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