473

Citation: Journal of Alzheimer's Disease, vol. 28, no. 2, pp. 337-344, 2012

Authors: Yang, ShaoNan | Wang, ShengQing | Peng, Nan | Xie, ZhaoHong | Wang, Ping | Zhao, CuiPing | Wei, LiFei | Yang, Hui | Zhao, BaoXiang | Miao, JunYing | Bi, JianZhong

Article Type: Research Article

Abstract: Excessive extracellular deposition of amyloid-β peptides (Aβ) is a characteristic pathologic feature of Alzheimer's disease (AD). Accumulating evidence indicates that macroautophagy is involved in the pathogenesis of AD, but the exact role of macroautophapy is still unclear. We investigated whether Aβ25-35 could cause reactive oxygen species (ROS) accumulation, decrease the activity of Na+ , K+ -ATPase, trigger an autophagy process, and inhibit the growth of PC12 cells and examined the effect of a new autophagy modulator, butyrolactone derivative 3-benzyl-5-((2-nitrophenoxy) methyl)-dihydrofuran-2(3 H)-one (3BDO). 3BDO could block the decrease in cell viability induced by Aβ25-35 by inhibiting ROS accumulation and …the decrease in activity of Na+ , K+ -ATPase and the autophagy process. In addition, 3BDO modulated the autophagy progress via a mammalian target of rampamycin-dependent pathway. 3BDO has a protective effect against the cytotoxicity induced by Aβ25-35 and might be a promising tool for AD research. Show more

Keywords: Alzheimer disease, amyloid-β, autophagy, Na+, K+-ATPase, mTOR, reactive oxygen species

DOI: 10.3233/JAD-2011-110863

Citation: Journal of Alzheimer's Disease, vol. 28, no. 2, pp. 345-356, 2012

Authors: Becerra, Judith | Fernández, Thalía | Roca-Stappung, Milene | Díaz-Comas, Lourdes | Galán, Lídice | Bosch, Jorge | Espino, Marbella | Moreno, Alma J | Harmony, Thalía

Article Type: Research Article

Abstract: In normal elderly subjects, the best electroencephalogram (EEG)-based predictor of cognitive impairment is theta EEG activity abnormally high for their age. The goal of this work was to explore the effectiveness of a neurofeedback (NFB) protocol in reducing theta EEG activity in normal elderly subjects who present abnormally high theta absolute power (AP). Fourteen subjects were randomly assigned to either the experimental group or the control group; the experimental group received a reward (tone of 1000 Hz) when the theta AP was reduced, and the control group received a placebo treatment, a random administration of the same tone. The results …show that the experimental group exhibits greater improvement in EEG and behavioral measures. However, subjects of the control group also show improved EEG values and in memory, which may be attributed to a placebo effect. However, the effect of the NFB treatment was clear in the EG, although a placebo effect may also have been present. Show more

Keywords: Cognitive impairment, electroencephalogram (EEG) biofeedback, global deterioration scale, healthy aging, neurofeedback, placebo, quantitative electroencephalogram (QEEG)

DOI: 10.3233/JAD-2011-111055

Citation: Journal of Alzheimer's Disease, vol. 28, no. 2, pp. 357-367, 2012

Authors: Velayudhan, Latha | Killick, Richard | Hye, Abdul | Kinsey, Anna | Güntert, Andreas | Lynham, Steven | Ward, Malcolm | Leung, Rufina | Lourdusamy, Anbarasu | To, Alvina W.M. | Powell, John | Lovestone, Simon

Article Type: Research Article

Abstract: Diagnosis of the progressive neurodegenerative disorder Alzheimer's disease (AD) can only definitively be made postmortem. The most promising AD biomarkers identified to date are found in cerebrospinal fluid (CSF). Among these, one of the most interesting candidates is transthyretin (TTR), the carrier of thyroxine and retinol, which also binds with amyloid-β (Aβ), and it has been suggested that it protects against Aβ deposition. A biomarker detectable in plasma would have great diagnostic value and could be of use for determining disease progression and the monitoring of therapeutic efficacy due to its greater accessibility over CSF-based markers. We aimed to validate …TTR as a prognostic marker in AD and to determine its relation with cognitive measures. We examined the plasma protein levels of TTR in 90 people with late-onset AD and 50 age-matched non-demented controls (NDC) by immunoblotting and found lower plasma TTR levels in AD compared to NDC (p = 0.004). We then quantified plasma TTR by enzyme-linked immunosorbent assays in a larger independent cohort (n = 270) including subjects with mild to severe AD. Plasma TTR levels were significantly lower in AD cases with rapid cognitive decline and with severe cognitive impairment. Regression analyses showed plasma TTR levels also predicted cognitive decline over the ensuing 6 months. These data indicate that plasma TTR is a strong candidate AD biomarker that should be included in the development of blood based biomarker panels for disease diagnosis and also suggests that plasma TTR is a marker of disease severity and progression. Show more

Keywords: Alzheimer's disease, cognitive impairment, plasma proteins, transthyretin

DOI: 10.3233/JAD-2011-110611

Citation: Journal of Alzheimer's Disease, vol. 28, no. 2, pp. 369-375, 2012

Authors: Gerrish, Amy | Russo, Giancarlo | Richards, Alexander | Moskvina, Valentina | Ivanov, Dobril | Harold, Denise | Sims, Rebecca | Abraham, Richard | Hollingworth, Paul | Chapman, Jade | Hamshere, Marian | Pahwa, Jaspreet Singh | Dowzell, Kimberley | Williams, Amy | Jones, Nicola | Thomas, Charlene | Stretton, Alexandra | Morgan, Angharad R. | Lovestone, Simon | Powell, John | Proitsi, Petroula | Lupton, Michelle K. | Brayne, Carol | Rubinsztein, David C. | Gill, Michael | Lawlor, Brian | Lynch, Aoibhinn | Morgan, Kevin | Brown, Kristelle S. | Passmore, Peter A. | Craig, David | McGuinness, Bernadette | Todd, Stephen | Johnston, Janet A. | Holmes, Clive | Mann, David | Smith, A. David | Love, Seth | Kehoe, Patrick G. | Hardy, John | Mead, Simon | Fox, Nick | Rossor, Martin | Collinge, John | Maier, Wolfgang | Jessen, Frank | Kölsch, Heike | Heun, Reinhard | Schürmann, Britta | Bussche, Hendrik van den | Heuser, Isabella | Kornhuber, Johannes | Wiltfang, Jens | Dichgans, Martin | Frölich, Lutz | Hampel, Harald | Hüll, Michael | Rujescu, Dan | Goate, Alison M. | Kauwe, John S. K | Cruchaga, Carlos | Nowotny, Petra | Morris, John C. | Mayo, Kevin | Livingston, Gill | Bass, Nicholas J. | Gurling, Hugh | McQuillin, Andrew | Gwilliam, Rhian | Deloukas, Panagiotis | Davies, Gail | Harris, Sarah E. | Starr, John M. | Deary, Ian J. | Al-Chalabi, Ammar | Shaw, Christopher E. | Tsolaki, Magda | Singleton, Andrew B. | Guerreiro, Rita | Mühleisen, Thomas W. | Nöthen, Markus M. | Moebus, Susanne | Jöckel, Karl-Heinz | Klopp, Norman | Wichmann, H-Erich | Carrasquillo, Minerva M | Pankratz, V Shane | Younkin, Steven G. | Jones, Lesley | Holmans, Peter A | O'Donovan, Michael C. | Owen, Michael J. | Williams, Julie

Article Type: Research Article

Abstract: Rare mutations in AβPP, PSEN1, and PSEN2 cause uncommon early onset forms of Alzheimer's disease (AD), and common variants in MAPT are associated with risk of other neurodegenerative disorders. We sought to establish whether common genetic variation in these genes confer risk to the common form of AD which occurs later in life (>65 years). We therefore tested single-nucleotide polymorphisms at these loci for association with late-onset AD (LOAD) in a large case-control sample consisting of 3,940 cases and 13,373 controls. Single-marker analysis did not identify any variants that reached genome-wide significance, a result which is supported by other recent …genome-wide association studies. However, we did observe a significant association at the MAPT locus using a gene-wide approach (p = 0.009). We also observed suggestive association between AD and the marker rs9468, which defines the H1 haplotype, an extended haplotype that spans the MAPT gene and has previously been implicated in other neurodegenerative disorders including Parkinson's disease, progressive supranuclear palsy, and corticobasal degeneration. In summary common variants at AβPP, PSEN1, and PSEN2 and MAPT are unlikely to make strong contributions to susceptibility for LOAD. However, the gene-wide effect observed at MAPT indicates a possible contribution to disease risk which requires further study. Show more

Keywords: Alzheimer's disease, amyloid-β protein precursor, genetics, human, MAPT protein, PSEN1 protein, PSEN2 protein

DOI: 10.3233/JAD-2011-110824

Citation: Journal of Alzheimer's Disease, vol. 28, no. 2, pp. 377-387, 2012

Authors: Sun, Jiya | Feng, Xuemei | Liang, Dapeng | Duan, Yong | Lei, Hongxing

Article Type: Research Article

Abstract: A central issue in the field of Alzheimer's disease (AD) is to separate the cause from the consequence among many observed pathological features, which may be resolved by studying the time evolution of these features at distinctive stages. In this work, comprehensive analyses on transcriptome studies of human postmortem brain tissues from AD patients at distinctive stages revealed stepwise breakdown of the cellular machinery during the progression of AD. At the early stage of AD, the accumulation of amyloid-β oligomers and amyloid plaques leads to the down-regulation of biosynthesis and energy metabolism. At the intermediate stage, the progression of the …disease leads to enhanced signal transduction, while the late stage is characterized by elevated apoptosis. The down-regulation of energy metabolism in AD has been considered by many as a consequence of mitochondrion damage due to oxidative stress. However, the non-existence of enhanced response to oxidative stress and the revelation of intriguing down-regulation patterns of the electron-transport chain at different stages suggest otherwise. In contrast to the damage-themed hypothesis, we propose that the down-regulation of energy metabolism in AD is a protective response of the neurons to the reduced level of nutrient and oxygen supply in the microenvironment. The elevated apoptosis at the late stage of AD is triggered by the conflict between the low level of energy metabolism and high level of regulatory and repair burden. This new hypothesis has significant implication for pharmaceutical intervention of Alzheimer's disease. Show more

Keywords: Brain tissue, microarray, signal transduction, neuronal cell death

DOI: 10.3233/JAD-2011-111313

Citation: Journal of Alzheimer's Disease, vol. 28, no. 2, pp. 389-402, 2012

Authors: Wei, Zelan | Gabriel, Geraldine G. | Rui, Lewei | Cao, Xia | Pennington, Paul R. | Chlan-Fourney, Jennifer | Nazarali, Adil J. | Baker, Glen B. | Mousseau, Darrell D.

Article Type: Research Article

Abstract: The concentration of presenilin-1 (PS-1) protein at the mitochondrial-associated aspect of the endoplasmic reticulum supports the potential for a mitochondrial influence of PS-1. Given that carriers of certain Alzheimer's disease (AD)-related PS-1 variants are predisposed to clinical depression and that depression has been historically associated with the mitochondrial enzyme, monoamine oxidase-A (MAO-A), we investigated cortical MAO-A function in the AD-related PS-1(M146V) knock-in mouse. The MAO-A system was clearly altered in the PS-1(M146V) mouse as revealed by (a) a mismatch between MAO-A protein expression and MAO-A activity; (b) changes in MAO-A-mediated monoaminergic neurotransmitter metabolism; (c) changes in non-cognitive behavior following treatment …with the irreversible MAO-A inhibitor clorgyline; and (d) an increase in the potency of clorgyline in these same mice. We next investigated whether PS-1(M146V) could be influencing MAO-A directly. We observed (a) an enhanced MAO-A activity in necropsied PS-1(M146V) mouse cortical extracts incubated with DAPT (a PS-1 substrate-competitor); (b) the proximity of PS-1 with MAO-A and mitochondrial markers in cortical sections and in primary cortical neurons; (c) the co-segregation and co-immunoprecipitation of PS-1 and MAO-A within the mitochondrial fraction; and (d) the co-immunoprecipitation of overexpressed PS-1(M146V) and MAO-A proteins from N2a lysates. The PS-1(ΔEx9) and PS-1(D257A) variants, known to have low substrate-binding capacity, co-immunoprecipitated weakly with MAO-A. These combined data support a physical interaction between PS-1 and MAO-A that could influence MAO-A activity and contribute to the monoaminergic disruptions common to disorders as seemingly diverse as depression and AD. Show more

Keywords: Alzheimer's disease, depression, mitochondria, monoamine oxidase, secretase

DOI: 10.3233/JAD-2011-111241

Citation: Journal of Alzheimer's Disease, vol. 28, no. 2, pp. 403-422, 2012

Authors: Lee, Sangmook | Lemere, Cynthia A. | Frost, Jeffrey L. | Shea, Thomas B.

Article Type: Research Article

Abstract: S-adenosyl methionine (SAM) contributes to multiple pathways in neuronal homeostasis, several of which are compromised in age-related neurodegeneration and Alzheimer's disease. Dietary supplementation of transgenic mice with SAM maintained acetylcholine levels, cognitive performance, oxidative buffering capacity, and phosphatase activity, and reduced aggression, calcium influx, endogenous PS-1 expression, γ-secretase activity, and levels of amyloid-β (Aβ) and phospho-tau. Herein, we examined whether or not SAM could delay neuropathology in 3xTg-AD mice, which harbor mutant genes for human AβPP, PS-1 and tau. Mice received a standard AIN-76 diet with or without SAM (100 mg/kg diet) for 1 month commencing at 10 months of …age or for 3 months commencing at 12.5 months of age; mice were sacrificed and examined for Aβ and tau neuropathology at 11 and 15.5 months of age, respectively. SAM supplementation reduced hippocampal intracellular AβPP/Aβ and phospho-tau immunoreactivity to a similar extent at both sampling intervals. Supplementation reduced the number of extracellular Aβ deposits by 80% (p < 0.01) at 11 months of age after 1 month of treatment but only by 24% (p < 0.34) at 15.5 months of age after 3 months of treatment. As anticipated, neurofibrillary tangles were not observed in mice at these young ages; however, supplementation reduced levels of phospho-tau and caspase-cleaved tau within Sarkosyl-insoluble preparations in mice at 15.5 months of age. These limited analyses indicate that SAM can modulate the time course of AD neuropathology, and support further long-term analyses. Show more

Keywords: Alzheimer's disease, amyloid-β, neurofibrillary tangles, S-adenosylmethionine, senile plaques, tau

DOI: 10.3233/JAD-2011-111025

Citation: Journal of Alzheimer's Disease, vol. 28, no. 2, pp. 423-431, 2012

Authors: Huang, Jeffrey Y. | Hafez, Daniel M. | James, Bryan D. | Bennett, David A. | Marr, Robert A.

Article Type: Research Article

Abstract: Neprilysin-2 (NEP2), a close homolog of neprilysin (NEP), degrades amyloid-β (Aβ) and serves an important role in clearing Aβ in vivo. We measured NEP2 and NEP mRNA levels from non-impaired (NI), mild cognitive impaired (MCI), and clinical Alzheimer's disease (AD) subjects in the mid-temporal gyrus, mid-frontal gyrus, caudate, and cerebellum. NEP2 activity levels were also determined. Our results indicate that NEP2 and NEP mRNA expression is altered in MCI subjects relative to NI subjects in AD-susceptible regions. NEP2 enzymatic activity was lowered in association with MCI and AD and was positively associated with cognitive function, independent of diagnostic category. Our …finding that NEP2 expression and activity are altered in MCI is significant as these changes may potentially serve as preclinical markers for AD and reduced NEP2 activity may be associated with the development of AD. Show more

Keywords: Alzheimer's disease, amyloid-β peptide, biomarker, human brain, neprilysin, neprilysin-2

DOI: 10.3233/JAD-2011-111307

Citation: Journal of Alzheimer's Disease, vol. 28, no. 2, pp. 433-441, 2012

Authors: Darreh-Shori, Taher | Siawesh, Manar | Mousavi, Malahat | Andreasen, Niels | Nordberg, Agneta

Article Type: Research Article

Abstract: Butyrylcholinesterase K (BCHE-K) is associated with increased risk of developing Alzheimer's disease (AD) in apolipoprotein ε (APOE4) carriers, while among APOE4 non-carriers BCHE-K appears to be protective. Nonetheless, pure pharmacogenetic reports have provided conflicting results. To provide insights about these controversies, we combined BCHE-K pharmacogenetic observations in AD patients (n = 179) with proteomic and enzymatic analysis of plasma, cerebrospinal fluid (CSF), or both samples. We found that BCHE-K genotype was overrepresented among the AD patients (χ2 = 14.21, p < 0.0001). Plasma BuChE activity was gene dose-dependently 20–50% less among K-carriers (p < 0.001). CSF BuChE activity did …not show such robust K-gene dosage-dependency, because K homozygotes (n = 9) had 30–40% less activity compared to both non-carriers (n = 78, p < 0.01) and heterozygotes (n = 42, p < 0.09). CSF ApoE protein expression was also altered by presence of K-allele (p < 0.001, n = 129). Mutually, APOE4 altered phenotypic display of BuChE variants in CSF (p < 0.01, n = 129). In absence of APOE4, CSF BuChE activity was essentially indistinguishable among K-carriers (n = 16) and non-carriers (n = 17, p < 0.8) although the K-carriers had 24–39% less circulating BuChE protein. In contrast in presence of APOE4, the K-carriers (n = 35) had K allele dose-dependently a BuChE phenotype with 14–46% reduced activity compared to K non-carriers (p < 0.001, n = 59), despite an essentially identical BChE concentration in CSF (1 ± 4%, p < 0.8). Pattern of the patients' cognitive performance in MMSE closely resembled the APOE4-derived phenotypic display of BuChE variants. APOE4-dependent outcome of BCHE-K genotype as AD risk factor arises through a differential phenotypic modulation of BuChE. Future pharmacogenetic studies should include assessment of the subjects' true phenotypic display of BuChE. Show more

Keywords: Acetylcholinesterase, Alzheimer's disease, apolipoprotein ε4 genotype, cutyrylcholinesterase K variant, central cholinergic system, pharmacogenetic

DOI: 10.3233/JAD-2011-111088

Citation: Journal of Alzheimer's Disease, vol. 28, no. 2, pp. 443-458, 2012

Authors: Avdesh, Avdesh | Martin-Iverson, Mathew T. | Mondal, Alinda | Chen, Mengqi | Askraba, Sreten | Morgan, Newman | Lardelli, Michael | Groth, David M. | Verdile, Giuseppe | Martins, Ralph N.

Article Type: Research Article

Abstract: There is growing interest in using zebrafish (Danio rerio) as a model of neurodegenerative disorders such as Alzheimer's disease. A zebrafish model of tauopathies has recently been developed and characterized in terms of presence of the pathological hallmarks (i.e., neurofibrillary tangles and cell death). However, it is also necessary to validate these models for function by assessing learning and memory. The majority of tools to assess memory and learning in animal models involve visual stimuli, including color preference. The color preference of zebrafish has received little attention. To validate zebrafish as a model for color-associated-learning and memory, it is necessary …to evaluate its natural preferences or any pre-existing biases towards specific colors. In the present study, we have used four different colors (red, yellow, green, and blue) to test natural color preferences of the zebrafish using two procedures: Place preference and T-maze. Results from both experiments indicate a strong aversion toward blue color relative to all other colors (red, yellow, and green) when tested in combinations. No preferences or biases were found among reds, yellows, and greens in the place preference procedure. However, red and green were equally preferred and both were preferred over yellow by zebrafish in the T-maze procedure. The results from the present study show a strong aversion towards blue color compared to red, green, and yellow, with yellow being less preferred relative to red and green. The findings from this study may underpin any further designing of color-based learning and memory paradigms or experiments involving aversion, anxiety, or fear in the zebrafish. Show more

Keywords: Alzheimer's disease, color preference, learning and memory, place preference, T-maze, zebrafish

DOI: 10.3233/JAD-2011-110704

Citation: Journal of Alzheimer's Disease, vol. 28, no. 2, pp. 459-469, 2012

Authors: Zhou, Jin-Wu | Cheng, Xiao-Rui | Cheng, Jun-Ping | Zhou, Wen-Xia | Zhang, Yong-xiang

Article Type: Research Article

Abstract: The senescence accelerated mouse prone 8 (SAMP8), an animal model of Alzheimer's disease, has amyloid-β deposition in the brain. This study showed that β-secretase activity increased age-dependently in cerebral cortex of SAMP8 and SAMP8's control, SAM resistant/1 (SAMR1), and was higher in the hippocampus of SAMP8 than that of age-matched SAMR1. Cathepsin D activity also increased age-dependently in the cerebral cortex of SAMP8. There was no significant difference between SAMP8 and SAMR1 with regards to activity of cathepsin B. β-secretase activity had a positive correlation with cathepsin D activity in the cerebral cortex of SAMR1 and SAMP8. There was a …tendency toward decreased mRNA expression of BACE1, cathepsin D, and cathepsin B in the hippocampus of SAMR1 and SAMP8 with aging. mRNA expression of cathepsin B was elevated significantly in the cerebral cortex of SAMP8 at 2 and 6 months of age compared to that of age-matched SAMR1, and similarly so was cathepsin D at 2 months. This data showed there was no correlation between mRNA expression and activity of β-secretase, cathepsin D, and cathepsin B in the brain of SAMR1 and SAMP8 with age. These findings also indicate it was cathepsin D, not cathepsin B, that contributed to β-secretase activity and the increased amyloid-β production in the SAMP8 brain. In addition, it was necessary to take into account the target selectivity of BACE1 and cathepsin D, not necessary to detect the mRNA expression, when SAMP8 was used as an animal model to determine the effect of β-secretase inhibitor. Show more

Keywords: β-secretase, cerebral cortex, hippocampus, senescence-accelerated mouse

DOI: 10.3233/JAD-2011-111469

Citation: Journal of Alzheimer's Disease, vol. 28, no. 2, pp. 471-480, 2012

Authors: White, Lon R.

Article Type: Research Article

DOI: 10.3233/JAD-2011-111269

Citation: Journal of Alzheimer's Disease, vol. 28, no. 2, pp. 481-483, 2012

Authors: Keage, Hannah A.D. | Ince, Paul G. | Matthews, Fiona E. | Wharton, Stephen B. | McKeith, Ian G. | Brayne, Carol | on behalf of MRC CFAS and CC75C

Article Type: Research Article

Abstract: Epidemiological studies investigating the pathological bases of late onset dementia focus on classical markers such as plaques and tangles. The significance of pathologies characteristically associated with rare dementia syndromes such as Pick bodies and severe neuronal loss are considered to be well defined. The significance of other pathologies, often accepted as a feature of neurodegenerative syndromes, such as Hirano bodies and gliosis is not clear. This study investigated the significance of these rarer and ‘disregarded’ pathologies to dementia in the population. A total of 627 individuals aged 71–103 from the Epidemiological CLInicoPathologial Studies in Europe (EClipSE) project with clinical dementia …status at death determined were assessed. Pathologies assessed included Pick bodies, severe neuronal loss, gliosis, and granulovacuolar degeneration (GVD) in the cortex and/or hippocampus, along with brainstem plaques, tangles, neuronal loss, gliosis, pigmentary incontinence, and Lewy bodies. All pathologies were associated with dementia when controlling for plaques and tangles except Hirano bodies, GVD, and brainstem plaques. These included hippocampal and entorhinal gliosis; cortical, hippocampal, and entorhinal neuronal loss; along with brainstem neuronal loss, gliosis, pigmentary incontinence, Lewy bodies, and tangles. Pick bodies were present in five individuals, all with clinical dementia. These epidemiological data indicate that dementia in old age is associated with a broad range of pathological and anatomical substrates pointing to potential areas for future research, particularly the brainstem. Show more

Keywords: Age, aging, brain, dementia, pathology

DOI: 10.3233/JAD-2011-111268

Citation: Journal of Alzheimer's Disease, vol. 28, no. 2, pp. 485-493, 2012

Article Type: Other

DOI: 10.3233/JAD-2011-111270

Citation: Journal of Alzheimer's Disease, vol. 28, no. 2, pp. 495-496, 2012