Journal of Alzheimer's Disease - Volume 16, issue 2

Authors: Xu, Xuemin

Article Type: Review Article

Abstract: The biogenesis of the amyloid-β peptide (Aβ) is a central issue in Alzheimer's disease (AD) research. Aβ is produced by β- and γ-secretases from the amyloid-β protein precursor (AβPP). These proteases are targets for the development of therapeutic compounds to downregulate Aβ production. γ-secretase has received more attention 1) because it generates the C-terminus of Aβ, which is important in the pathogenesis of AD because the longer Aβ species are more amyloidogenic, and 2) because it cleaves AβPP within its transmembrane domain. In the understanding the mechanism of γ-secretase cleavage, three major cleavage sites have been identified, namely, γ-cleavage site …at Aβ40/42 , ζ-cleavage site at Aβ46 , and ε-cleavage site at Aβ49 . Moreover, the novel finding that some of the known γ-secretase inhibitors inhibit the formation of secreted Aβ40 and Aβ42 , but cause an intracellular accumulation of long Aβ46 , provided information extremely important for the development of strategies aimed at the design of γ-secretase inhibitors to prevent and treat AD. In addition, it has been established that the C-terminus of Aβ is generated by a series of sequential cleavages: first, ε-cleavage, followed by ζ-cleavage and finally by γ-cleavage, commencing from the membrane boundary to the middle of the AβPP membrane domain. Show more

Keywords: Alzheimer's disease, amyloid, amyloid-β protein precursor, presenilin, secretase

DOI: 10.3233/JAD-2009-0957

Citation: Journal of Alzheimer's Disease, vol. 16, no. 2, pp. 211-224, 2009

Authors: Small, David H. | Gasperini, Robert | Vincent, Adele J. | Hung, Amos C. | Foa, Lisa

Article Type: Review Article

Abstract: Although many of the biochemical mechanisms which regulate production or clearance of the amyloid-β protein (Aβ) of Alzheimer's disease (AD) are now well understood, the mechanism of Aβ neurotoxicity remains unclear. A number of studies have shown that Aβ can disrupt neuronal Ca2+ homeostasis by inducing influx of extracellular Ca2+ into the neuronal cytoplasm. Ca2+ is known to play an important role in neuronal excitability, synaptic plasticity and neurotoxicity. Therefore, Aβ-induced Ca2+ dysregulation may contribute to many of the cognitive and neuropathologic features of AD. In vitro studies show that Aβ can increase ion permeability in …lipid membranes. This increased permeability is reportedly associated with the formation of artificial ion pores formed from Aβ oligomers. However, a number of other studies show that Aβ can activate endogenous ion channels on the cell surface. There is also increasing evidence that presenilin mutations alter intracellular Ca2+ stores. It is likely that elucidation of the mechanism by which Aβ and presenilin cause Ca2+ dysregulation in neurons will help to identify new drug targets for the treatment of AD. Show more

Keywords: Alzheimer's disease, amyloid, calcium, neurotoxicity, synaptic plasticity

DOI: 10.3233/JAD-2009-0951

Citation: Journal of Alzheimer's Disease, vol. 16, no. 2, pp. 225-233, 2009

Authors: Andrieu, Sandrine | Coley, Nicola | Aisen, Paul | Carrillo, Maria C. | DeKosky, Steven | Durga, Jane | Fillit, Howard | Frisoni, Giovanni B. | Froelich, Lutz | Gauthier, Serge | Jones, Roy | Jönsson, Linus | Khachaturian, Zaven | Morris, John C. | Orgogozo, Jean-Marc | Ousset, Pierre-Jean | Robert, Philippe | Salmon, Eric | Sampaio, Cristina | Verhey, Frans | Wilcock, Gordon | Vellas, Bruno

Article Type: Review Article

Abstract: The prevention of neurodegenerative dementias, such as Alzheimer's disease, is a public health priority. Due to the large numbers of affected patients, even interventions bringing about a relatively small delay in disease onset could have large public health effects. Randomized controlled trials (RCTs) are required to demonstrate the effectiveness of preventive interventions, but such trials raise specific methodological questions because they are new in the field of neurodegenerative diseases, and require large numbers of elderly subjects and lengthy follow-up periods. We performed a literature search to identify primary prevention RCTs for neurodegenerative dementia. The methodology of the trials was summarized …and discussed during two expert meetings. Overall, 39 trials were identified that assessed dementia incidence or cognitive decline as a primary or secondary study outcome. Age was the most common selection criteria for target populations. Follow-up periods ranged from one month to nine years and were longest in studies measuring dementia incidence as an outcome. Results of RCTs have so far been generally negative and conflicting with those of observational studies, perhaps due to methodological issues. Future trials must therefore carefully consider the target population, outcomes and duration of follow-up to be used, and should assess the problem of attrition. Show more

Keywords: Alzheimer's disease, clinical trials, clinical trials methodology, cognitive aging, cognitive decline, dementia, prevention trials, study design

DOI: 10.3233/JAD-2009-0971

Citation: Journal of Alzheimer's Disease, vol. 16, no. 2, pp. 235-270, 2009

Authors: Veo, Bethany L. | Krushel, Les A.

Article Type: Short Communication

Abstract: Neurofibrillary tangles are a pathological phenotype in Alzheimer's disease (AD) and are caused by the hyperphosphorylation of the microtubule associated protein tau. In mouse models of AD, decreasing tau protein expression limits the severity of symptoms and inhibits progression of AD. We now report that the 5' leader in the human tau mRNA contains an internal ribosomal entry site (IRES) and that IRES-dependent translation plays a role in the synthesis of tau protein. Consequently, targeting the tau IRES provides a novel target for regulating tau expression in AD and other tauopathies.

Keywords: Alzheimer's disease, internal ribosomal entry site, protein synthesis, tauopathy

DOI: 10.3233/JAD-2009-0978

Citation: Journal of Alzheimer's Disease, vol. 16, no. 2, pp. 271-275, 2009

Authors: Okereke, Olivia I. | Xia, Weiming | Irizarry, Michael C. | Sun, Xiaoyan | Qiu, Wei Q. | Fagan, Anne M. | Mehta, Pankaj D. | Hyman, Bradley T. | Selkoe, Dennis J. | Grodstein, Francine

Article Type: Research Article

Abstract: Identifying biomarkers of Alzheimer's disease (AD) risk will be critical to effective AD prevention. Levels of circulating amyloid-β (Aβ) 40 and 42 may be candidate biomarkers. However, properties of plasma Aβ assays must be established. Using five different protocols, blinded samples were used to assess: intra-assay reproducibility; impact of EDTA vs. heparin anticoagulant tubes; and effect of time-to-blood processing. In addition, percent recovery of known Aβ concentrations in spiked samples was assessed. Median intra-assay coefficients of variation for the assay protocols ranged from 6–24% for Aβ40 , and 8–14% for Aβ42 . There were no systematic differences in reproducibility by …collection method. Plasma concentrations of Aβ (particularly Aβ42 ) appeared stable in whole blood kept in ice packs and processed as long as 24 hours after collection. Recovery of expected concentrations was modest, ranging from −24% to 44% recovery of Aβ40 , and 17% to 61% of Aβ42 . In conclusion, across five protocols, plasma Aβ40 and Aβ42 levels were measured with generally low error, and measurements appeared similar in blood collected in EDTA versus heparin. While these preliminary findings suggest that measuring plasma Aβ40 and Aβ42 may be feasible in varied research settings, additional work in this area is necessary. Show more

Keywords: Alzheimer's disease, amyloid, assay reliability, biomarker, quality control

DOI: 10.3233/JAD-2009-0948

Citation: Journal of Alzheimer's Disease, vol. 16, no. 2, pp. 277-285, 2009

Authors: Ling, Zhi-Qun | Tian, Qing | Wang, Li | Fu, Zheng-Qi | Wang, Xiao-Chuan | Wang, Qun | Wang, Jian-Zhi

Article Type: Research Article

Abstract: Most patients with Alzheimer's disease (AD) present decreased levels of melatonin, a day-night rhythm-related hormone. To investigate the role of melatonin deficiency in AD, we used constant illumination to interrupt melatonin metabolism and measured some of the AD-like alterations in rats. Concomitant with decreased serum melatonin, the rats developed spatial memory deficits, tau hyperphosphorylation at multiple sites, activation of glycogen synthase kinase-3 and protein kinase A, as well as suppression of protein phosphatase-1. Prominent oxidative damage and organelle lesions, demonstrated by increased expression of endoplasmic reticulum (ER) stress-related proteins including BiP/GRP78 and CHOP/GADD153, decreased number of rough ER and free …ribosome, thinner synapses, and increased superoxide dismutase and monoamine oxidase were also observed in the light exposed rats. Simultaneous supplement of melatonin partially arrested the behavioral and molecular impairments. It is suggested that melatonin deficiency may be an upstream effector responsible for the AD-like behavioral and molecular pathologies with ER stress-involved mechanisms. Show more

Keywords: Alzheimer's disease, endoplasmic reticulum stress, light illumination, melatonin, tau

DOI: 10.3233/JAD-2009-0949

Citation: Journal of Alzheimer's Disease, vol. 16, no. 2, pp. 287-300, 2009

Authors: Zhou, Dawang | Zambrano, Nicola | Russo, Tommaso | D'Adamio, Luciano

Article Type: Research Article

Abstract: The phosphorylation of Tyr-682 residue in the intracellular domain (AID) of amyloid-β protein precursor (AβPP) is significantly enhanced in Alzheimer's disease patients' brain. The role of this phosphotyrosine, however, remains elusive. Here we report that phosphorylation of Tyr-682 inhibits the interactions between AβPP and Fe65, which is the main regulatory mechanism controlling Fe65 nuclear signaling. Furthermore, we show that tyrosine phosphorylation of AβPP also inhibits interaction of the two other Fe65 family members, Fe65L1 and Fe65L2. Likewise, docking of Fe65, Fe65L1 and Fe65L2 to APLP1 and APLP2, the two other members of the AβPP-gene family, is abolished by analogous phosphorylation …events. Our results indicate that phosphorylation of the cytoplasmic tail of AβPP on Tyr-682 represents a second mechanism, alternative to AβPP processing by secretases, that regulates AβPP/Fe65 downstream signaling pathways. Show more

Keywords: Amyloid-β protein precursor, Fe65, phosphorylation, threonine, tyrosine

DOI: 10.3233/JAD-2009-0970

Citation: Journal of Alzheimer's Disease, vol. 16, no. 2, pp. 301-307, 2009

Authors: Schroeder, Anja | Fahrenholz, Falk | Schmitt, Ulrich

Article Type: Research Article

Abstract: The α-secretase cleaves in the non-amyloidogenic pathway the amyloid-β protein precursor (AβPP) within the region of the amyloid-β peptides to prevent their formation and aggregation in the brain. Members of the ADAM family (a disintegrin and metalloprotease) are the main candidates for physiologically relevant α-secretases. We recently demonstrated that overexpression of ADAM10 in mice transgenic for human AβPP (ADAM10 x APP[V717I] ) alleviated functional deficits related to Alzheimer's disease. To further demonstrate that this is due to the specific activity of α-secretase, we characterized mice overexpressing an inactive form of ADAM10 (ADAM10[E384A] ; ADAM10-dn). Three lines of mice (controls (C57Bl/6 …x FVB), APP[V717I] transgenics and ADAM10-dn x APP[V717I] double-transgenics) were investigated with respect to learning and memory in the Morris water maze. Double-transgenic mice overexpressing ADAM10-dn behaved similar to APP[V717I] overexpressing mice. This provides further evidence that ADAM10 in vivo by its enzymatic activity is able to counteract cognitive deficits. Stimulation of α-secretase activity might thus be a suitable approach to study treatment strategies of Alzheimer's disease. Show more

Keywords: ADAM10 dominant-negative, α-secretase, Alzheimer's disease, transgenic mice

DOI: 10.3233/JAD-2009-0952

Citation: Journal of Alzheimer's Disease, vol. 16, no. 2, pp. 309-314, 2009

Authors: Nuntagij, Paworn | Oddo, Salvatore | LaFerla, Frank M. | Kotchabhakdi, Naiphinich | Ottersen, Ole P. | Torp, Reidun

Article Type: Research Article

Abstract: Little is known about how amyloid-β (Aβ) is deposited in relation to the complex ultrastructure of the brain. Here we combined serial section immunoelectron microscopy with 3D reconstruction to elucidate the spatial relationship between Aβ deposits and ultrastructurally identified cellular compartments. The analysis was performed in a transgenic mouse model with mutant presenilin-1, and mutant amyloid-β protein precursor (AβPP) and tau transgenes (3xTg-AD mice) and in aged dogs that develop Aβ plaques spontaneously. Reconstructions based on serial ultrathin sections of hippocampus (mice) or neocortex (dogs) that had been immunolabeled with Aβ (Aβ1–42 ) antibodies showed that the organization of extracellular …Aβ deposits is more complex than anticipated from light microscopic analyses. In both species, deposits were tightly associated with plasma membranes of pyramidal cell bodies and major dendrites. The deposits typically consisted of thin sheets as well as slender tendrils that climbed along the large caliber dendritic stems of pyramidal neurons. No preferential association was observed between Aβ deposits and thin dendritic branches or spines, nor was there any evidence of preferential accumulation of Aβ around synaptic contacts or glial processes. Our data suggest that plaque formation is a precisely orchestrated process that involves specialized domains of dendrosomatic plasma membranes. Show more

Keywords: Aged dogs, amyloid-β, electron microscopy, 3D images, immunocytochemistry, 3xTg mice

DOI: 10.3233/JAD-2009-0962

Citation: Journal of Alzheimer's Disease, vol. 16, no. 2, pp. 315-323, 2009

Authors: Marques, Marcos A. | Kulstad, J. Jacob | Savard, Christopher E. | Green, Pattie S. | Lee, Sum P. | Craft, Suzanne | Watson, G. Stennis | Cook, David G.

Article Type: Research Article

Abstract: Amyloid-β (Aβ) is cleared from the brain by both proteolytic digestion and transport across the blood-brain-barrier into the peripheral circulatory system. To investigate the role peripheral Aβ levels play in regulating Aβ brain clearance, we measured the clearance of [125 I]-Aβ1–40 injected into the brains of liver-ligated rats that allowed peripheral Aβ levels to be maintained at elevated levels for approximately one hour with/without a single peripheral bolus of unlabeled Aβ1–40 . We found that elevating peripheral Aβlevels significantly decreased [125 ]-Aβ1–40 brain clearance, thus supporting the hypothesis that peripheral Aβ levels regulate Aβ clearance from the central …nervous system. Show more

Keywords: Alzheimer's disease, blood-brain-barrier, hepatic clearance, liver, passive immunization, peripheral sink

DOI: 10.3233/JAD-2009-0964

Citation: Journal of Alzheimer's Disease, vol. 16, no. 2, pp. 325-329, 2009

Authors: Ji, Chao | Li, Qing | Aisa, HajiAkber | Yang, Nan | Dong, Yi-Long | Liu, Yan-Yong | Wang, Tao | Hao, Qiang | Zhu, Hai-Bo | Zuo, Ping-Ping

Article Type: Research Article

Abstract: Excitotoxicity is one of the most extensively studied processes of neuronal death and plays an important role in Alzheimer's disease. In the present study, the protective effects of Gossypium herbaceam extracts (GHE) on learning and memory impairment induced by excitatory neurotoxin ibotenic acid were examined in vivo using Morris water maze. Furthermore, neuroprotective effects of GHE were investigated with methods of immunohistochemistry and biochemistry. Our data showed that oral administration with GHE at the doses of 35, 70 and 140 mg/kg exerted an improved effect on the learning and memory impairment in rats induced by intracerebral injection of ibotenic acid. …To confirm the precise mechanism of memory improvement by presence of GHE, we further investigated the potential protection on the hippocampus. Our findings suggest that GHE afforded a beneficial inhibition on pro-apoptosis proteins expression following ibotenic acid. Additionally, calcium pump activity and calbindin-D28k expression were dramatically increased after GHE treatment, implicating that the modulation of calcium homeostasis could be involved in the mechanism underlying neuroprotection of GHE against ibotenic acid-induced excitotoxicity. These data suggested that GHE could be a potential agent for preventing or retarding the development or progression of Alzheimer's disease. Show more

Keywords: Alzheimer's disease, apoptosis regulatory proteins, calbindin, Gossypium herbaceam, ibotenic acid

DOI: 10.3233/JAD-2009-0979

Citation: Journal of Alzheimer's Disease, vol. 16, no. 2, pp. 331-339, 2009

Authors: Wozniak, Matthew A. | Frost, Alison L. | Itzhaki, Ruth F.

Article Type: Research Article

Abstract: Neurofibrillary tangles are one of the main neuropathological features of Alzheimer's disease (AD) and are composed of abnormally phosphorylated forms of a microtubule-associated protein called tau. What causes this abnormal phosphorylation is unknown. Our previous studies have implicated herpes simplex virus type 1 (HSV1) as an etiological agent in AD, and so we investigated whether infection with this virus induces AD-like tau phosphorylation. Here we demonstrate that HSV1 causes tau phosphorylation at several sites, including serine 202, threonine 212, serine 214, serine 396 and serine 404. In addition, we have elucidated the mechanism involved by showing that the virus induces …glycogen synthase kinase 3β and protein kinase A, the enzymes that cause phosphorylation at these sites. Our data clearly reveal the importance of HSV1 in AD-type tau phosphorylation, and support the case that the virus is a cause of the disease. Together with our previous data, our results point to the use of antiviral agents to slow the progression of the disease. Show more

Keywords: Alzheimer's disease, glycogen synthase kinase 3β, herpes simplex virus type 1, phosphorylation, protein kinase A, tau

DOI: 10.3233/JAD-2009-0963

Citation: Journal of Alzheimer's Disease, vol. 16, no. 2, pp. 341-350, 2009

Authors: Brys, Miroslaw | Glodzik, Lidia | Mosconi, Lisa | Switalski, Remigiusz | De Santi, Susan | Pirraglia, Elizabeth | Rich, Kenneth | Kim, Byeong C. | Mehta, Pankaj | Zinkowski, Ray | Pratico, Domenico | Wallin, Anders | Zetterberg, Henrik | Tsui, Wai H. | Rusinek, Henry | Blennow, Kaj | de Leon, Mony J.

Article Type: Research Article

Abstract: Little is known of combined utility of magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) biomarkers for prediction of Alzheimer's disease (AD) and longitudinal data is scarce. We examined these biomarkers at baseline and longitudinally in incipient AD. Forty-five subjects [21 controls (NL-NL), 16 stable MCI (MCI-MCI), 8 MCI who declined to AD (MCI-AD)] received MRI and lumbar puncture at baseline and after 2 years. CSF measures included total and phosphorylated tau (T-tau, P-tau231 ), amyloid-β (Aβ42 /Aβ40 ) and isoprostane. Voxel-based morphometry identified gray matter concentration (GMC) differences best distinguishing study groups and individual GMC values were calculated. Rate …of medial temporal lobe (MTL) atrophy was examined using regional boundary shift (rBS) method. At baseline, for MRI, MCI-AD showed reduced GMC-MTL, and for CSF higher CSF T-tau, P-tau231 , IP and lower Aβ42 /Aβ40 as compared with MCI-MCI or NL-NL. Longitudinally, rBS-MTL atrophy was higher in MCI-AD than in either MCI-MCI or NL-NL, particularly in the left hemisphere. CSF data showed longitudinally greater increases of isoprostane in MCI-AD as compared with NL-NL. Combining baseline CSF-P-tau231 and GMC-MTL significantly increased overall prediction of AD from 74% to 84% (pstep < 0.05). These results provide support for including multiple modalities of biomarkers in the identification of memory clinic patients at increased risk for dementia. Show more

Keywords: Alzheimer's disease, brain atrophy, cerebrospinal fluid biomarkers, early diagnosis

DOI: 10.3233/JAD-2009-0968

Citation: Journal of Alzheimer's Disease, vol. 16, no. 2, pp. 351-362, 2009

Authors: Spies, Petra E. | Melis, René J.F. | Sjögren, Magnus J.C. | Olde Rikkert, Marcel G.M. | Verbeek, Marcel M.

Article Type: Research Article

Abstract: α-Synuclein is the major constituent of Lewy bodies found in neurons in dementia with Lewy bodies (DLB) and might be of diagnostic value as a biomarker for DLB. We hypothesized that, as a consequence of increased accumulation of α-synuclein intraneuronally in DLB, the levels of α-synuclein in cerebrospinal fluid (CSF) of DLB patients would be lower than in other dementias. Our objective was to investigate the CSF levels of α-synuclein in several dementia disorders compared to control levels and to investigate the diagnostic value of CSF α-synuclein as a marker to discriminate between DLB and other types of dementia. We …analyzed the levels of α-synuclein in CSF of 40 DLB patients, 131 patients with Alzheimer's disease, 28 patients with vascular dementia, and 39 patients with frontotemporal dementia. We did not find any significant differences in CSF α-synuclein levels between DLB patients and patients with Alzheimer's disease, vascular dementia or frontotemporal dementia. We conclude that in clinically diagnosed patients, α-synuclein does not appear to be a useful biomarker for the differentiation between DLB and other types of dementia. Show more

Keywords: α-synuclein, Alzheimer's disease, cerebrospinal fluid, dementia, Lewy bodies

DOI: 10.3233/JAD-2009-0955

Citation: Journal of Alzheimer's Disease, vol. 16, no. 2, pp. 363-369, 2009

Authors: Capsoni, Simona | Covaceuszach, Sonia | Ugolini, Gabriele | Spirito, Francesca | Vignone, Domenico | Stefanini, Barbara | Amato, Gianluca | Cattaneo, Antonino

Article Type: Research Article

Abstract: Nerve growth factor (NGF) has a great potential for the treatment of Alzheimer's disease. However, the therapeutic administration of NGF represents a significant challenge, due to the difficulty to deliver relevant doses to the brain, in a safe and non-invasive way. We previously demonstrated the efficacy of a non-invasive delivery of NGF to the brain in animal models, by an intranasal route. Recently, topical eye application of NGF was proposed, as an option for the delivery of NGF to the brain. Here, we compare the efficacy of the two delivery routes of hNGF-61, a recombinant traceable form of human NGF, …in the mouse neurodegeneration model AD11. The intranasal administration appeared to be significantly more effective than the ocular one, in rescuing the neurodegenerative phenotypic hallmarks in AD11 mice. The ocular administration of hNGF-61 showed a more limited efficacy, even at higher doses. Thus, NGF nasal drops represent a viable and effective option to successfully deliver therapeutic NGF to the brain in a non-invasive manner. Show more

Keywords: Alzheimer's disease, delivery, dosage, intranasal, nerve growth factor, non-invasive, ocular, pharmacokinetic, side effects, therapeutic window

DOI: 10.3233/JAD-2009-0953

Citation: Journal of Alzheimer's Disease, vol. 16, no. 2, pp. 371-388, 2009

Authors: Hansson, Sara F. | Andréasson, Ulf | Wall, Mariann | Skoog, Ingmar | Andreasen, Niels | Wallin, Anders | Zetterberg, Henrik | Blennow, Kaj

Article Type: Research Article

Abstract: Amyloid-β(Aβ) aggregation is a major hallmark of Alzheimer's disease (AD). Previous studies have suggested that only unbound Aβ can take part in the aggregation process. Therefore, endogenous Aβ-binding proteins may have an important role in preventing AD. Here, we analyzed cerebrospinal fluid (CSF) samples from 35 subjects with AD, 18 subjects with frontotemporal dementia (FTD) and 29 non-demented controls to test if reduced Aβ-binding capacity in CSF is a specific feature of AD. A panel of known Aβ-binding CSF proteins, including β-trace/prostaglandin D2 synthase (β-trace), transthyretin (TTR), cystatin C (CysC) and α1 -antitrypsin (AAT), were quantified and related to diagnosis …and CSF levels of Aβ1–38 , Aβ1–40 and Aβ1–42 . AD patients displayed a mild reduction in the CSF levels of β-trace (p = 0.020), CysC (p = 0.017), AAT (p = 0.019) and TTR (p = 0.012) compared with controls. While the reductions in AAT and TTR were AD-specific, the levels of β-trace and CysC were also reduced in FTD. As expected, CSF Aβ1–42 was reduced in AD compared with controls (p = 0.00005) and with FTD patients (p = 0.015). Positive correlations between Aβ1–42 and β-trace, CysC and TTR, respectively, were seen only in the AD group, suggesting that deficient Aβ-binding capacity in CSF may contribute to the amyloidogenic process in AD. Show more

Keywords: α1-antitrypsin, Alzheimer's disease, amyloid-β, β-trace, cerebrospinal fluid, cystatin C, electrochemiluminescence, frontotemporal dementia, nephelometry, transthyretin

DOI: 10.3233/JAD-2009-0966

Citation: Journal of Alzheimer's Disease, vol. 16, no. 2, pp. 389-397, 2009

Authors: López-Bastida, Julio | Hart, Warren | García-Pérez, Lidia | Linertová, Renata

Article Type: Research Article

Abstract: Available treatments for Alzheimer's disease (AD) need to be evaluated in order to determine whether the clinical benefits justify their additional costs. This study evaluated the cost-effectiveness of donepezil treatment compared with no-drug treatment of mild and moderate AD from the perspective of society and the health care system in Spain. A Markov model was designed to simulate the natural history of a cohort of patients with mild and moderate AD. Monthly transition probabilities were estimated from the international literature and donepezil clinical trials. Direct medical and non-medical costs and utilities were derived from Spanish studies. Local data on tolerance …and medication withdrawal rates were incorporated into the model. Incremental cost-effectiveness ratios for a range of realistic treatment options were calculated. A probabilistic sensitivity analysis was carried out using a Monte Carlo approach with 10,000 iterations. In the baseline scenario (24 months, patients initially with mild AD) incremental cost-effectiveness for direct medical costs was 20,353 eur/QALY. When all costs were taken into account, donepezil treatment was the dominant strategy. Incremental cost-effectiveness ratios vary according to the selected perspective. For the baseline scenario, donepezil treatment is cost-effective with a probability of 95% for a threshold efficiency of 25,000 eur/QALY. Show more

Keywords: Alzheimer's disease, cost-effectiveness, donepezil, modeling, quality of life

DOI: 10.3233/JAD-2009-0965

Citation: Journal of Alzheimer's Disease, vol. 16, no. 2, pp. 399-407, 2009

Authors: Amadio, Marialaura | Pascale, Alessia | Wang, Jun | Ho, Lap | Quattrone, Alessandro | Gandy, Sam | Haroutunian, Vahram | Racchi, Marco | Pasinetti, Giulio Maria

Article Type: Research Article

Abstract: Neuronal ELAV (nELAV) proteins are RNA-binding proteins which play a physiological role in controlling gene expression in memory formation, and their alteration may contribute to cognitive impairment associated with neurodegenerative pathologies such as Alzheimer's disease (AD). Indeed, we found that the content of nELAV proteins is significantly decreased along with clinical dementia progression in the hippocampi of AD brains, where it inversely correlates with the amount of amyloid-β (Aβ). To check the direct influence of Aβ on nELAV, we performed in vitro experiments using human SH-SY5Y cells, finding that Aβ1–42 specifically determines nELAV proteins reduction. Since ADAM10 mRNA has …the predicted sequences targeted by nELAV, we investigated whether Aβ, through nELAV proteins, could originate a vicious circle affecting amyloid-β protein precursor (AβPP) processing. Immunoprecipitation experiments showed that indeed nELAV proteins bind to ADAM10 mRNA and that this binding is disrupted by Aβ1–42 exposure, resulting in a decreased ADAM10 protein expression. ADAM10 protein diminution was also found in AD hippocampi. These data show for the first time the involvement of nELAV in AD pathology and suggest that their alteration may affect genes implicated in AβPP processing. Show more

Keywords: ADAM10, Alzheimer's disease, amyloid-β, amyloid-β protein precursor processing, nELAV

DOI: 10.3233/JAD-2009-0967

Citation: Journal of Alzheimer's Disease, vol. 16, no. 2, pp. 409-419, 2009

Authors: Hatcher, Kristen | Zheng, Jian | Chen, Shu G.

Article Type: Research Article

Abstract: Prion diseases are a group of fatal neurodegenerative disorders characterized by the accumulation of a misfolded form (PrPSc ) of the cellular prion protein (PrPC ) in the brains of affected individuals. The conversion of PrPC to PrPSc is thought to involve a change in protein conformation from a normal, primarily α-helical structure into a β-sheet conformer. Few proteins have been identified that differentially interact with the two forms of PrP. It has been reported that plasminogen binds to PrPSc from a variety of prion phenotypes. We have examined potential motifs within the kringle region that may …be responsible for binding to PrP. We synthesized 12–15-mer peptides that contain small, repetitive stretches of amino acid residues found within the kringle domains of plasminogen. These synthetic peptides were found to capture PrPSc from the brain homogenates of bovine spongiform encephalopathy affected cattle, chronic wasting disease affected elk, experimental scrapie of hamsters and that of subjects affected by Creutzfeldt-Jakob disease, without binding to PrPC in unaffected controls. Therefore, we have identified critical peptide motifs that may be important for protein-protein interactions in prion disease pathogenesis. The ability of these synthetic peptides to bind preferentially to PrPSc suggests a potential application in the diagnosis of prion diseases. Show more

Keywords: Bovine spongiform encephalopathy, Creutzfeldt-Jakob disease, diagnosis, kringle domain, prion disease, prion protein

DOI: 10.3233/JAD-2009-0980

Citation: Journal of Alzheimer's Disease, vol. 16, no. 2, pp. 421-431, 2009

Authors: Ho, Lap | Yemul, Shrishailam | Wang, Jun | Pasinetti, Giulio Maria

Article Type: Research Article

Abstract: Abnormal misfoldings of the microtubule-associated protein tau, leading to the aggregation of tau into paired helical filaments that are ultimately deposited as neurofibrillary tangles, is a key neuropathologic feature of a number of neurodegenerative disorders collectively referred to as tauopathies. We recently observed that a particular grape seed polyphenolic extract (GSPE), namely, Meganatural-Az® may attenuate the generation and stability of misfolded proteins. We hypothesized that Meganatural-Az® GSPE might also attenuate tau protein misfolding that leads to the generation of tau filamentary aggregates that are critical for the initiation and progression of neurodegeneration and/or cognitive dysfunctions in tauopathies. In this study, …we used in vitro aggregations of synthetic Ac-306 VQIVYK311 tau peptide as a model system to explore whether Meganatural-Az® GSPE might modulate aggregations of tau protein. We demonstrate that this GSPE is capable of inhibiting tau peptide aggregations, as well as dissociating preformed tau peptide aggregates. Results from this study suggest that this GSPE might provide beneficial disease-modifying bioactivities in tau-associated neurodegenerative disorders by modulating tau-mediated neuropathologic mechanisms. Our observation, in conjunction with the demonstrated bioavailability, as well as safety and tolerability, of this GSPE, supports the development of Meganatural-Az® GSPE for the prevention and/or treatment of tau-associated neurodegenerative disorders. Show more

Keywords: Neurodegeneration, neurofibrillary tangles, polyphenols, tauopathies

DOI: 10.3233/JAD-2009-0969

Citation: Journal of Alzheimer's Disease, vol. 16, no. 2, pp. 433-439, 2009

Article Type: Discussion

DOI: 10.3233/JAD-2009-1007

Citation: Journal of Alzheimer's Disease, vol. 16, no. 2, pp. 441-444, 2009

Article Type: Announcement

DOI: 10.3233/JAD-2009-1029

Citation: Journal of Alzheimer's Disease, vol. 16, no. 2, pp. 445-447, 2009

Article Type: Announcement

DOI: 10.3233/JAD-2009-1001

Citation: Journal of Alzheimer's Disease, vol. 16, no. 2, pp. 449-450, 2009