Journal of Alzheimer's Disease - Volume 28, issue 3

Authors: Lee, Sangmook | Doulames, Vanessa | Donnelly, Michelle | Levasseaur, James | Shea, Thomas B.

Article Type: Short Communication

Abstract: Alzheimer's disease encompasses multiple risk factors; convergence may be necessary for clinical manifestation. Mice received a complete diet or one lacking folate and vitamin E and containing iron as a pro-oxidant, in a standard environment (SE) or a large cage containing objects to stimulate exploration/activity (enriched environment; EE). Mice declined in maze navigation on the deficient versus complete diet in the SE but not the EE. Mice on the complete diet demonstrated superior performance in the EE versus SE. The EE reduced brain lipid and protein oxidation. These findings suggest that maintaining nutrition and activity may delay age-related cognitive decline.

Keywords: Antioxidant, cognitive performance, dementia, environment, folate, nutrition, vitamin E

DOI: 10.3233/JAD-2011-111562

Citation: Journal of Alzheimer's Disease, vol. 28, no. 3, pp. 497-501, 2012

Authors: Dlugaj, Martha | Gerwig, Marcus | Wege, Natalia | Siegrist, Johannes | Mann, Klaus | Bröcker-Preuß, Martina | Dragano, Nico | Moebus, Susanne | Jöckel, Karl-Heinz | Bokhof, Beate | Möhlenkamp, Stefan | Erbel, Raimund | Weimar, Christian | on behalf of the Heinz Nixdorf Recall Study Investigative Group

Article Type: Research Article

Abstract: As high-sensitivity C-reactive protein (hsCRP) seems to be associated with an increased risk of cognitive decline, this nested case-control study examined the relation of hsCRP and mild cognitive impairment (MCI) at different time points. 148 MCI cases (106 amnestic, 42 non-amnestic (aMCI/naMCI)) and 148 matched controls were identified from a prospective population based cohort study of 4,359 participants (aged 50–80). HsCRP levels were measured 5 years before (baseline) and at the time of neuropsychological testing (follow-up). Odds ratios (OR) for hsCRP quartiles serum levels were calculated for the two time points using logistic regression analyses and were adjusted for cardiovascular …covariates. In the fully adjusted model, baseline hsCRP levels were significantly associated with both MCI and aMCI (OR = 2.29, 95% confidence interval (CI), 1.01–5.15, first versus fourth quartile, respective OR = 2.73, 95% CI, 1.09–6.84). At follow-up, the fourth hsCRP quartile was associated with MCI (OR = 3.60, 95% CI, 1.55–8.33), aMCI (OR = 3.73, 95% CI, 1.52–9.17) and naMCI (OR = 3.66, 95% CI, 1.00–13.77). Elevated hsCRP levels, even detected five years before diagnosis, are associated with an at least twofold increased probability of MCI. These findings suggest that inflammation plays an important role in the development and presence of cognitive impairment. Show more

Keywords: Case-control study, high-sensitivity C-reactive protein (hsCRP), inflammation, mild cognitive impairment (MCI)

DOI: 10.3233/JAD-2011-111352

Citation: Journal of Alzheimer's Disease, vol. 28, no. 3, pp. 503-514, 2012

Authors: Moussavi Nik, Seyyed Hani | Wilson, Lachlan | Newman, Morgan | Croft, Kevin | Mori, Trevor A. | Musgrave, Ian | Lardelli, Michael

Article Type: Research Article

Abstract: Oxygen homeostasis is essential for the development and normal physiology of an organism. Hypoxia causes the mitochondrial electron transport chain to generate higher levels of reactive oxygen species resulting in oxidative stress. Hypoxia can be a direct consequence of hypoperfusion, a common vascular component among Alzheimer's disease (AD) risk factors, and may play an important role in AD pathogenesis. Beta-site amyloid-β A4 precursor protein-cleaving enzyme 1 (BACE1) is responsible, with γ-secretase, for cleavage of the amyloid-β protein precursor (AβPP) to produce amyloid-β (Aβ) peptide. A recent study observed that oxidative stress increases BACE1 expression via a regulatory pathway dependent on …γ-secretase cleavage of AβPP and this increases Aβ peptide production. Zebrafish embryos represent normal cells in which complex and subtle manipulations of gene activity can be performed to facilitate analysis of genes involved in human disease. Here we identify and describe the expression of bace1, the zebrafish ortholog of human BACE1. We observe that the zebrafish AD-related genes bace1, psen1, psen2, appa, and appb all show increased mRNA levels under hypoxia. A dominant negative form of psen1 putatively blocking γ-secretase activity blocks bace1 upregulation under hypoxia. Hypoxia increases catalase gene mRNA indicating increased oxidative stress but we did not observe increased levels of F2-isoprostanes that indicate peroxidation of arachidonic acid, possibly due to relatively low levels of arachidonic acid in zebrafish. Our results demonstrate that upregulation of PSEN1 & 2, AβPP and the γ-secretase-dependent upregulation of BACE1 is an ancient, conserved, and thus selectively advantageous response to hypoxia/oxidative stress. Show more

Keywords: Alzheimer's disease, amyloid-β protein precursor, BACE1, hypoxia, oxidative stress, presenilins, γ-secretase, zebrafish

DOI: 10.3233/JAD-2011-110533

Citation: Journal of Alzheimer's Disease, vol. 28, no. 3, pp. 515-530, 2012

Authors: Freeman, Gary B. | Lin, John C. | Pons, Jaume | Raha, Nancy M.

Article Type: Research Article

Abstract: Ponezumab (PF-04360365) is a novel humanized IgG2Δa monoclonal antibody that binds to amyloid-β (Aβ). It is designed to have reduced immune effector function compared to other passive immunotherapies for Alzheimer's disease (AD). Toxicity was evaluated in cynomolgus monkeys treated intravenously with vehicle or 10, 30, or 100 mg/kg of ponezumab every 10th day for up to 39 weeks, and after a 12-week recovery phase. The Aβ peptide sequence of monkeys is identical to that of humans. No substantial difference in test article exposure between sexes was observed, and mean plasma Cmax and AUC0-n were approximately dose-proportional. Ponezumab was …detectable approximately 9 weeks after cessation of dosing. All animals, except two males given 10 mg/kg, maintained exposure to test article. One of these males tested positive for anti-ponezumab antibodies. Ponezumab was detected in the cerebrospinal fluid (CSF) of animals given active treatment. The estimated CSF/plasma ponezumab concentration ratio was <0.008 after multiple doses. At the end of the dosing and recovery phases, plasma Aβ1-40 and Aβ1-x were increased in treated animals versus controls. No test article-related effects were seen after ophthalmogical, cardiovascular, physical examinations, and clinical and anatomic pathology evaluations. Plasma concentrations of ponezumab on day 261 at the no observed adverse effect level of 100 mg/kg were 22.4 and 5.3 times greater on a Cmax and AUC basis, respectively, than human exposures at the highest dose (10 mg/kg) in a single-dose Phase I trial. These data suggest an acceptable safety profile for ponezumab as an immunotherapy for AD. Show more

Keywords: Alzheimer's disease, Macaca fascicularis, primates, toxicity

DOI: 10.3233/JAD-2011-110869

Citation: Journal of Alzheimer's Disease, vol. 28, no. 3, pp. 531-541, 2012

Authors: Alexopoulos, Panagiotis | Guo, Liang-Hao | Tsolakidou, Amalia | Kratzer, Martina | Grimmer, Timo | Westerteicher, Christine | Jiang, Meizi | Bujo, Hideaki | Diehl-Schmid, Janine | Kurz, Alexander | Perneczky, Robert

Article Type: Research Article

Abstract: Recently, light has been shed on possible interrelations between the two most important pathological hallmarks of Alzheimer's disease (AD): the amyloid cascade and axonal degeneration. In this study, we investigated associations between sβAPPβ, a product of the cleavage of the amyloid-β protein precursor (AβPP) by β-secretase, amyloid-β 1-42 (Aβ42 ), soluble SORL1 (also called LR11 or SORLA), a receptor that is involved in AβPP processing, and the marker of axonal degeneration tau in the cerebrospinal fluid (CSF) of 76 patients with mild cognitive impairment (MCI), 61 patients with AD, and 17 patients with frontotemporal dementia, which neuropathologically is not related …to the amyloid pathology. In the AD group, significant associations between sAβPPβ, tau (p < 0.001), and soluble SORL1 (p < 0.001) were detected according to linear regression models. In patients with MCI, sAβPPβ correlated significantly with tau (p < 0.001) and soluble SORL1 (p = 0.003). In the FTD group, only SORL1 (p = 0.011) was associated with sAβPPβ and not tau. Aβ42 was found to be significantly related to tau levels in CSF in the MCI group (p < 0.001) and they tended to be associated in the AD group (p = 0.05). Our results provide further evidence for a link between the two facets of AD pathology, which is likely to be mediated by the binding of Aβ oligomers to specifically targeted neurons, resulting in stimulating tau hyperphosphorylation and neurodegeneration. Show more

Keywords: Alzheimer's disease, amyloid, amyloid-β 1-42, association, soluble AβPPβ, SORL1, tau

DOI: 10.3233/JAD-2011-110983

Citation: Journal of Alzheimer's Disease, vol. 28, no. 3, pp. 543-552, 2012

Authors: Natunen, Teemu | Helisalmi, Seppo | Vepsäläinen, Saila | Sarajärvi, Timo | Antikainen, Leila | Mäkinen, Petra | Herukka, Sanna-Kaisa | Koivisto, Anne Maria | Haapasalo, Annakaisa | Soininen, Hilkka | Hiltunen, Mikko

Article Type: Research Article

Abstract: Accumulation of amyloid β-peptide (Aβ) in the brain of Alzheimer's disease (AD) patients has been postulated to reflect defects in Aβ degradation or clearance. Here, we selected 12 genes (MMEL1, ECE1, ECE2, AGER, PLG, PLAT, NR1H3, MMP3, LRP1, TTR, NR1H2, and MMP9) involved in Aβ catabolism on the basis of PubMed-based literature search and elucidated their genetic role in AD among Finnish case-control cohort consisting of total ∼1,300 AD patients and control subjects. Thirty one single nucleotide polymorphisms (SNPs) were selected for genotyping. In a smaller subset of AD patients, cerebrospinal fluid (CSF) levels of Aβ42 (n = 124), …total-tau (n = 59), and phospho-tau (n = 54) analyses were performed with respect to SNPs. Moreover, age of onset analyses with respect to the studied SNPs were conducted among the AD patient cohort (n = 642). Association analysis of the liver X receptor α (NR1H3) gene SNPs showed a protective effect for C allele carriers of rs7120118 (OR = 0.70, 95% CI 0.53–0.93), while the total-tau and phospho-tau levels in CSF were decreased in AD patients carrying the C allele. Also, a decrease in the age of onset was observed in AD patients carrying the A allele of rs723744 and the C allele of rs3794884 in transthyretin (TTR) gene. However, after adjusting the p-values for multiple comparisons, these results were not statistically significant, suggesting that genetic variations in MMEL1, ECE1, ECE2, AGER, PLG, PLAT, NR1H3, MMP3, LRP1, TTR, NR1H2, and MMP9 genes do not play major role among the Finnish AD patient cohort. Show more

Keywords: Alzheimer's disease, Aβ clearance, Aβ degradation, NR1H3, risk gene, TTR

DOI: 10.3233/JAD-2011-111109

Citation: Journal of Alzheimer's Disease, vol. 28, no. 3, pp. 553-559, 2012

Authors: Pottier, Cyril | Wallon, David | Lecrux, Anne Rovelet | Maltete, David | Bombois, Stephanie | Jurici, Snejana | Frebourg, Thierry | Hannequin, Didier | Campion, Dominique

Article Type: Research Article

Abstract: Several lines of evidence suggest that AβPP gene expression could influence risk for Alzheimer's disease (AD). Using a highly sensitive multiplex fluorescent RT-PCR assay, we compared peripheral blood cells expression of AβPP mRNA among sporadic AD patients (n = 133), autosomal dominant early-onset AD cases (ADEOAD, n = 21), Down syndrome patients (n = 21), AD patients with AβPP duplication (n = 9), patients with recent ischemic stroke (n = 25), and healthy controls (n = 58). Compared to healthy controls (median = 0.98), AβPP expression was not increased in sporadic AD patients (median = 1.01, p = 0.42) nor …in ADEOAD patients (median = 0.96, p = 0.26). Down syndrome patients as well as patients with AβPP duplication had significantly increased levels of AβPP mRNA compared to controls (median = 1.48 and median = 1.36, p < 0.0001 and p = 0.0007, respectively). A weaker but significant increase in relative amount of AβPP transcripts in patients who suffered from recent stroke was observed (median = 1.14, p = 0.0007). Our results do not support a pathogenic role of AβPP overexpression in sporadic AD although a small subset of patients displays AβPP overexpression in the same range as Down syndrome patients. Show more

Keywords: Alzheimer's disease, amyloid-β protein precursor, Down syndrome, early-onset, late-onset, stroke, transcript expression analysis

DOI: 10.3233/JAD-2011-111148

Citation: Journal of Alzheimer's Disease, vol. 28, no. 3, pp. 561-566, 2012

Authors: Cuadrado-Tejedor, Mar | Ricobaraza, Ana | Frechilla, Diana | Franco, Rafael | Pérez-Mediavilla, Alberto | Garcia-Osta, Ana

Article Type: Research Article

Abstract: The etiology of the more common (sporadic) forms of Alzheimer's disease (AD) remains unknown, although age is the most important risk factor. Nevertheless, interactions between environmental risk factors and genetic background may also influence the onset and progression of sporadic AD. Chronic stress, associated with altered memory and other neurological processes, is thought to influence the pathogenesis of AD. Hence, we evaluated the effect of unpredictable and consecutive chronic mild stressors on the onset of an AD-related pathology in the Tg2576 mouse line that overexpresses the human amyloid-β protein precursor with the Swedish mutation (hAβPPSwe ). Two months after exposure …to chronic mild stress, 4 month-old animals that normally display no pathological features of AD, not only expressed pathological markers but also experienced cognitive dysfunction in the Morris water maze test. These findings suggest that chronic mild stress accelerates the onset of cognitive impairment and produces an increase in hippocampal amyloid-β and phospho-tau levels on a background of AD susceptibility. Show more

Keywords: Amyloid-β, cognitive impairment, GSK3β, stress, tau

DOI: 10.3233/JAD-2011-110572

Citation: Journal of Alzheimer's Disease, vol. 28, no. 3, pp. 567-578, 2012

Authors: Dong, Hongxin | Murphy, Keely M. | Meng, Liping | Montalvo-Ortiz, Janitza | Zeng, Ziling | Kolber, Benedict J. | Zhang, Shanshan | Muglia, Louis J. | Csernansky, John G.

Article Type: Research Article

Abstract: Chronic stress has been suggested to influence the pathogenesis of Alzheimer's disease (AD); however, the mechanism underlying this influence remains unknown. In this study, we created a triple transgenic mouse model that overexpresses corticotrophin-releasing factor (CRF) and human amyloid-β protein precursor (AβPP), to investigate whether increases in the expression of CRF can mimic the effects of stress on amyloid metabolism and the neurodegeneration. Tg2576 mice that overexpresses human AβPP gene were crossbreed with Tetop-CRF (CRF) mice and CaMKII-tTA (tTA) mice to create a novel triple transgenic mouse model that conditioned overexpresses CRF in forebrain and overexpresses human AβPP (called AβPP+/CRF+/tTA+, …or TT mice). Then we evaluated serial neuro-anatomical and behavioral phenotypes on TT mice using histological, biochemical, and behavioral assays. TT mice showed a Cushingoid-like phenotype starting at 3 months of age. At 6 months of age, these mice demonstrated increases in tissue-soluble amyloid-β (Aβ) and Aβ plaques in the cortex and hippocampus, as compared to control mice. Moreover, TT mice characterized substantial decreases in dendritic branching and dendritic spine density in pyramidal neurons in layer 4 of the frontal cortex and CA1 of the hippocampus. Finally, TT mice showed significantly impaired working memory and contextual memory, with a modest increase in anxiety-like behavior. Our results suggested genetic increases in the brain of CRF expression mimicked chronic stress on the effects of amyloid deposition, neurodegeneration, and behavioral deficits. The novel transgenic mouse model will provide a unique tool to further investigate the mechanisms between stress and AD. Show more

Keywords: Alzheimer's disease, amyloid-β, cognitive function, corticotrophin-releasing factor, neurodegeneration, stress

DOI: 10.3233/JAD-2011-111328

Citation: Journal of Alzheimer's Disease, vol. 28, no. 3, pp. 579-592, 2012

Authors: Kiko, Takehiro | Nakagawa, Kiyotaka | Tsuduki, Tsuyoshi | Suzuki, Toshihide | Arai, Hiroyuki | Miyazawa, Teruo

Article Type: Research Article

Abstract: Red blood cells (RBC) of Alzheimer's disease (AD) patients are known to be in an excessively oxidized state (i.e., with a high accumulation of peroxidized phospholipids (PLOOH)). Previously we confirmed in vitro, in vivo murine, and in human studies that carotenoids can effectively inhibit accumulation of RBC PLOOH. Thus, the relationship between RBC carotenoids and PLOOH concentrations in AD patients is of interest. In this study, RBC carotenoids and PLOOH were evaluated in 28 normal control subjects (age: 74.1 ± 1.3 years) and 28 patients with AD (age: 72.5 ± 1.4 years). The concentrations of RBC carotenoids, especially lutein, in …AD patients were significantly lower than in control subjects. An inverse relationship was seen between RBC carotenoids, especially lutein, and PLOOH concentrations in AD patients. These results suggest that RBC lutein, in particular, may contribute to suppression of PLOOH accumulation in RBC of AD patients. Show more

Keywords: Alzheimer's disease, carotenoid, lipid peroxidation, lutein, red blood cells

DOI: 10.3233/JAD-2011-111493

Citation: Journal of Alzheimer's Disease, vol. 28, no. 3, pp. 593-600, 2012