Journal of Alzheimer's Disease - Volume 22, issue 2

Authors: Arbel-Ornath, Michal | Becker, Maria | Rabinovich-Toidman, Polina | Gartner, Myra | Solomon, Beka

Article Type: Research Article

Abstract: Among the different paradigms aimed at interfering with amyloid-β (Aβ)-related pathology, the attenuation of amyloid-β protein precursor (AβPP) processing to limit Aβ levels seems to be a promising one. Along with the development of BACE1 inhibitors, and the generation of its knock-out mice, accumulating data raise concerns regarding a total inhibition of the enzyme as it shares the processing of other substrates. We described a novel approach to interfere with the specific interaction between AβPP and BACE1 using monoclonal antibodies directed to the β-secretase cleavage site upon the substrate, AβPP. Such antibodies limit AβPP cleavage in a cellular model of …Alzheimer's disease (AD) and avoid the total inhibition of BACE1. Here, we demonstrate the ability of AβPP β-site antibodies to interfere with Aβ production in vivo. Systemic antibody treatment diminished Aβ plaques, membrane-associated oligomers, and intracellular Aβ accumulation, all of which have been implicated in cellular death and synaptic loss, suggesting that this approach may be an applicable strategy for AD treatment. Show more

Keywords: Alzheimer's disease, amyloid-β, AβPP β-site, β-secretase, immunotherapy, intracellular Aβ, monoclonal antibodies

DOI: 10.3233/JAD-2010-100753

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 469-482, 2010

Authors: Gu, Yian | Luchsinger, Jose A. | Stern, Yaakov | Scarmeas, Nikolaos

Article Type: Research Article

Abstract: We aimed to investigate the association between adherence to the Mediterranean diet (MeDi) and Alzheimer's disease (AD) risk in a prospective study. Specifically, we analyzed reduced inflammation and improved metabolic profile as a potential medium through which the MeDi reduced the risk of AD. During a 4-year follow-up, 118 incident AD cases were identified among the 1219 non-demented elderly (age ⩾ 65) subjects who provided dietary information and blood samples at baseline. We used high-sensitivity C-reactive protein (hsCRP) as an index of systemic inflammation, and fasting insulin and adiponectin as indexes of metabolic profile. We investigated whether there was a …change in the association between MeDi and incident AD risk when the biomarkers were introduced into multivariable adjusted COX models. Better adherence to MeDi was associated with lower level of hsCRP (p = 0.003), but not fasting insulin or adiponectin. Better adherence to MeDi was significantly associated with lower risk for AD: compared to those in the lowest tertile of MeDi, subjects in the highest tertile had a 34% less risk of developing AD (p-for-trend = 0.04). Introduction of the hsCRP, fasting insulin, adiponectin, or combinations of them into the COX model did not change the magnitude of the association between MeDi and incident AD. Ultimately, the favorable association between better adherence to MeDi and lower risk of AD did not seem to be mediated by hsCRP, fasting insulin, or adiponectin. Other aspects of inflammatory and metabolic pathways not captured by these biomarkers, or non-inflammatory or non-metabolic pathways, may be relevant to the MeDi-AD association. Show more

Keywords: Adiponectin, Alzheimer's disease, C-reactive protein, cohort studies, epidemiology, insulin, Mediterranean diet

DOI: 10.3233/JAD-2010-100897

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 483-492, 2010

Authors: Blanco, Almudena | Álvarez, Susana | Fresno, Manuel | Muñoz-Fernández, Maria Ángeles

Article Type: Research Article

Abstract: Both amyloid-β peptide 1–42 (Aβ1–42 ) formation and cyclooxygenase-2 (COX-2) have been involved in the pathogenesis of Alzheimer's disease (AD), a devastating neurological disorder. However, the relationship between Aβ1–42 and COX-2 is unclear. We found that the addition of Aβ1–42 to astrocytoma cultures induced COX-2 mRNA and protein and PGE2 synthesis in primary human astrocytes and in human astrocytoma cell lines. Moreover, Aβ1–42 induced COX-2 promoter transcription. Deletion of nuclear factor-κB (NF-κB) sites of the promoter diminished Aβ1–42 -COX-2 dependent transcription. In agreement with this, Aβ1–42 induced transcription of NF-κB reporter gene. In contrast, Aβ1–42 …neither did not induce NFAT not AP-1 factors activation suggesting that both NFAT and AP-1 was not necessary to control COX-2 transcription induced by Aβ1–42 . Over expression of NF-κB inhibitory subunit, IκB, completely abrogated Aβ1–42 -induced COX-2 activity in U-87 cells, whereas the opposite effect was shown when p65/rel A NF-κB was over expressed. In addition, Aβ1–42 induced p65/rel A subunit translocation to the nucleus and binding to the distal site of the COX-2 promoter. The importance of NF-κB in COX-2 induction and PGE2 synthesis by Aβ1–42 was corroborated by using the pharmacological inhibitor of the NF-κB pathway, PDTC. In addition, Aβ1–42 treated astrocytoma supernatants were toxic for neuroblastoma cells, an effect which was blocked by PDTC. Summing up, our results indicate that Aβ1–42 was able to induce COX-2 and PGE2 synthesis in astrocytic cells through a NF-κB dependent mechanism. This may have implicated in our understanding of AD pathology. Show more

Keywords: Alzheimer's disease, amyloid-β1–42, astrocytes, COX-2, NF-κB, PGE2

DOI: 10.3233/JAD-2010-100309

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 493-505, 2010

Authors: Teipel, Stefan J. | Meindl, Thomas | Wagner, Maximilian | Stieltjes, Bram | Reuter, Sigrid | Hauenstein, Karl-Heinz | Filippi, Massimo | Ernemann, Ulrike | Reiser, Maximilian F. | Hampel, Harald

Article Type: Research Article

Abstract: Cross-sectional studies using diffusion tensor imaging (DTI) suggest decline of the integrity of intracortically projecting fiber tracts with aging and in neurodegenerative diseases, such as Alzheimer's disease (AD). Longitudinal studies on the change of fiber tract integrity in normal and pathological aging are still rare. Here, we prospectively studied 11 healthy elderly subjects and 14 subjects with amnestic mild cognitive impairment (MCI), a clinical risk group for AD, using high-resolution DTI and MRI at baseline and after 13 to 16 months follow-up. Fractional anisotropy (FA), a DTI measure of fiber tract integrity, was compared across time points and groups using …a repeated measures linear model and tract based spatial statistics. Additionally, we determined rates of grey matter and white matter atrophy using automated deformation based morphometry. Healthy elderly subjects showed decline of FA in intracortical projecting fiber tracts, such as corpus callosum, superior longitudinal fasciculus, uncinate fasciculus, inferior fronto-occipital fasciculus, and cingulate bundle (p < 0.05, corrected for multiple comparisons). MCI subjects showed significant FA decline predominantly in the anterior corpus callosum (p < 0.05, corrected for multiple comparisons). Grey and white matter atrophy involved prefrontal, parietal, and temporal lobe areas in controls and prefrontal, cingulate, and parietal lobe areas in MCI subjects and agreed with the pattern of fiber tract changes. Our findings indicate that DTI allows detection of microstructural changes in subcortical fiber tracts over time that are related to aging as well as to early stages of AD type neurodegeneration. The underlying mechanisms for these changes are unknown. Show more

Keywords: Cortical connectivity, fractional anisotropy, longitudinal study

DOI: 10.3233/JAD-2010-100234

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 507-522, 2010

Authors: Sala-Llonch, Roser | Bosch, Beatriz | Arenaza-Urquijo, Eider M. | Rami, Lorena | Bargalló, Núria | Junqué, Carme | Molinuevo, José-Luis | Bartrés-Faz, David

Article Type: Research Article

Abstract: We conducted an integrated multi-modal magnetic resonance imaging (MRI) study based on functional MRI (fMRI) data during a complex but cognitively preserved visual task in 15 amnestic mild cognitive impairment (a-MCI) patients and 15 Healthy Elders (HE). Independent Component Analysis of fMRI data identified a functional network containing an Activation Task Related Pattern (ATRP), including regions of the dorsal and ventral visual stream, and a Deactivation Task Related Pattern network (DTRP), with high spatial correspondence with the default-mode network (DMN). Gray matter (GM) volumes of the underlying ATRP and DTRP cortical areas were measured, and probabilistic tractography (based on diffusion …MRI) identified fiber pathways within each functional network. For the ATRP network, a-MCI patients exhibited increased fMRI responses in inferior-ventral visual areas, possibly reflecting compensatory activations for more compromised dorsal regions. However, no significant GM or white matter group differences were observed within the ATRP network. For the DTRP/DMN, a-MCI showed deactivation deficits and reduced GM volumes in the posterior cingulate/precuneus, excessive deactivations in the inferior parietal lobe, and less fiber tract integrity in the cingulate bundles. Task performance correlated with DTRP-functionality in the HE group. Besides allowing the identification of functional reorganizations in the cortical network directly processing the task-stimuli, these findings highlight the importance of conducting integrated multi-modal MRI studies in MCI based on spared cognitive domains in order to identify functional abnormalities in critical areas of the DMN and their precise anatomical substrates. These latter findings may reflect early neuroimaging biomarkers in dementia. Show more

Keywords: Alzheimer's disease, compensation, default-mode network, diffusion MRI, fMRI, mild cognitive impairment, structural magnetic resonance, tractography, visual pathways

DOI: 10.3233/JAD-2010-101038

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 523-539, 2010

Authors: Liu, Jinping | Chang, Lirong | Roselli, Francesco | Almeida, Osborne F.X. | Gao, Xiulai | Wang, Xiaomin | Yew, David T. | Wu, Yan

Article Type: Research Article

Abstract: Soluble oligomeric amyloid-β (Aβ) is thought to induce synaptic dysfunction during early stages of Alzheimer's disease (AD). In this report, we show that soluble Aβ downregulates the levels of two synaptic proteins, PSD-95 and synaptophysin, and that this effect can be blocked by MK-801 (NMDAR antagonist) and ifenprodil (NR2B antagonist). Low (1 μM) and high (10 μM) doses of NMDA, respectively, prevented and potentiated the actions of Aβ. Blockade of NR2A or synaptic NMDAR eliminated the protective effect of 1 μM NMDA, while the effects of 10 μM NMDA were only abolished by ifenprodil. Caspase-8, acting upstream of caspase-3, was …found to mediate the synaptotoxic actions of Aβ in an ifenprodil-reversible fashion. Thus, Aβ leads to a loss of synaptic proteins by suppression of NR2A function and activation of NR2B function and subsequent induction of caspase-8 and caspase-3 activities. The identified novel mechanism through which Aβ initiates synaptic dysfunction suggests that selective enhancement of NR2A activity and/or reduction of NR2B activity can halt the manifestation of a key early-stage event in AD. Show more

Keywords: Alzheimer's disease, amyloid-β peptide, caspase, hippocampus, NMDA receptor

DOI: 10.3233/JAD-2010-100948

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 541-556, 2010

Authors: Viana, Ricardo J.S. | Ramalho, Rita M. | Nunes, Ana F. | Steer, Clifford J. | Rodrigues, Cecília M.P.

Article Type: Research Article

Abstract: Amyloid-β (Aβ) peptide- induced neurotoxicity is typically associated with apoptosis. In previous studies, we have shown that tauroursodeoxycholic acid (TUDCA), an endogenous anti-apoptotic bile acid, modulates Aβ-induced apoptosis. Here, we investigated stress signaling events triggered by soluble Aβ and further explored alternative pathways of neuroprotection by TUDCA in differentiated rat neuronal-like PC12 cells. Morphologic evaluation of apoptosis confirmed that Aβ-induced nuclear fragmentation was prevented by TUDCA. In addition, Aβ exposure resulted in activation of the early stress c-Jun N-terminal kinase (JNK) pathway, JNK nuclear translocation, and caspase-2 activation. Knock-down experiments of JNK established caspase-2 as a specific downstream target of …JNK in Aβ-induced apoptosis. Furthermore, active caspase-2 cleaved golgin-160 and was localized to the Golgi complex. Importantly, TUDCA abrogated Aβ-induced JNK/caspase-2 signaling. In conclusion, we show that JNK is the proximal stress sensor for soluble Aβ-induced toxicity, which translocates to the nucleus, activates caspase-2, and is strongly modulated by TUDCA in PC12 neuronal cells. Active caspase-2 cleaves golgin-160, suggesting caspase-2-dependent transduction of Aβ apoptotic signaling through the Golgi complex. These data provide new information linking apoptotic properties of Aβ peptide to distinct subcellular mechanisms of toxicity. Further characterization of this signaling pathway and exact targets of modulation are likely to provide new perspectives for modulation of amyloid-induced apoptosis by TUDCA. Show more

Keywords: Amyloid-β, apoptosis, c-Jun N-terminal kinase, caspase-2, Golgi complex, tauroursodeoxycholic acid

DOI: 10.3233/JAD-2010-100909

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 557-568, 2010

Authors: Baker, Laura D. | Frank, Laura L. | Foster-Schubert, Karen | Green, Pattie S | Wilkinson, Charles W. | McTiernan, Anne | Cholerton, Brenna A. | Plymate, Stephen R. | Fishel, Mark A. | Watson, G. Stennis | Duncan, Glen E. | Mehta, Pankaj D. | Craft, Suzanne

Article Type: Research Article

Abstract: Impaired glucose regulation is a defining characteristic of type 2 diabetes mellitus (T2DM) pathology and has been linked to increased risk of cognitive impairment and dementia. Although the benefits of aerobic exercise for physical health are well-documented, exercise effects on cognition have not been examined for older adults with poor glucose regulation associated with prediabetes and early T2DM. Using a randomized controlled design, twenty-eight adults (57–83 y old) meeting 2-h tolerance test criteria for glucose intolerance completed 6 months of aerobic exercise or stretching, which served as the control. The primary cognitive outcomes included measures of executive function (Trails B, …Task Switching, Stroop, Self-ordered Pointing Test, and Verbal Fluency). Other outcomes included memory performance (Story Recall, List Learning), measures of cardiorespiratory fitness obtained via maximal-graded exercise treadmill test, glucose disposal during hyperinsulinemic-euglycemic clamp, body fat, and fasting plasma levels of insulin, cortisol, brain-derived neurotrophic factor, insulin-like growth factor-1, amyloid-β (Aβ40 and Aβ42 ). Six months of aerobic exercise improved executive function (MANCOVA, p = 0.04), cardiorespiratory fitness (MANOVA, p = 0.03), and insulin sensitivity (p = 0.05). Across all subjects, 6-month changes in cardiorespiratory fitness and insulin sensitivity were positively correlated (p = 0.01). For Aβ42 , plasma levels tended to decrease for the aerobic group relative to controls (p = 0.07). The results of our study using rigorous controlled methodology suggest a cognition-enhancing effect of aerobic exercise for older glucose intolerant adults. Although replication in a larger sample is needed, our findings potentially have important therapeutic implications for a growing number of adults at increased risk of cognitive decline. Show more

Keywords: Aerobic exercise, Alzheimer's disease, cognition, dementia, diabetes, executive function, glucose intolerance, prediabetes

DOI: 10.3233/JAD-2010-100768

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 569-579, 2010

Authors: Förster, Stefan | Vaitl, Andreas | Teipel, Stefan J. | Yakushev, Igor | Mustafa, Mona | la Fougère, Christian | Rominger, Axel | Cumming, Paul | Bartenstein, Peter | Hampel, Harald | Hummel, Thomas | Buerger, Katharina | Hundt, Walter | Steinbach, Silke

Article Type: Research Article

Abstract: We used [18 F]fluorodeoxyglucose (FDG) PET analysis to determine performance in different olfactory domains of patients with early AD compared to cognitively healthy subjects, and to map the functional metabolic representation of olfactory impairment in the patient sample. A cohort of patients with early AD (n = 24), consisting of 6 subjects with incipient AD and 18 subjects with mild AD, and a control group of 28 age-matched non-demented individuals were assembled. Patients and controls were tested for olfactory performance using the “Sniffin' Sticks” test battery [odor identification (ID), discrimination (DIS) and threshold (THR)], while patients additionally underwent resting state …FDG-PET. Voxel-wise PET results in the patients were correlated with olfaction scores using the general linear model in SPM5. Patients with early AD showed significantly reduced function in all three olfactory subdomains compared to controls. After controlling for effects due to patients' age, gender, cognitive status, and treating scores in the two other olfactory subdomains as nuisance variables, ID scores correlated with normalized FDG uptake in clusters with peaks in the right superior parietal lobule, fusiform gyrus, inferior frontal gyrus, and precuneus, while DIS scores correlated with a single cluster in the left postcentral cortex, and THR scores correlated with clusters in the right thalamus and cerebellum. The subtests employed in the “Sniffin' Sticks” test battery are complementary indicators of different aspects of olfactory dysfunction in early AD, and support the theory of a parallel organized olfactory system, revealed by FDG-PET correlation analysis. Show more

Keywords: Alzheimer's disease, FDG PET, mild cognitive impairment, olfactory system, smell test

DOI: 10.3233/JAD-2010-091549

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 581-591, 2010

Authors: Ellis, Grace | Fang, Erica | Maheshwari, Mukesh | Roltsch, Emily | Holcomb, Leigh | Zimmer, Danna | Martinez, Daniel | Murray, Ian V.J.

Article Type: Research Article

Abstract: Oxidative damage and amyloid-β (Aβ) protein misfolding are prominent features of Alzheimer's disease (AD). In vitro studies indicated a direct linkage between these two features, where lipid oxidation products augmented Aβ misfolding. We tested this linkage further, mimicking specific conditions present in amyloid plaques. In vitro lipid oxidation and lipid modification of Aβ were thus performed with elevated levels of copper or physiological levels of calcium. These in vitro experiments were then confirmed by in vivo immunohistochemical and chemical tagging of oxidative damage in brains from the PSAPP mouse model of AD. Our in vitro findings indicate that: 1) high …levels of copper prevent lipid oxidation; 2) physiological concentrations of calcium reduce 4 hydroxy-2-nonenal (HNE) modification of Aβ; and 3) anti-Aβ and HNE antibody epitopes are differentially masked. In vivo we demonstrated increased lipid oxidation around plaques but 4) a lack of immunological colocalization of HNE-adducts with Aβ. Thus, the lack of colocalization of Aβ and HNE-adduct immunostaining is most likely due to a combination of metals inhibiting HNE modification of Aβ, quenching lipid oxidation and a masking of HNE-Aβ histopathology. However, other forms of oxidative damage colocalize with Aβ in plaques, as demonstrated using a chemical method for identifying oxidative damage. Additionally, these findings suggest that HNE modification of Aβ may affect therapeutic antibodies targeting the amino terminal of Aβ and that metals effect on lipid oxidation and lipid modification of Aβ could raise concerns on emerging anti-AD treatments with metal chelators. Show more

Keywords: Alzheimer's disease, amyloid-β, free radicals, hydrazide, 4-hydroxy-2-nonenal, immunohistochemistry, oxidative stress

DOI: 10.3233/JAD-2010-100960

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 593-607, 2010