Journal of Alzheimer's Disease - Volume 18, issue 1

Authors: Ji, Lina | Chauhan, Abha | Wegiel, Jerzy | Essa, Musthafa M. | Chauhan, Ved

Article Type: Research Article

Abstract: Gelsolin, a multifunctional actin-binding protein, forms a complex with amyloid-β protein and reduces the amyloid load in the transgenic mouse model of Alzheimer's disease (AD). Gelsolin consists of six homologous domains, which have specific affinities for phosphatidylinositol 4, 5-bisphosphate, calcium, and actin. During apoptosis, gelsolin is cleaved by the caspase-3 resulting in a 48 kDa carboxyl-terminal fragment (gelsolin-CTF). We report here that gelsolin is significantly cleaved in the frontal cortex of individuals with AD as compared to age-matched controls. A positive correlation was observed between the appearance of gelsolin-CTF in frontal cortex and severity of AD. Gelsolin-CTF was also observed …in apoptotic SH-SY5Y cells induced by H2 O2 or calcium ionophore A23187. In addition, lipid peroxidation was increased in the frontal cortex of AD suggesting that oxidative stress occurs in AD brain. Taken together, these results suggest that there may be a link among oxidative stress, neuronal apoptosis, and gelsolin cleavage in AD. Show more

Keywords: Alzheimer's disease, apoptosis, gelsolin, oxidative stress

DOI: 10.3233/JAD-2009-1127

Citation: Journal of Alzheimer's Disease, vol. 18, no. 1, pp. 105-111, 2009

Authors: Ferruzzi, Mario G. | Lobo, Jessica K. | Janle, Elsa M. | Cooper, Bruce | Simon, James E. | Wu, Qing-Li | Welch, Cara | Ho, Lap | Weaver, Connie | Pasinetti, Giulio M.

Article Type: Research Article

Abstract: The present study explored the bioavailability and brain deposition of a grape seed polyphenolic extract (GSPE) previously found to attenuate cognitive deterioration in a mouse model of Alzheimer's disease (AD). Plasma pharmacokinetic response of major GSPE phenolic components was measured following intragastric gavage of 50, 100, and 150 mg GSPE per kg body weight. Liquid chromatography-mass spectrometry (LC-MS) analysis identified gallic acid (GA), catechin (C), and epicatechin (EC) in plasma of rats gavaged acutely with GSPE. Additionally, 4-methylgallic acid (4-OMeGA), 3'-methylcatechin (3'-OMeC), and 3'-methylepicatechin (3'-OMeEC) were identified as circulating metabolites of GSPE phenolic constituents. Cmax for individual GSPE constituents …and their metabolites increased in a dose-dependent fashion (with increasing GSPE oral dose). Repeated daily exposure to GSPE was found to significantly increase bioavailability (defined as plasma AUC0-8h ) of GA, C, and EC by 198, 253, and 282% relative to animals receiving only a single acute GSPE dose. EC and C were not detectable in brain tissues of rats receiving a single GSPE dose but reached levels of 290.7 ± 45.9 and 576.7 ± 227.7 pg/g in brain tissues from rats administered GSPE for 10 days. This study suggests that brain deposition of GA, C, and EC is affected by repeated dosing of GSPE. Show more

Keywords: Alzheimer's disease, Bioavailability, brain, catechins, gallic acid, grape seed extract, pharmacokinetics

DOI: 10.3233/JAD-2009-1135

Citation: Journal of Alzheimer's Disease, vol. 18, no. 1, pp. 113-124, 2009

Authors: Albani, Diego | Prato, Francesca | Tettamanti, Mauro | Lovati, Carlo | Galimberti, Daniela | Restelli, Ilaria | Mariani, Claudio | Quadri, Pier Luigi | Scarpini, Elio | Lucca, Ugo | Forloni, Gianluigi

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by memory loss and often accompanied during its progression by behavioral and psychological symptoms of dementia (BPSD). We decided to evaluate the association between AD-related behavioral disturbances and the short/long (S/L) polymorphism of the promoter region of the 5-hydroxytryptamine (5-HT) transporter gene (SLC6A4). This functional polymorphism modulates SLC6A4 transcription rate, with the S-allele having a 2-fold reduced efficiency, leading to a diminished availability of 5-HT that might in turn trigger behavioral and cognitive alterations. The SLC6A4 promoter functional single nucleotide polymorphism rs25531 (A→G) was genotyped as well. We collected 235 sporadic AD …subjects that were classified as AD with (n = 122) or without (n = 113) behavioral alterations, assessed with the Spontaneous Behavior Interview scale, section Behavioral Problems (SBI-BP). Comparing the genotypic and allelic frequencies of AD without and with BPSD, we did not find a difference for the 5-HTTLPR or the rs25531, even after stratification according to single SBI-BP item. We conclude that 5-HTTLPR and rs25531 are not major genetic modulators of BPSD development in AD. Show more

Keywords: Alzheimer's disease, behavioral and psychological symptoms of dementia (BPSD), genetics, 5-HTTLPR, rs25531, serotonin, serotonin transporter

DOI: 10.3233/JAD-2009-1129

Citation: Journal of Alzheimer's Disease, vol. 18, no. 1, pp. 125-130, 2009

Authors: Francis, Yitshak I. | Fà, Mauro | Ashraf, Haider | Zhang, Hong | Staniszewski, Agnieszka | Latchman, David S. | Arancio, Ottavio

Article Type: Research Article

Abstract: Epigenetic mechanisms such as post-translational histone modifications are increasingly recognized for their contribution to gene activation and silencing in the brain. Histone acetylation in particular has been shown to be important both in hippocampal long-term potentiation (LTP) and memory formation in mice. The involvement of the epigenetic modulation of memory formation has also been proposed in neuropathological models, although up to now no clear-cut connection has been demonstrated between histone modifications and the etiology of Alzheimer's disease (AD). Thus, we have undertaken preclinical studies in the APP/PS1 mouse model of AD to determine whether there are differences in histone acetylation …levels during associative memory formation. After fear conditioning training, levels of hippocampal acetylated histone 4 (H4) in APP/PS1 mice were about 50% lower than in wild-type littermates. Interestingly, acute treatment with a histone deacetylase inhibitor, Trichostatin A (TSA), prior to training rescued both acetylated H4 levels and contextual freezing performance to wild-type values. Moreover, TSA rescued CA3-CA1 LTP in slices from APP/PS1 mice. Based on this evidence, we propose the hypothesis that epigenetic mechanisms are involved in the altered synaptic function and memory associated with AD. In this respect, histone deacetylase inhibitors represent a new therapeutic target to effectively counteract disease progression. Show more

Keywords: Acetylation, Alzheimer's disease, HDACs, histone, long term potentiation

DOI: 10.3233/JAD-2009-1134

Citation: Journal of Alzheimer's Disease, vol. 18, no. 1, pp. 131-139, 2009

Authors: Barrantes, Alejandro | Sotres, Javier | Hernando-Pérez, Mercedes | Benítez, Maria J. | de Pablo, Pedro J. | Baró, Arturo M. | Ávila, Jesus | Jiménez, Juan S.

Article Type: Research Article

Abstract: Intracellular neurofibrillary tangles, composed mainly of tau protein, and extracellular plaques, containing mostly amyloid-β, are the two types of protein aggregates found upon autopsy within the brain of Alzheimer's disease patients. Polymers of tau protein can also be found in other neurodegenerative disorders known as tauopathies. Tau is a highly soluble protein, intrinsically devoid of secondary or tertiary structure, as many others proteins particularly prone to form fibrillar aggregations. The mechanism by which this unfolded molecule evolves to the well ordered helical filaments has been amply studied. In fact, it is a very slow process when followed in the absence …of aggregation inducers. Herein we describe the use of surface plasmon resonance, atomic force microscopy, and atomic force spectroscopy to detect tau-tau interactions and to follow the process of aggregation in the absence of aggregation inducers. Tau-tau interactions are clearly detected, although a very long period of time is needed to observe filaments formation. Tau oligomers showing a granular appearance, however, are observed immediately as a consequence of this interaction. These granular tau oligomers slowly evolve to larger structures and eventually to filaments having a size smaller than those reported for paired helical filaments purified from Alzheimer's disease. Show more

Keywords: Alzheimer's disease, neurodegeneration, tau protein aggregation and interaction

DOI: 10.3233/JAD-2009-1130

Citation: Journal of Alzheimer's Disease, vol. 18, no. 1, pp. 141-151, 2009

Authors: Hou, Yan | Yu, Young-Beob | Liu, Gengtao | Luo, Yuan

Article Type: Research Article

Abstract: Substantial evidence supports a central role of Aβ in the pathogenesis of Alzheimer's disease (AD). We have demonstrated that FLZ, a synthetic cyclic analogue of natural squamosamide, exhibits neuroprotective actions in cells and mouse models, suggesting future investigation of FLZ as a candidate compound for the treatment of AD. In this study, we found that the production of amyloid-β (Aβ) was reduced by FLZ in Aβ-expressing neuroblastoma cells, and correlated with an increase in the soluble α-secretase derived fragment of the amyloid-β protein precursor (sAβPPα) in the medium. Moreover, the active form of ADAM10 and AβPP were elevated at the …cell surface of FLZ-treated cells, consistent with an enhanced co-localization of ADAM10 and AβPP on the membrane. Pretreatment with brefeldin, a protein trafficking inhibitor, blocked FLZ-induced translocation of ADAM10 to the cell surface and release of sAβPPα to the culture medium. Furthermore, oral administration of FLZ to APPswe/PS1 transgenic mice significantly reduced the levels of Aβ, paralleling with activation of ADAM10, in the hippocampus. In silico prediction indicates that the structure of FLZ is compatible with the drug-like rules for absorption and permeability. These findings suggest that FLZ reduces Aβ production by promoting AβPP non-amyloidogenic α-secretase processing. As such, FLZ may have therapeutic potential for the treatment of AD. Show more

Keywords: Amyloid-β, amyloid-β protein precursor (AβPP) processing, natural compound, α-secretase

DOI: 10.3233/JAD-2009-1133

Citation: Journal of Alzheimer's Disease, vol. 18, no. 1, pp. 153-165, 2009

Authors: Mao, Guozhang | Tan, Jianxin | Cui, Mei-Zhen | Chui, Dehua | Xu, Xuemin

Article Type: Research Article

Abstract: γ-secretase-mediated processing of the amyloid-β protein precursor (AβPP) is a crucial step in the formation of the amyloid-β peptide (Aβ), but little is known about how the substrate AβPP interacts with the γ-secretase complex. To understand the molecular events involved in γ-secretase-mediated AβPP processing and Aβ formation, in the present study we determined the role of a well conserved GxxxG motif in the transmembrane domain of AβPP. Our data clearly demonstrate that substitution of aspartic acid for the key glycine residues in the GxxxG motif almost completely abolished the formation of Aβ. Furthermore, our data revealed that substitution of aspartic …acid for the glycine in this GxxxG motif disrupts the interaction of AβPP with the γ-secretase complex. Thus, the present study revealed an essential role for the GxxxG motif in the interaction of AβPP with the γ-secretase complex and the formation of Aβ. Show more

Keywords: Alzheimer's disease, amyloid-β peptide, amyloid-β precursor protein, GxxxG motif, γ-secretase

DOI: 10.3233/JAD-2009-1132

Citation: Journal of Alzheimer's Disease, vol. 18, no. 1, pp. 167-176, 2009

Authors: Peters, Oliver | Schipke, Carola G. | Philipps, Andreas | Haas, Brigitte | Pannasch, Ulrike | Wang, Li Ping | Benedetti, Bruno | Kingston, Ann E. | Kettenmann, Helmut

Article Type: Research Article

Abstract: Alzheimer's disease (AD) may affect all cell types in the central nervous system. Astrocytes have rarely been investigated in the aged brain and the role of astrocytes in AD is poorly understood. In this study, we used acute brain slices from an amyloid-β overexpressing double transgenic mouse line where astrocytes express the enhanced green fluorescent protein under the control of the glial fibrillary acidic protein promoter. Using the patch-clamp technique, we analyzed cell coupling and glutamate reactivity, two main features of astrocytes, in the living tissue of aged mice in an AD mouse model. We found large astrocytic networks in …the aged (20 to 27 months) transgenic animals in the neocortex, but not in the hippocampus. In contrast, coupling was low in all brain regions of aged control mice. We furthermore noticed significant changes in the responses of astrocytes to glutamate. The expression of functional glutamate transporters and AMPA/kainate-type glutamate receptors increases in the amyloid-β protein precursor overexpressing mice. Thus, exposure to amyloid-β leads to altered astrocyte properties and this change might be beneficial to maintain synaptic function. Show more

Keywords: Alzheimer's disease, astrocyte, coupling, gap junction, glia, glutamate receptor, glutamate transporter, neurodegeneration

DOI: 10.3233/JAD-2009-1140

Citation: Journal of Alzheimer's Disease, vol. 18, no. 1, pp. 177-189, 2009

Authors: Pilotto, Alberto | Sancarlo, Daniele | Panza, Francesco | Paris, Francesco | D'Onofrio, Grazia | Cascavilla, Leandro | Addante, Filomena | Seripa, Davide | Solfrizzi, Vincenzo | Dallapiccola, Bruno | Franceschi, Marilisa | Ferrucci, Luigi

Article Type: Research Article

Abstract: Aim of this study was to evaluate the usefulness of a Multidimensional Prognostic Index (MPI) based on a Comprehensive Geriatric Assessment (CGA) for predicting mortality risk in older patients with dementia. The present was a retrospective study with a year of follow-up that included 262 patients aged 65 years and older with a diagnosis of dementia. A standardized CGA that included information on clinical, cognitive, functional, and nutritional aspects, as well as comorbidity, medications, and social support network, was used to calculate MPI. The predictive value of the MPI for all-cause mortality over 1 month, 6 months, and 12 months …of follow-up was evaluated. Higher MPI values were significantly associated with higher mortality at 1 month (MPI-1, low risk = 0%, MPI-2, moderate risk = 5.2%, MPI-3, severe risk = 13.7%; p < 0.002), 6-months (MPI-1 = 2.7%, MPI-2 = 11.2%, MPI-3 = 28.8%; p < 0.001), and 12-months (MPI-1 = 2.7%, MPI-2 = 18.2%, MPI-3 = 35.6%; p < 0.001) of follow-up. The discrimination of the MPI was also good, with areas under the ROC curves of 0.77 (sensitivity = 82.9%, specificity = 66.0%, with a cut off value > 0.16) at 12-months of follow up. In conclusion, the MPI, calculated from information collected in a standardized CGA, accurately stratified hospitalized elderly patients with dementia into groups at varying risk of short- and long-term mortality. Show more

Keywords: Comprehensive Geriatric Assessment (CGA), dementia, mortality, Multidimensional Prognostic Index (MPI), prognosis, survival

DOI: 10.3233/JAD-2009-1139

Citation: Journal of Alzheimer's Disease, vol. 18, no. 1, pp. 191-199, 2009

Authors: Mueller, Claudius | Magaki, Shino | Schrag, Matthew | Ghosh, Manik C. | Kirsch, Wolff M.

Article Type: Research Article

Abstract: Trace metal homeostasis is tightly controlled in the brain, as even a slight dysregulation may severely impact normal brain function. This is especially apparent in Alzheimer's disease, where brain homeostasis of trace metals such as copper and iron is dysregulated. As it is known that iron and copper metabolism are linked, we wanted to investigate if a common mechanism could explain the increase in iron and decrease in copper seen in Alzheimer's disease brain. Amyloid-β protein precursor (AβPP) has been implicated in copper efflux from the brain. Furthermore, it was shown that iron regulatory proteins (IRP), which regulate iron homeostasis, …can block AβPP mRNA translation. In a correlative study we have therefore compared brain regional copper levels and AβPP expression in mice with a targeted deletion of IRP2-/-. Compared with controls, six week old IRP2-/- mice had significantly less brain copper in the parietal cortex, hippocampus, ventral striatum, thalamus, hypothalamus, and whole brain, while AβPP was significantly upregulated in the hippocampus (p < 0.05) and showed a trend toward upregulation in the thalamus (p < 0.1). This is the first study to demonstrate that iron regulatory proteins affect brain copper levels, which has significant implications for neurodegenerative diseases. Show more

Keywords: Alzheimer's disease, amyloid-β, amyloid-β protein precursor (AβPP), iron regulatory protein 2 (IRP2)

DOI: 10.3233/JAD-2009-1136

Citation: Journal of Alzheimer's Disease, vol. 18, no. 1, pp. 201-210, 2009