Journal of Alzheimer's Disease - Volume 40, issue 1

Authors: Bamji-Mirza, Michelle | Callaghan, Debbie | Najem, Dema | Shen, Shanshan | Hasim, Mohamed Shaad | Yang, Ze | Zhang, Wandong

Article Type: Research Article

Abstract: One of the hallmarks of Alzheimer's disease (AD) is the accumulation and deposition of amyloid-β (Aβ) peptides in the brain and cerebral vasculature. Aβ evokes neuroinflammation and has been implicated in insulin signaling disruption and JNK-AP1 activation, contributing to AD neuropathologies including oxidative injury and vascular insufficiencies. In this study we aim to better understand the protective mechanisms of insulin signaling and JNK-AP1 inhibition on the adverse effects of Aβ. Four-hour treatment of hCMEC/D3, the immortalized human brain endothelial cells (iHBEC), with Aβ1-42 resulted in significant c-Jun phosphorylation, oxidative stress, and cell toxicity. Concurrent treatment with Aβ1-42 and …insulin or Aβ1-42 and JNK inhibitor SP600125 significantly improved cell viability. Cytokine array on conditioned media showed that insulin and SP600125 strongly reduced all Aβ1-42 -induced cytokines. ELISA confirmed the protective effect of insulin and SP600125 on Aβ-induced expression of interleukin (IL)-8 and Growth related oncogene-α (Gro-α). qRT-PCR revealed that insulin and SP600125 protected iHBEC from Aβ1-42 -induced inflammatory gene expression. Transcription factor profiling showed that treatment of iHBEC with Aβ1-42 , insulin, or SP600125 alone or in combination resulted in profound changes in modulating the activities of multiple transcription factors and relevant pathways, some of which were validated by western blot. Insulin treatment and JNK inhibition in vitro synergistically reduced c-Jun phosphorylation and thus JNK-AP1 signaling activation. The study suggests that activation of insulin and blocking of JNK-AP1 signaling inhibits Aβ-induced dysregulation of insulin signaling and inflammatory response. Show more

Keywords: Alzheimer's disease, amyloid-β peptides, inflammatory response insulin signaling, JNK-AP1 signaling

DOI: 10.3233/JAD-131949

Citation: Journal of Alzheimer's Disease, vol. 40, no. 1, pp. 105-122, 2014

Authors: Sun, Xuan | Liang, Ying | Wang, Jun | Chen, Kewei | Chen, Yaojing | Zhou, Xiaoqing | Jia, Jianjun | Zhang, Zhanjun

Article Type: Research Article

Abstract: White matter lesions (WMLs) are of considerable research interest because of their high prevalence and serious consequences, such as stroke and dementia. Most existing studies of WMLs have focused on severe WMLs, but mild WMLs, which are clinically and fundamentally significant, have been largely neglected. The present study is a comprehensive investigation on the injury pattern and on the anatomical, functional, and cognitive changes related to mild WMLs. These results may provide better understanding mild WMLs. Fifty-one human subjects with mild WMLs and 49 control participants completed serial neuropsychological tests and underwent a 3-T magnetic resonance imaging (MRI) scan that …included diffusion tensor imaging, a resting-state functional MRI, and a structural MRI. We found declines in cognitive functions such as global function, executive function, and episodic memory in mild WMLs subjects. The white matter injuries in the mild WMLs subjects were mainly in the fibers that projected to frontal areas, while gray matter structures were relatively intact. The overall resting state function of the frontal area was significantly increased. The integrity of the neural fibers in the inferior fronto-occipital fasciculus and the inferior longitudinal fasciculus was significantly correlated with the cognitive scores in executive function and episodic memory in both the control and the mild WMLs group. These findings demonstrate that mild WMLs subjects exhibit abnormalities in both white matter structure and functional intrinsic brain activity and that such changes are related to several types of cognitive dysfunction. Show more

Keywords: Cognition, diffusion tensor imaging, mild white matter lesions, resting-state functional magnetic resonance imaging

DOI: 10.3233/JAD-131709

Citation: Journal of Alzheimer's Disease, vol. 40, no. 1, pp. 123-134, 2014

Authors: Gerschütz, Anne | Heinsen, Helmut | Grünblatt, Edna | Wagner, Anne Kristin | Bartl, Jasmin | Meissner, Christoph | Fallgatter, Andreas J. | Al-Sarraj, Safa | Troakes, Claire | Ferrer, Isidro | Arzberger, Thomas | Deckert, Jürgen | Riederer, Peter | Fischer, Matthias | Tatschner, Thomas | Monoranu, Camelia Maria

Article Type: Research Article

Abstract: The hallmarks of sporadic Alzheimer's disease (AD) are extracellular amyloid deposits, intracellular neurofibrillary tangles (NFTs), and neuronal death. Hyperphosphorylation of tau is a key factor in the generation of NFTs. Mitogen activated protein kinase 1 (MAPK1) and protein kinase C beta (PRKCB) are thought to play a role in hyperphosphorylation, and PRCKB is thought to be involved in hypoxic stress and vascular dysfunction, and to trigger MAPK phosphorylation pathways. We performed single-cell analyses of neurons with different vulnerabilities to AD-related changes. Using quantitative PCR (qPCR), we measured the levels of MAPK1 and PRKCB transcript in CA1 (high vulnerability), CA2 pyramidal …cells from the hippocampus, granule cells from the cerebellum (low vulnerability), and neurons from the brain stem (nucleus tractus spinalis nervi trigemini, characterized by early neurophysiological deficits) at progressive Braak stages compared to age-matched controls. The highly vulnerable CA1 pyramidal neurons were characterized by age- and disease-unrelated increases in PRCKB levels and by age- and disease-related increases in MAPK1 levels. In contrast, low PRKCB levels were found in CA2 pyramidal neurons, and MAPK1 levels were elevated in controls and intermediate AD stages. Both PRKCB and MAPK1 were increased in the late AD stages. MAPK1 and PRKCB levels were low in the brainstem and cerebellum. We propose that alterations in the expression of these two genes occur early in the pathogenesis of AD in a region-specific manner. In addition, multiple signal transduction pathways need to be affected to result in AD instead of physiological aging. Show more

Keywords: Alzheimer's disease, MAPK1, neurodegeneration, PRKCB, selective vulnerability, signal transduction pathway

DOI: 10.3233/JAD-131280

Citation: Journal of Alzheimer's Disease, vol. 40, no. 1, pp. 135-142, 2014

Authors: Pérez, Mar | Cuadros, Raquel | Pallas-Bazarra, Noemi | García, Carlos | Langa, Elena | Jurado-Arjona, Jerónimo | Hernández, Félix | Avila, Jesús

Article Type: Research Article

Abstract: We modified tau protein with boronic acid to facilitate its delivery into non neural or neural cultured cells lacking tau protein. Our results indicate that the incorporated tau promotes the formation of cytoplasmic extensions in non-neuronal cells, as well as the appearance of neurites in cultured tau knockout hippocampal neurons. In addition, boronated tau is incorporated into hippocampal neurons of tau knockout mice after intracranial injection in vivo. These findings describe a novel method to deliver exogenous tau protein into cells.

Keywords: Boronic acid, protein delivery, tau protein

DOI: 10.3233/JAD-131655

Citation: Journal of Alzheimer's Disease, vol. 40, no. 1, pp. 143-151, 2014

Authors: Zhang, Jian | Zhang, Chun-Hua | Li, Rong-Jie | Lin, Xiao-Li | Chen, Ying-Dao | Gao, Huai-Qing | Shi, Sheng-Liang

Article Type: Research Article

Abstract: Background: Alzheimer-associated neuronal thread protein (AD7c-NTP) has been reported to have high diagnostic accuracy in patients with Alzheimer’s disease (AD). Objective: To determine the diagnostic accuracy of urinary AD7c-NTP for the diagnosis of AD in patients with suspected AD. Methods: We searched MEDLINE (January 1950 to date) and other electronic databases (from inception to date) for diagnostic accuracy studies that compared urinary AD7c-NTP to the standard clinical diagnosis of AD. We conducted citation searches and screened the reference lists of included studies. Studies were assessed for methodological quality using QUADAS. Summary receiver operating characteristic curves were …used to summarize overall test performance. Result: Nine studies met our inclusion criteria. The summary estimates of the urinary AD7c-NTP assay for probable or possible AD were as follows: SEN, 0.87 (95%CI: 0.80–0.91); SPE, 0.89 (95%CI: 0.87–0.91); PLR, 8.13 (95% CI: 6.60–10.02); and NLR, 0.15 (95% CI: 0.10–0.22). The four summary estimates of urinary AD7c-NTP assay for probable AD were 0.89 (95% CI: 0.86–0.92), 0.90 (95% CI: 0.88–0.92), 8.88 (95% CI: 7.09–11.12), and 0.12 (95% CI: 0.09–0.16), with no obvious heterogeneity. Conclusion: Urinary AD7c-NTP is a sensitive and specific test for the diagnosis of probable AD. However, whether urinary AD7c-NTP can be used as an early marker is still unknown. Show more

Keywords: AD7c-NTP, Alzheimer's disease, biomarker, meta-analysis, urine

DOI: 10.3233/JAD-131445

Citation: Journal of Alzheimer's Disease, vol. 40, no. 1, pp. 153-159, 2014

Authors: Meckler, Xavier | Checler, Frédéric

Article Type: Research Article

Abstract: γ-secretase is involved in the regulated intramembrane proteolysis of amyloid-β protein precursor (AβPP) and of many other important physiological substrates. γ-secretase is a multiproteic complex made of four main core components, namely presenilin 1 or 2, APH-1, PEN-2, and Nicastrin. Since APH-1 exists as different variants, combinations of these proteins can theoretically yield distinct γ-secretase complexes. Whether γ-secretase complexes trafficking and targeting to either similar or distinct subcellular compartments depend upon their molecular composition remains unknown. A differential complex-specific distribution may drive a narrow specificity for a subset of substrates that would traffic within the same cellular compartments. Here, we …generated bigenic expression vectors to co-express untagged nicastrin or presenilin 1 together with either PEN-2 or distinct variants of APH-1 (aL, aS and b) tagged with complementary fragments of the fluorescent protein Venus. We show that these constructs allow the formation of functional γ-secretase complexes and their visualization with bimolecular fluorescence complementation (BiFC). BiFC can be detected at the plasma membrane as well as in endosomes/lysosomes in addition to the endoplasmic reticulum (ER) of COS-7 cells transfected with the different variants of APH-1. However, the majority of cells co-transfected with APH-1b presented BiFC signal only in the ER, suggesting enhanced retention/retrieval of APH-1b-containing γ-secretase complexes. Therefore, the new tools described here should be helpful to decipher the precise subcellular trafficking of γ-secretase complexes and to delineate the distinct variant-linked pathways in various cellular systems. Show more

Keywords: APH-1, fluorescence microscopy, γ-secretase, nicastrin, PEN-2, presenilin, transmembrane protein transport

DOI: 10.3233/JAD-131268

Citation: Journal of Alzheimer's Disease, vol. 40, no. 1, pp. 161-176, 2014

Authors: Bayer, Antony | Phillips, Michelle | Porter, Gillian | Leonards, Ute | Bompas, Aline | Tales, Andrea

Article Type: Research Article

Abstract: Although there is some evidence that amnestic mild cognitive impairment (aMCI) can be characterized by significant deficits in visuospatial function, the cross-sectional design of the majority of these studies renders it impossible to determine whether such deficits occur in aMCI as a result of, or accompany, amnestic dysfunction per se or whether they are the result of disproportionately poorer performance in a sub-group of patients for whom aMCI represents prodromal dementia. Similarly, whether the absence of aMCI-related functional deficit stems from the masking of dementia-specific abnormality by the preserved performance of those with a different cause of aMCI cannot be …ascertained. Here we report the outcome of a cross-sectional and 2.5-year longitudinal evaluation follow-up, computer-based study of visuospatial attention, specifically attentional disengagement and inhibition of return and the mean (RTSPEED ) and intra-individual variability (IIVRT ) of their component reaction times, in 45 patients with aMCI and 31 cognitively healthy older adults. Reduced inhibition of return (p = 0.01 and p = 0.037 in response to 400 and 800 ms cue to target interval conditions), slowed RTSPEED (p = 0.038 and p = 0.03 in response to 400 and 800 ms cue), and raised IIVRT at baseline testing (p = 0.003, p = 0.026, p = 0.013 in response to 200, 400 and 800 ms cue) were associated with the development of dementia within the 2.5-year follow-up period, whereas the performance of patients with aMCI who did not develop dementia did not differ significantly from that of the cognitively healthy controls. Attentional disengagement appeared insensitive to the presence of prodromal dementia or amnestic dysfunction per se. The results indicate that those patients for whom aMCI represents prodromal dementia may experience, in addition to amnestic dysfunction, a decline in the functional integrity of some fundamental aspects of visual information processing, an effect potentially capable of increasing disease burden and reducing quality of life. Show more

Keywords: Aging, attentional disengagement, inhibition of return, mild cognitive impairment, methodology, reaction time, visual attention

DOI: 10.3233/JAD-131934

Citation: Journal of Alzheimer's Disease, vol. 40, no. 1, pp. 177-189, 2014

Authors: Solberg, Nathan O. | Chamberlin, Ryan | Vigil, Jenette R. | Deck, Lorraine M. | Heidrich, John E. | Brown, David C. | Brady, Christina I. | Vander Jagt, Thomas A. | Garwood, Michael | Bisoffi, Marco | Severns, Virginia | Vander Jagt, David L. | Sillerud, Laurel O.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is associated with a microglia-dependent neuroinflammatory response against plaques containing the fibrous protein amyloid-β (Aβ). Activation of microglia, which closely associate with Aβ plaques, engenders the release of pro-inflammatory cytokines and the internalization of Aβ fibrils. Since the pro-inflammatory transcription factor NF-κB is one of the major regulators of Aβ-induced inflammation, we treated transgenic amyloid-β protein protein/presenilin-1 (AβPP/PS1) mice for one year with a low dose (0.01% by weight in the diet) of either of two trans-stilbene NF-κB inhibitors, resveratrol or a synthetic analog LD55. The 3D distribution of Aβ plaques was measured ex vivo in intact …brains at 60 μm resolution by quantitative magnetic resonance imaging (MRI) using blood-brain barrier-permeable, anti-AβPP-conjugated superparamagentic iron oxide nanoparticles (SPIONs). The MRI measurements were confirmed by optical microscopy of thioflavin-stained brain tissue sections and indicated that supplementation with either of the two trans-stilbenes lowered Aβ plaque density in the cortex, caudoputamen, and hippocampus by 1.4 to 2-fold. The optical measurements also included the hippocampus and indicated that resveratrol and LD55 reduced average Aβ plaque density by 2.3-fold and 3.1-fold, respectively. Ex vivo measurements of the regional distribution of microglial activation by Iba-1 immunofluorescence of brain tissue sections showed that resveratrol and LD55 reduced average microglial activation by 4.2- fold and 3.5-fold, respectively. Since LD55 lacked hydroxyl groups but both resveratrol and LD55 concomitantly reduced both Aβ plaque burden and neuroinflammation to a similar extent, it appears that the antioxidant potential of resveratrol is not an important factor in plaque reduction. Show more

Keywords: LD55, magnetic resonance imaging, microglia, neuroinflammation, NF-κB, resveratrol, SPIONs, transgenic mice

DOI: 10.3233/JAD-131031

Citation: Journal of Alzheimer's Disease, vol. 40, no. 1, pp. 191-212, 2014

Authors: Minati, Ludovico | Chan, Dennis | Mastropasqua, Chiara | Serra, Laura | Spanò, Barbara | Marra, Camillo | Caltagirone, Carlo | Cercignani, Mara | Bozzali, Marco

Article Type: Research Article

Abstract: We investigated changes in functional network architecture in amnestic mild cognitive impairment using graph-based analysis of task-free functional magnetic resonance imaging and fine cortical parcellation. Widespread disconnection was observed primarily in cortical hubs known to manifest early Alzheimer's disease pathology, namely precuneus, parietal lobules, supramarginal and angular gyri, and cuneus, with additional involvement of subcortical regions, sensorimotor cortex and insula. The connectivity changes determined using graph-based analysis significantly exceed those detected using independent component analysis both in amplitude and topographical extent, and are largely decoupled from the presence of overt atrophy. This superior ability of graph-based analysis to detect disease-related …disconnection highlights its potential use in the determination of biomarkers of early dementia. Graph-based analysis source code is provided as supplementary material. Show more

Keywords: Amnestic mild cognitive impairment (aMCI), functional connectivity, graph theory, prodromal Alzheimer's disease, resting-state functional MRI

DOI: 10.3233/JAD-131766

Citation: Journal of Alzheimer's Disease, vol. 40, no. 1, pp. 213-220, 2014

Authors: Brodaty, Henry | Connors, Michael H. | Xu, Jing | Woodward, Michael | Ames, David | on behalf of the PRIME study group

Article Type: Research Article

Abstract: Patients with dementia often require institutionalization when they can no longer care for themselves. The study examined demographic and clinical variables that predict the time until institutionalization in patients with dementia attending memory clinics. Of 970 patients recruited from nine memory clinics around Australia, 779 patients had dementia at baseline. Measures of dementia severity, cognition, functional ability, neuropsychiatric symptoms, caregiver burden, and medication use were completed for all patients. Patients were followed for three years. Overall, 197 (25.3%) of the patients with dementia were institutionalized within three years. Lower cognitive ability, lower functional ability, and more neuropsychiatric symptoms at baseline …predicted a shorter time until institutionalization, as did use of antipsychotic medication. In addition, greater deterioration in cognitive ability, functional ability, and neuropsychiatric symptoms over the initial three months predicted a shorter time to institutionalization. The findings confirm that clinical features of dementia at baseline predict the time to institutionalization, as do greater changes in symptoms over three months independent of baseline levels. Show more

Keywords: Alzheimer's disease, dementia, institutionalization, longitudinal, nursing home, survival analysis

DOI: 10.3233/JAD-131850

Citation: Journal of Alzheimer's Disease, vol. 40, no. 1, pp. 221-226, 2014