Journal of Alzheimer's Disease - Volume 24, issue 4

Authors: Kaarniranta, Kai | Salminen, Antero | Haapasalo, Annakaisa | Soininen, Hilkka | Hiltunen, Mikko

Article Type: Review Article

Abstract: Age-related macular degeneration (AMD) is a late-onset, neurodegenerative retinal disease that shares several clinical and pathological features with Alzheimer's disease (AD), including stress stimuli such as oxidative stress and inflammation. In both diseases, the detrimental intra- and extracellular deposits have many similarities. Aging, hypercholesterolaemia, hypertension, obesity, arteriosclerosis, and smoking are risk factors to develop AMD and AD. Cellular aging processes have similar organelle and signaling association in the retina and brain tissues. However, it seems that these diseases have a different genetic background. In this review, differences and similarities of AMD and AD are thoroughly discussed.

Keywords: Age-related macular degeneration (AMD), aggregation, aging, Alzheimer's disease, autophagy, lysosome, oxidative stress, proteasome

DOI: 10.3233/JAD-2011-101908

Citation: Journal of Alzheimer's Disease, vol. 24, no. 4, pp. 615-631, 2011

Authors: Antoniou, Xanthi | Falconi, Mattia | Di Marino, Daniele | Borsello, Tiziana

Article Type: Review Article

Abstract: c-Jun N-terminal kinases (JNKs) and in particular JNK3 the neuronal specific isoform, have been recognized as important enzymes in the pathology of diverse neurological disorders. Indeed, several efforts have been made to design drugs that inhibit JNK signaling. The success that characterized the new generation of cell permeable peptides raise the hope in the field of neurodegeneration for new therapeutic routes. However, in order to design new and more efficient therapeutical approaches careful re-examination of current knowledge is required. Scaffold proteins are key endogenous regulators of JNK signaling: they can modulate spatial and temporal activation of the JNK signaling and …can thus provide the basis for the design of more specific inhibitors. This review focuses on delineating the role of scaffold proteins on the regulation of JNK signaling in neurons. Furthermore the possibility to design a new JNK3 cell permeable peptide inhibitor by targeting the β-arrestin-JNK3 interaction is discussed. Show more

Keywords: JNK3, JIP1, β-arrestin-2, Alzheimer disease, signalling pathways, neuroprotection

DOI: 10.3233/JAD-2011-091567

Citation: Journal of Alzheimer's Disease, vol. 24, no. 4, pp. 633-642, 2011

Authors: Palmer, Alan M.

Article Type: Review Article

Abstract: Neurodegenerative disorders represent a major medical challenge that is set to increase substantially in the decades ahead with the massive increase in the number of people in the world aged 65 or more. Neuroprotective therapeutics have the potential to play a key role in helping manage this growing global burden of long-term neurological care. However, neuropharmaceutical research is associated with significant challenges including: 1) the complexity of the brain (the cause of the majority of neurodegenerative disorders remains unknown); 2) the liability of central nervous system (CNS) drugs to cause CNS side effects (which limits their use); and 3) the …requirement of neuropharmaceuticals to cross the blood-brain barrier (BBB). The BBB itself also plays a key role in most (if not all) neurodegenerative disorders since BBB dysfunction inevitably leads to inflammatory change including the movement of immune cells and immune mediators into the brain, which then contribute to the process of neurodegeneration. This review focuses on the role of the BBB in both neurodegenerative disorders and neuropharmaceutical research. Show more

Keywords: Blood-brain barrier, brain injuries, drug discovery, neurodegeneration, neuroinflammation, neurological disorders, neuroprotection, therapeutics

DOI: 10.3233/JAD-2011-110368

Citation: Journal of Alzheimer's Disease, vol. 24, no. 4, pp. 643-656, 2011

Authors: de la Torre, Jack C.

Article Type: Research Article

Abstract: Two centuries ago, the German bacteriologist Robert Koch proposed three postulates to support a causal relationship between a specific microbe and an infectious disease. Similarly, three postulates are formulated here to help evaluate hypothetical proposals attempting to explain the pathogenesis of Alzheimer's disease (AD). The first postulate requires that the cause of AD precedes the cognitive decline and neurodegenerative pathology that characterize AD. This rule identifies a primary event from a neuropathological effect generated by the disease process. The second postulate stipulates that interventions aimed at the proposed causal event should prevent or reverse the cognitive and neurodegenerative pathology associated …with AD prior to disease onset. This postulate emphasizes prevention or reversal of emerging neurocognitive pathology considerably before AD onset. If the first and second postulate requirements are met, the third postulate follows that interventions targeting the causal event should significantly lower the incidence of AD. For a causal hypothesis to be considered “likely” pathogenic to AD, support from all three postulates is a requisite. The pragmatic potential of the three postulates was applied to seven proposals using evidence-based meta-analysis mainly from randomized controlled trials. Proposals included the amyloid-β, cell cycle, cholinergic, inflammatory, oxidative stress, tau, and vascular hypotheses. Clinical evidence derived from each proposal formed the basis for an inferential conclusion based on the level of confidence provided by the trial data. The three postulates may challenge or help validate a proposed cause-effect relationship to AD and serve as a useful model for designing more intelligent therapeutic interventions aimed at preventing AD. Show more

Keywords: Alzheimer's disease, amyloid-β, cell cycle, cholinergic, Cochrane Central Register of Controlled Trials, inflammation, oxidative stress, postulates, randomized controlled trials, tau, vascular hypothesis

DOI: 10.3233/JAD-2011-101884

Citation: Journal of Alzheimer's Disease, vol. 24, no. 4, pp. 657-668, 2011

Authors: Mateos, Laura | Ismail, Muhammad-Al-Mustafa | Gil-Bea, Francisco-Javier | Leoni, Valerio | Winblad, Bengt | Björkhem, Ingemar | Cedazo-Mínguez, Angel

Article Type: Research Article

Abstract: In spite of the fact that cholesterol does not pass the blood-brain barrier, hypercholesterolemia has been linked to increase Alzheimer's disease (AD) risk. Hypertension is another risk factor and angiotensin converting enzyme (ACE) activity is known to be increased in AD. Furthermore, a lower incidence of AD has been reported in patients taking anti-hypertensive drugs. Here we show that the levels of angiotensinogen (AGT) and ACE are increased in the cerebrospinal fluid (CSF) of patients with mild cognitive impairment and AD. Moreover, we show ACE activity in the CSF to be positively correlated with both plasma and CSF levels of …27-hydroxycholesterol (27-OH), an oxysterol known to pass through the BBB and taken up from the circulation by the brain. In addition, treatment of rat primary neurons, astrocytes, and human neuroblastoma cells with 27-OH resulted in increased production of AGT. Our results demonstrate that upregulation of renin-angiotensin system (RAS) in AD brains occurs not only at the enzymatic level (ACE) but also at the substrate level (AGT). The possibility that 27-OH is part of a mechanism linking hypercholesterolemia with increased brain RAS activity and increased AD risk is discussed. Show more

Keywords: Angiotensin I/II, angiotensinogen, cholesterol, 24-hydroxycholesterol, mild cognitive impairment, neurodegeneration

DOI: 10.3233/JAD-2011-101512

Citation: Journal of Alzheimer's Disease, vol. 24, no. 4, pp. 669-679, 2011

Authors: Marsden, Ian T. | Minamide, Laurie S. | Bamburg, James R.

Article Type: Research Article

Abstract: Amyloid-β (Aβ) peptides, 36–43 amino acids in length, are produced from β- and γ-secretase cleavage of the amyloid-β protein precursor (AβPP), and are one of the causative agents of Alzheimer's disease (AD). Here we show that an ELISA can detect total rodent Aβ without interference from physiological concentrations of human Aβ. In cultured dissociated rat cortical neurons and rat and mouse hippocampal organotypic slices, we apply the assay to measure the production of Aβ in response to treatment with hydrogen peroxide, a known stimulator of Aβ secretion, or human Aβ dimer/trimer (Aβd/t), fractionated from the culture medium of 7PA2 cells. …Peroxide increases Aβ secretion by about 2 fold, similar to results from previous reports that used a different assay. Of greater significance is that physiologically relevant concentrations (~250 pM) of human Aβd/t increase rodent Aβ secretion from cultured rat cortical neurons by >3 fold over 4 days. Surprisingly, neither treatment with peroxide nor human Aβd/t leads to accumulation of intracellular Aβ. Human Aβd/t increased >2 fold the Aβ secreted by organotypic hippocampal slices from tau knock-out mice whether or not they expressed a human tau transgene, suggesting tau plays no role in enhanced Aβ secretion. Together, these results support an Aβ-mediated feed-forward mechanism in AD progression. Show more

Keywords: Aβ dimer/trimer, cortical neurons, hippocampal neurons, organotypic hippocampal slice culture, rodent Aβ ELISA, tau knockout mice

DOI: 10.3233/JAD-2011-101899

Citation: Journal of Alzheimer's Disease, vol. 24, no. 4, pp. 681-691, 2011

Authors: Lykhmus, Olena | Koval, Lyudmyla | Skok, Maryna | Zouridakis, Marios | Zisimopoulou, Paraskevi | Tzartos, Socrates | Tsetlin, Victor | Granon, Sylvie | Changeux, Jean-Pierre | Komisarenko, Sergiy | Cloëz-Tayarani, Isabelle

Article Type: Research Article

Abstract: Nicotinic acetylcholine receptors (nAChRs) of α4β2 and α7 subtypes expressed in the brain neurons are involved in regulating memory and cognition. Their level is decreased upon several neurodegenerative disorders including Alzheimer's disease (AD), although the reasons for such a decrease are not completely understood. To test whether the nAChR-specific antibodies can affect the brain nAChRs and influence the behavior, we either immunized mice with recombinant extracellular domains of α4 and α7, subunits α4(1-209) and α7(1-208), or injected them with α7(1-208)-specific antibodies. A decrease of α4β2- and α7-nAChRs accompanied with an increase of α4β4-nAChRs in brain membranes of immunized mice was …observed. Both α4(1-209)- and α7(1-208)-specific antibodies were detected in the brain membrane lysates of immunized mice. Antibody injection resulted in brain nAChR decrease only if mice were co-injected intraperitoneally with bacterial lipopolysaccharide. Brain sections of immunized mice were analyzed for the binding of [125 I]-α-bungarotoxin and [125 I]-epibatidine. A decrease in α-bungarotoxin binding in striatum (nucleus accumbens and caudate putamen) accompanied with an increase of epibatidine binding in the forebrain and caudate putamen was observed in mice immunized with either α4 or α7 nAChR domains compared to those immunized with BSA. Mice immunized with α7(1-208) demonstrated significantly worse episodic memory measured in a novel object recognition task compared to non-immunized animals but did not differ from the controls in locomotor or anxiety-related tests. These results suggest that nAChR-specific antibodies are able to penetrate the brain upon inflammation with resulting decreases of brain nAChRs and worsening episodic memory. Show more

Keywords: Alzheimer's disease, antibodies, brain, episodic memory, ligand binding, nicotinic acetylcholine receptor

DOI: 10.3233/JAD-2011-101842

Citation: Journal of Alzheimer's Disease, vol. 24, no. 4, pp. 693-704, 2011

Authors: Fragkouli, Apostolia | Tzinia, Athina K. | Charalampopoulos, Ioannis | Gravanis, Achille | Tsilibary, Effie C.

Article Type: Research Article

Abstract: Amyloid-β protein precursor (AβPP) is a ubiquitously expressed glycoprotein, which under physiological conditions can be cleaved following two alternative routes; the non-amyloidogenic and the amyloidogenic pathway. Shift of AβPP processing in favor of the amyloidogenic pathway is a key event in the pathogenesis of Alzheimer's disease (AD). Among the factors that regulate AβPP processing, nerve growth factor (NGF) appears to play an important role; abnormal NGF signaling has been implicated in the onset of AD. In the present study, we used PC12 cells to study the effects of NGF on AβPP processing and provide evidence that NGF, through binding to …its high affinity receptor, TrkA moderately down-regulates the expression of the β-secretase β-site AβPP cleaving enzyme-1 and, most importantly, upregulates the expression of two enzymes with α-secretase activity, a disintegrin and metalloprotease-17 and to a greater extent matrix metalloproteinase-9 (MMP9) in a phosphoinositide kinase-3 dependent manner. Finally, we demonstrate that MMP9 actively participates in NGF-induced α-secretase cleavage of AβPP, thus it contributes to the shift of AβPP processing towards the non-amyloidogenic pathway precluding the formation of neurotoxic Aβ peptides. Show more

Keywords: AβPP, α-secretase, ADAM10, ADAM17, BACE1, MMP9, NGF, PC12 cells, TrKA

DOI: 10.3233/JAD-2011-101893

Citation: Journal of Alzheimer's Disease, vol. 24, no. 4, pp. 705-719, 2011

Authors: Arisi, Ivan | D'Onofrio, Mara | Brandi, Rossella | Felsani, Armando | Capsoni, Simona | Drovandi, Guido | Felici, Giovanni | Weitschek, Emanuel | Bertolazzi, Paola | Cattaneo, Antonino

Article Type: Research Article

Abstract: The identification of early and stage-specific biomarkers for Alzheimer's disease (AD) is critical, as the development of disease-modification therapies may depend on the discovery and validation of such markers. The identification of early reliable biomarkers depends on the development of new diagnostic algorithms to computationally exploit the information in large biological datasets. To identify potential biomarkers from mRNA expression profile data, we used the Logic Mining method for the unbiased analysis of a large microarray expression dataset from the anti-NGF AD11 transgenic mouse model. The gene expression profile of AD11 brain regions was investigated at different neurodegeneration stages by whole …genome microarrays. A new implementation of the Logic Mining method was applied both to early (1–3 months) and late stage (6–15 months) expression data, coupled to standard statistical methods. A small number of “fingerprinting” formulas was isolated, encompassing mRNAs whose expression levels were able to discriminate between diseased and control mice. We selected three differential “signature” genes specific for the early stage (Nudt19, Arl16, Aph1b), five common to both groups (Slc15a2, Agpat5, Sox2ot, 2210015, D19Rik, Wdfy1), and seven specific for late stage (D14Ertd449, Tia1, Txnl4, 1810014B01Rik, Snhg3, Actl6a, Rnf25). We suggest these genes as potential biomarkers for the early and late stage of AD-like neurodegeneration in this model and conclude that Logic Mining is a powerful and reliable approach for large scale expression data analysis. Its application to large expression datasets from brain or peripheral human samples may facilitate the discovery of early and stage-specific AD biomarkers. Show more

Keywords: Alzheimer's disease, biomarkers, data mining, gene expression, microarray, mouse models, nerve growth factor, statistical data interpretation

DOI: 10.3233/JAD-2011-101881

Citation: Journal of Alzheimer's Disease, vol. 24, no. 4, pp. 721-738, 2011

Authors: Zhang, Xin | Heng, Xin | Li, Ting | Li, Lixi | Yang, Dehua | Zhang, Xiaojie | Du, Yunlan | Doody, Rachelle S. | Le, Weidong

Article Type: Research Article

Abstract: The glycogen synthase kinase-3β (GSK3β) pathway plays a central role in Alzheimer's disease (AD) and its deregulation accounts for many of the pathological hallmarks of AD. Lithium, which modulates GSK3β activity, has been shown to reduce amyloid production and tau phosphorylation in pre-pathological AD mouse models. In this study, we investigated the effects of chronic LiCl treatment in aged double transgenic mice (AβPPSwe /PS1A246E ). We found that chronic lithium treatment decreased the γ-cleavage of amyloid-β protein precursor, further reduced amyloid-β production and senile plaque formation, accompanied by the improvement in spatial learning and memory abilities. Because autophagy may play …an important role in the pathology of AD, we also assessed the autophagy activity and found that the chronic lithium treatment attenuated the autophagy activation in this AD mouse model. Our results suggest that prolonged lithium treatment, even during the later stages of AD, could be an effective therapeutics. Show more

Keywords: Alzheimer's disease, AβPP processing, autophagy, GSK3β, lithium chloride, spatial learning and memory

DOI: 10.3233/JAD-2011-101875

Citation: Journal of Alzheimer's Disease, vol. 24, no. 4, pp. 739-749, 2011

Authors: Carrasquillo, Minerva M. | Belbin, Olivia | Hunter, Talisha A. | Ma, Li | Bisceglio, Gina D. | Zou, Fanggeng | Crook, Julia E. | Pankratz, V. Shane | Sando, Sigrid B. | Aasly, Jan O. | Barcikowska, Maria | Wszolek, Zbigniew K. | Dickson, Dennis W. | Graff-Radford, Neill R. | Petersen, Ronald C. | Morgan, Kevin | for the Alzheimer's Research Trust Consortium (ART) | Younkin, Steven G.

Article Type: Research Article

Abstract: The most recent late-onset Alzheimer's disease (LOAD) genome-wide association study revealed genome-wide significant association of two new loci: rs744373 near BIN1 (p = 1.6 × 10−11 ) and rs597668 near EXOC3L2/BLOC1S3/MARK4 (p = 6.5 × 10−9 ). We have genotyped these variants in a large (3,287 LOAD, 4,396 controls), independent dataset comprising eleven case-control series from the USA and Europe. We performed meta-analyses of the association of these variants with LOAD and also tested for association using logistic regression adjusted by age-at-diagnosis, gender, and APOE ε4 status. Meta-analysis results showed no evidence of series heterogeneity and logistic regression analysis successfully …replicated the association of BIN1 (rs744373) with LOAD with an odds ratio (OR = 1.17, p = 1.1 × 10−4 ) comparable to that previously reported (OR = 1.15). The variant near EXOC3L2 (rs597668) showed only suggestive association with LOAD (p = 0.09) after correcting for the presence of the APOE ε4 allele. Addition of our follow-up data to the results previously reported increased the strength of evidence for association with BIN1 (11,825 LOAD, 32,570 controls, rs744373 Fisher combined p = 3.8 × 10−20 ). We also tested for epistatic interaction between these variants and APOE ε4 as well as with the previously replicated LOAD GWAS genes (CLU: rs11136000, CR1: rs3818361, and PICALM: rs3851179). No significant interactions between these genes were detected. In summary, we provide additional evidence for the variant near BIN1 (rs744373) as a LOAD risk modifier, but our results indicate that the effect of EXOC3L2 independent of APOE ε4 should be studied further. Show more

Keywords: Alzheimer's disease, case-control studies, heterogeneity, late onset, meta-analysis

DOI: 10.3233/JAD-2011-101932

Citation: Journal of Alzheimer's Disease, vol. 24, no. 4, pp. 751-758, 2011

Authors: Arai, Masaya | Saito, Mitsunari | Takatsu, Hirokatsu | Fukui, Koji | Urano, Shiro

Article Type: Research Article

Abstract: To define whether hyperoxia induces the dysfunction of membrane fusion between synaptic vesicles with pre-synaptic plasma membranes in the nerve terminals, and whether vitamin E prevents this abnormal event, we investigated the influence of hyperoxia on the fusion ability of isolated synaptic vesicles and the inside-out type pre-synaptic plasma membrane vesicles from rat brain using the fluorescence tracing method. The membrane fusion ability of both membranes from rats subjected to hyperoxia was markedly decreased compared with the membranes from a normal rat. Rats subjected to hyperoxia in the form of oxidative stress showed significant increases in the levels of thiobarbituric …acid reactive substances (TBARS), conjugated dienes, and protein carbonyl moieties in both synaptic vesicles and pre-synaptic plasma membranes. When rats were supplemented with vitamin E, these abnormalities were inhibited even when rats were subjected to hyperoxia. Show more

Keywords: Neurotransmission, oxidative brain damage, oxidative stress, synaptic membrane fusion, vitamin E

DOI: 10.3233/JAD-2011-101785

Citation: Journal of Alzheimer's Disease, vol. 24, no. 4, pp. 759-766, 2011

Authors: Hensley, Kenneth | Barnes, Lisa L. | Christov, Alexandar | Tangney, Christy | Honer, William G. | Schneider, Julie A. | Bennett, David A. | Morris, Martha Clare

Article Type: Research Article

Abstract: Ventricular cerebrospinal fluid (vCSF) obtained at autopsy from 230 participants in the Religious Orders Study was analyzed for alpha tocopherol (αT, vitamin E) and gamma tocopherol (γT) in relation to brain tissue neuropathological diagnoses (NIA-Reagan criteria); neuritic plaque density and neurofibrillary tangle state (Braak stage); and cognitive function proximate to death. Neither vCSF αT nor γT was related to the pathological diagnosis of Alzheimer's disease, but vCSF αT concentration was inversely related to neuritic plaque density (β = −0.21, SE = 0.105, p = 0.04) in regression models adjusted for age, gender, education, and APOE-4. Ventricular CSF αT concentration was …positively associated with perceptual speed (β = 0.27, SE = 0.116, p = 0.02) whereas the γT/αT ratio was negatively associated with episodic memory (β = −0.037, SE = 0.017, p = 0.04). Only vCSF αT, but not γT, was correlated with postmortem interval (PMI). Adjustment for PMI had no effect on significance of associations between αT and perceptual speed or γT/αT and episodic memory, but after this adjustment the αT concentration was no longer significantly associated with neuritic plaques. These data suggest that vCSF αT, but not γT, is weakly associated with less Alzheimer's disease neuropathology, specifically neuritic plaques, and correlates with better performance on tests of perceptual speed. Show more

Keywords: Alzheimer's disease, cerebrospinal fluid, Religious Orders Study, tocopherol, vitamin E

DOI: 10.3233/JAD-2011-101995

Citation: Journal of Alzheimer's Disease, vol. 24, no. 4, pp. 767-774, 2011

Authors: Yang, Wenlu | Lui, Ronald L.M. | Gao, Jia-Hong | Chan, Tony F. | Yau, Shing-Tung | Sperling, Reisa A. | Huang, Xudong

Article Type: Research Article

Abstract: There is an unmet medical need to identify neuroimaging biomarkers that allow us to accurately diagnose and monitor Alzheimer's disease (AD) at its very early stages and to assess the response to AD-modifying therapies. To a certain extent, volumetric and functional magnetic resonance imaging (fMRI) studies can detect changes in structure, cerebral blood flow, and blood oxygenation that distinguish AD and mild cognitive impairment (MCI) subjects from healthy control (HC) subjects. However, it has been challenging to use fully automated MRI analytic methods to identify potential AD neuroimaging biomarkers. We have thus proposed a method based on independent component analysis …(ICA) for studying potential AD-related MR image features that can be coupled with the use of support vector machine (SVM) for classifying scans into categories of AD, MCI, and HC subjects. The MRI data were selected from the Open Access Series of Imaging Studies (OASIS) and the Alzheimer's Disease Neuroimaging Initiative databases. The experimental results showed that the ICA method coupled with SVM classifier can differentiate AD and MCI patients from HC subjects, although further methodological improvement in the analytic method and inclusion of additional variables may be required for optimal classification. Show more

Keywords: Alzheimer's disease, independent component analysis, magnetic resonance imaging, mild cognitive impairment, neuroimaging biomarker, support vector machine

DOI: 10.3233/JAD-2011-101371

Citation: Journal of Alzheimer's Disease, vol. 24, no. 4, pp. 775-783, 2011

Authors: Tiribuzi, Roberto | Orlacchio, Antonio | Crispoltoni, Lucia | Maiotti, Mariangela | Zampolini, Mauro | De Angeliz, Massimiliano | Mecocci, Patrizia | Cecchetti, Roberta | Bernardi, Giorgio | Datti, Alessandro | Martino, Sabata | Orlacchio, Aldo

Article Type: Research Article

Abstract: Multiple epidemiological studies have shown that individuals affected by type-2 diabetes mellitus (T2DM) carry a 2-to-5-fold higher risk of developing Alzheimer's disease (AD) when compared to non-diabetic subjects. Thus, biochemical parameters that can be easily and routinely assessed for high-confidence evaluation of diabetic conditions leading to AD (AD-T2DM) are regarded as efficient tools aimed at early diagnosis and, in turn, timely AD treatment. In this regard, the activity of lysosomal glycohydrolases may of use, in light of the implication of these enzymes in early events that underlie AD pathology and an overt correlation, in diabetes, between altered metabolic homeostasis, abnormal …glycohydrolase secretion in body fluids, and occurrence of diabetic complications. Based on marked up-regulation previously shown in a peripheral, cell-based model of AD, we selected β-Galactosidase, β-Hexosaminidase, and α-Mannosidase to discriminate T2DM from AD-T2DM subjects. A screen of 109, 114, and 116 patients with T2DM, AD and AD-T2DM, respectively, was performed by testing enzyme activities in both blood plasma and peripheral blood mononuclear cells. Compared to age-matched, healthy controls (n = 122), β-Galactosidase and β-Hexosaminidase activities markedly diverged across the three groups, whereas virtually unchanged values were observed for α-Mannosidase. In particular, plasma β-Galactosidase and β-Hexosaminidase levels were higher in patients with AD-T2DM compared to those with T2DM, suggesting different mechanisms leading to enzyme secretion. Statistical analyses based on ROC curves showed that both β-Galactosidase and β-Hexosaminidase activities, either intracellular or plasma-secreted, may be used to discriminate AD patients from controls and AD-T2DM from T2DM patients. Show more

Keywords: Alzheimer's disease, diagnostic correlation, lysosomal glycohydrolases, type 2 diabetes

DOI: 10.3233/JAD-2011-100525

Citation: Journal of Alzheimer's Disease, vol. 24, no. 4, pp. 785-797, 2011

Authors: Balducci, Claudia | Mehdawy, Bisan | Mare, Lydia | Giuliani, Alessandro | Lorenzini, Luca | Sivilia, Sandra | Giardino, Luciana | Calzà, Laura | Lanzillotta, Annamaria | Sarnico, Ilenia | Pizzi, Marina | Usiello, Alessandro | Viscomi, Arturo R. | Ottonello, Simone | Villetti, Gino | Imbimbo, Bruno P. | Nisticò, Giuseppe | Forloni, Gianluigi | Nisticò, Robert

Article Type: Research Article

Abstract: Abnormal amyloid-β (Aβ) production and deposition is believed to represent one of the main causes of Alzheimer's disease (AD). γ-Secretase is the enzymatic complex responsible for Aβ generation from its precursor protein. Inhibition or modulation of γ-secretase represents an attractive therapeutic approach. CHF5074 is a new γ-secretase modulator that has been shown to inhibit brain plaque deposition and to attenuate memory deficit in adult AD transgenic mice after chronic treatment. To date, it is not known whether the positive behavioral effects of this compound also occur in young transgenic mice without plaque deposition. Here, we evaluated the effects of acute …and subchronic treatment with CHF5074 on contextual and recognition memory and on hippocampal synaptic plasticity in plaque-free Tg2576 mice. We found that at 5 months of age, contextual memory impairment was significantly attenuated after acute subcutaneous administration of 30 mg/kg CHF5074. At 6 months of age, recognition memory impairment was fully reversed after a 4-week oral treatment in the diet (≈60 mg/kg/day). These cognitive effects were associated with a reversal of long-term potentiation (LTP) impairment in the hippocampus. A significant reduction in brain intraneuronal AβPP/Aβ levels and hyperphosphorylated tau, but no change in soluble or oligomeric Aβ levels was detected in Tg2576 mice showing functional recovery following CHF5074 treatment. We conclude that the beneficial effects of CHF5074 treatment in young transgenic mice occurred at a stage that precedes plaque formation and were associated with a reduction in intraneuronal AβPP/Aβ and hyperphosphorylated tau. Show more

Keywords: Alzheimer's disease, amyloid-β, fear conditioning, γ-secretase modulators, long-term potentiation, non-steroidal anti-inflammatory drugs, recognition memory

DOI: 10.3233/JAD-2011-101839

Citation: Journal of Alzheimer's Disease, vol. 24, no. 4, pp. 799-816, 2011

Authors: Echeverria, Valentina | Zeitlin, Ross | Burgess, Sarah | Patel, Sagar | Barman, Arghya | Thakur, Garima | Mamcarz, Magorzota | Wang, Li | Sattelle, David B. | Kirschner, Daniel A. | Mori, Takashi | Leblanc, Roger M. | Prabhakar, Rajeev | Arendash, Gary W.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) affects millions of people world-wide and new effective and safe therapies are needed. Cotinine, the main metabolite of nicotine, has a long half-life and does not have cardiovascular or addictive side effects in humans. We studied the effect of cotinine on amyloid-β (Aβ) aggregation as well as addressed its impact on working and reference memories. Cotinine reduced Aβ deposition, improved working and reference memories, and inhibited Aβ oligomerization in the brains of transgenic (Tg) 6799 AD mice. In vitro studies confirmed the inhibitory effect of cotinine on Aβ1-42 aggregation. Cotinine stimulated Akt signaling, including the inhibition …of glycogen synthase kinase 3β (GSK3β), which promotes neuronal survival and the synaptic plasticity processes underlying learning and memory in the hippocampus and cortex of wild type and Tg6799 AD mice. Simulation of the cotinine–Aβ1-42 complex using molecular dynamics showed that cotinine may interact with key histidine residues of Aβ1-42 , altering its structure and inhibiting its aggregation. The good safety profile in humans and its beneficial effects suggest that cotinine may be an excellent therapeutic candidate for the treatment of AD. Show more

Keywords: Alzheimer's disease, amyloid-β, cotinine, neurodegeneration, oligomerization

DOI: 10.3233/JAD-2011-102136

Citation: Journal of Alzheimer's Disease, vol. 24, no. 4, pp. 817-835, 2011

Article Type: Correction

Abstract: Erratum to [Journal of Alzheimer's Disease 22(1), 2010, 135-150], DOI 10.3233/JAD-2010-100639.

DOI: 10.3233/JAD-2011-111438

Citation: Journal of Alzheimer's Disease, vol. 24, no. 4, pp. 837-837, 2011

Article Type: Other

DOI: 10.3233/JAD-2011-102137

Citation: Journal of Alzheimer's Disease, vol. 24, no. 4, pp. 839-841, 2011