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

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